Original Research

Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m² has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.¹ The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.²

To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.

In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.

Sympathomimetics

Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion³ and benzphetamine,⁴ both approved in 1960; phendimetrazine, approved in 1976;⁵ phentermine, approved in 1980;⁶ and phentermine hydrochloride, approved in 2012.⁷ Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.⁸

Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.⁹

Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.⁵ All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.

The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.¹⁰

Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.

Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.¹¹ Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.

Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.

Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.^12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.

There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.¹⁵

Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.¹⁶

These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.¹⁷ However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.¹⁸

Orlistat

Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.¹⁹ Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.²⁰

Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.²¹Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.

One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.^21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.

One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m² and 47 kg/m² from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).²³

A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m² and 44 kg/m². Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).²⁴

In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m². All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26

Lorcaserin

In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.

Indications for lorcaserin include patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.

The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m², evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).

The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).

The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.

The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.²⁹ Patients had a hemoglobin A_1c (A_1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A_1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A_1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.

As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).

Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.

Qsymia

The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m² or adults with a BMI ≥ 27 kg/m² who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.³⁰

In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.³¹ The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.¹⁴

The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.

Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.

In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.³¹ In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.

Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.³² The study randomized 756 obese patients with a BMI range of 30 kg/m² to 45 kg/m² to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.

OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m² without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m². Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.

CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m² to 45 kg/m² and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.

Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.

Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.

Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.

Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.

The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Contrave

In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.³⁵

This drug is approved for adults with BMI ≥ 30 kg/m²  and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.

Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.

Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.

Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.

The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.

The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁶ To be included adults must be aged 18 to 65 years with a BMI 30 kg/m² to 45 kg/m² or a BMI 27 kg/m² to 45 kg/m² with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.

The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.

Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁷ Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m² to 45 kg/m², A_1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.

The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A_1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.³⁷

Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.

Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.³⁸Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.³⁸ The heart rate also increased by about 1.7 beats per minute.³⁸ Patients with uncontrolled hypertension should avoid Contrave.

Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.

Liraglutide

Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.

Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.³⁹ Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.

In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.

The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.

A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.

Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m². Subjects in the liraglutide group had a weekly titration regimen.

After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.⁴¹

Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.

In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.

Conclusion

The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.

The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.⁴²

Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.

Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.

Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m² has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.¹ The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.²

To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.

In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.

Sympathomimetics

Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion³ and benzphetamine,⁴ both approved in 1960; phendimetrazine, approved in 1976;⁵ phentermine, approved in 1980;⁶ and phentermine hydrochloride, approved in 2012.⁷ Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.⁸

Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.⁹

Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.⁵ All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.

The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.¹⁰

Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.

Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.¹¹ Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.

Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.

Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.^12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.

There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.¹⁵

Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.¹⁶

These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.¹⁷ However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.¹⁸

Orlistat

Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.¹⁹ Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.²⁰

Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.²¹Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.

One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.^21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.

One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m² and 47 kg/m² from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).²³

A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m² and 44 kg/m². Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).²⁴

In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m². All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26

Lorcaserin

In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.

Indications for lorcaserin include patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.

The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m², evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).

The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).

The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.

The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.²⁹ Patients had a hemoglobin A_1c (A_1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A_1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A_1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.

As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).

Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.

Qsymia

The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m² or adults with a BMI ≥ 27 kg/m² who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.³⁰

In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.³¹ The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.¹⁴

The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.

Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.

In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.³¹ In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.

Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.³² The study randomized 756 obese patients with a BMI range of 30 kg/m² to 45 kg/m² to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.

OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m² without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m². Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.

CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m² to 45 kg/m² and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.

Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.

Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.

Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.

Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.

The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Contrave

In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.³⁵

This drug is approved for adults with BMI ≥ 30 kg/m²  and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.

Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.

Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.

Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.

The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.

The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁶ To be included adults must be aged 18 to 65 years with a BMI 30 kg/m² to 45 kg/m² or a BMI 27 kg/m² to 45 kg/m² with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.

The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.

Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁷ Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m² to 45 kg/m², A_1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.

The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A_1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.³⁷

Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.

Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.³⁸Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.³⁸ The heart rate also increased by about 1.7 beats per minute.³⁸ Patients with uncontrolled hypertension should avoid Contrave.

Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.

Liraglutide

Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.

Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.³⁹ Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.

In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.

The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.

A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.

Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m². Subjects in the liraglutide group had a weekly titration regimen.

After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.⁴¹

Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.

In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.

Conclusion

The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.

The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.⁴²

Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.

Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.

Over the past decade the prevalence of obesity as defined by a body mass index (BMI) ≥ 30 kg/m² has significantly increased. In the U.S. more than 78 million adults are estimated to be obese.¹ The World Health Organization projects that by 2025 up to half the U.S. population will be obese. Cardiovascular disease (CVD) and diabetes mellitus (DM) are the main comorbid conditions that are complicated by obesity. Initial weight loss of 5% to 10% of total body weight reduces CVD risk factors, prevents or delays the development of type 2 DM (T2DM) and improves the health consequences of obesity.²

To date, public health initiatives that have focused on obesity prevention and lifestyle intervention have had marginal success. In recent years, anti-obesity drug therapies have had a limited role in clinical treatment algorithms. In 2013, the American Medical Association acknowledged obesity as a disease. In turn, this acknowledgement allowed the recognition of anti-obesity drugs as acceptable therapeutic adjuncts to intensive lifestyle intervention that could address the growing obesity endemic.

In the past, medications for weight reduction were limited. Several that were FDA approved had to be removed from the market due to safety concerns. With few approved options, clinicians often had to resort to off-label use of medications. However, the landscape has changed with 4 new medications gaining recent FDA approval. This review covers older available medications and the newer medications that are now available.

Sympathomimetics

Sympathomimetic drugs have been approved for use as a pharmacological method to lose weight since 1960. Of the many versions of this drug class that have been available since then, there are 4 major versions available today. These include diethylpropion³ and benzphetamine,⁴ both approved in 1960; phendimetrazine, approved in 1976;⁵ phentermine, approved in 1980;⁶ and phentermine hydrochloride, approved in 2012.⁷ Despite the existence of several other classes of drugs to treat obesity, phentermine remains the most often prescribed weight loss drug in the U.S.⁸

Although the mechanism of action (MOA) of sympathomimetic drugs is not particularly clear, weight loss from these medications is believed to be due to the increase in the release of biogenic amines (mainly norepinephrine, but also possibly dopamine), from storage sites in nerve terminals. It is possible that these drugs slow catecholamine metabolism by inhibiting the actions of monoamine oxidase. The resulting increase in amine availability, particularly in the lateral hypothalamic feeding center, is associated with reduced food intake. Interestingly, injection of these drugs into the ventromedial satiety center dooes not seem to suppress food intake, and the effects of biogenic amines on increasing metabolism does not seem to play a significant role in weight loss in patients on these medications.⁹

Each of these drugs is rapidly absorbed from the gastrointestinal (GI) tract except for phentermine hydrochloride, the newest of the medications in this class. Phentermine hydrochloride is a sublingual tablet that is readily absorbed through the buccal mucosa.⁵ All of the drugs in this class are excreted through the kidneys, with varying rates. Each drug’s excretion is highly dependent on the pH of the urine—more alkaline conditions result in less excretion and more acidic conditions result in more excretion. As a result, these drugs should be used with caution in patients with renal impairment; however, there are no specific contraindications listed for patients with poor renal function.

The adverse effects (AEs) for this drug class are to be expected from an increase in the release of biogenic amines in the central nervous system (CNS). The most common AEs include palpitations, tremors, restlessness, insomnia, dry mouth, constipation, diaphoresis, changes in libido, and irritability. The more dangerous AEs that have been observed include arrhythmias, hypertension, dependency/abuse, convulsions, acute transient ischemic colitis, and acute urinary retention secondary to increased bladder sphincter tone, transient hyperthyroxemia, and paranoia.¹⁰

Several contraindications exist for sympathomimetics, including the presence of advanced arteriosclerosis, symptomatic CVD, moderate to severe hypertension, hyperthyroidism, glaucoma, patients in an agitated state, or those with a history of amphetamine abuse. The warnings for prescribers include pulmonary hypertension and cardiomyopathy secondary to chronic use of sympathomimetics, and valvular heart disease secondary to use of sympathomimetics with additional anorectic agents.

Additional precautions should be considered in those with a history of anxiety/psychosis, those who operate machinery and motor vehicles, and even those with mild hypertension. The data surrounding the effects of sympathomimetics on blood pressure (BP) appears to be conflicting and the relationship does not seem to have been significantly studied in depth to warrant any definitive conclusions. The MOA of this drug class itself is enough to urge caution to prescribers.¹¹ Special attention should be given to patients with diabetes when using sympathomimetics. A reduction of insulin dose or oral hypoglycemic dose may be necessary in some people with diabetes.

Only diethylpropion is pregnancy category B, whereas the others drugs in this class are pregnancy category X. It has been demonstrated that diethylpropion and benzphetamine are secreted into breastmilk; insufficient data exist to suggest whether or not phentermine and phendimetrazine are present in breastmilk. All drugs in this class should be used in caution with breastfeeding mothers.

Although all 4 drugs are registered as controlled substances, benzphetamine and phendimetrazine are schedule III and phentermine and diethylpropion are schedule IV, despite evidence suggesting the potential for abuse to be extremely low.^12,13 Phentermine has been approved for adults aged > 18 years, phendimetrazine has been approved for those aged > 17 years, diethylpropion has been approved for those aged > 16 years, and benzphetamine has been approved for those aged > 12 years.

There is a wealth of literature surrounding the effectiveness of this drug class for weight loss. One of the longest trials of phentermine was recently conducted as part of the initial component of a FDA study for the newly approved topiramate-phentermine combination. Weight loss at 6 months in the phentermine-only group was significantly higher at -5.8% compared with -1.5% with the placebo group in the last observation carried forward-Intent to treat (LOCF-ITT) analysis.14 Similarly, a long-term study looking at diethylpropion examined the use of diethylpropion for up to a year vs placebo. Participants administered diethylpropion lost a mean 9.8% of original weight vs 3.7% in the placebo group in the first 6 months alone.¹⁵

Several meta-analyses and review papers have been authored that examine and analyze the published data on this drug class overall and comparatively within this class. Haddock and colleagues in 2002 reviewed the numerous clinical trials associated with each drug in this class, in addition to several other classes, and found that although each drug demonstrated a significant advantage vs placebo in weight loss, there was not a specific drug that was significantly superior to any of the others.¹⁶

These results seem to be in relative agreement with additional studies like that published by Suplicy and colleagues, which demonstrated that several sympathomimetics were better than placebo in weight loss, and that there was little difference between the specific drugs in the class.¹⁷ However, it should be noted that as highlighted in a review by Ioannides-Demos and colleagues in 2005, the vast majority of studies that had been performed on this drug class focused on short-term use (< 16 weeks) and none of the sympathomimetics listed here have been approved for long-term use.¹⁸

Orlistat

Orlistat 120 mg was approved in 1999 as a reversible inhibitor of GI lipases that specifically reduced the absorption of dietary fat due to the inhibition of triglyceride hydrolysis.¹⁹ Orlistat was later approved in 2007 for release in a reduced dosage form (60 mg) for over-the-counter sales.²⁰

Orlistat forms a covalent bond with the active serine residue site of gastric and pancreatic lipases in the lumen of the stomach and small intestine. The inhibition of these enzymes causes dietary fat to remain undigested as triglycerides, which cannot be converted to absorbable free fatty acids and monoglycerides, leading to decreased calorie absorption. Orlistat is not systemically absorbed and is eliminated mainly through feces. Some metabolism occurs in the GI wall.²¹Orlistat is most known for its GI AEs. Because it is most active in the lumen of the GI system and reduces the absorption of triglycerides, many AEs are related to malabsorption. The most common issues 1 year after starting the drug were oily spotting (26.6% vs 1.3% placebo); flatus with discharge (23.9% vs 1.4% placebo); fecal urgency (22.1% vs 6.7% placebo); fatty/oily stool (20% vs 2.9% placebo); increased defecation (10.8% vs 4.1% placebo); and fecal incontinence (7.7% vs 0.9% placebo) (Table 1). Most of these AEs were greatly reduced after taking the drug for 2 years. Orlistat also has more serious AEs noted, including abdominal pain/discomfort; nausea; infectious diarrhea; rectal pain/discomfort; tooth disorder; gingival disorder; vomiting; upper respiratory infection; lower respiratory infection; ear, nose and throat symptoms; back pain; arthritis; myalgia; joint disorders; tendonitis; headache; dizziness; fatigue; sleep disorders; rash; dry skin; menstrual irregularity; vaginitis; urinary tract infection; and psychiatric disorders, although these did not differ markedly from placebo.

One of the most serious AEs reported was fulminate hepatic failure, though this AE is rare. Thirteen cases of liver injury were reported with the 120-mg prescription dose of orlistat and 1 case report in the U.S. involved the 60-mg over-the-counter dosage of orlistat.^21,22 The FDA suggests that patients talk to their physicians about risks of liver failure, and that physicians should educate their patients about signs and symptoms of liver failure so that patients can stop taking orlistat and seek immediate medical help if symptoms occur.

One of the first published trials was the European Multicentre Orlistat Study Group, which included 743 participants with BMI between 28 kg/m² and 47 kg/m² from 15 different European centers. To test adherence, a 4-week single blind placebo lead-in was started with a hypocaloric diet. The first stage was completed by 688 patients who then proceeded to the double blind randomized control trial portion with a hypocaloric diet. From the start of lead-in to the end of year 1, the orlistat group weight decreased 10.2% (10.3 kg) vs 6.1% (6.1 kg) in the placebo group. The placebo subtracted difference between the groups was 3.9 kg (P < .001).²³

A U.S.-based randomized double-blind placebo-controlled multicenter study included 796 obese patients with BMI between 30 kg/m² and 44 kg/m². Patients were assigned to 1 of 3 groups: placebo, orlistat 60 mg 3 times daily, or orlistat 120 mg 3 times daily. All groups were given a reduced energy diet. Patients in the orlistat 120 mg group lost significantly more weight than did the placebo group, -8.78% vs -4.26% respectively in year 1 in the completer analysis (P = .001). More participants who were treated with orlistat 120 mg lost 5% or more of their initial weight in year 1 compared with placebo, 50.5% vs 30.7% respectively (P < .001).²⁴

In the XENDOS study the primary outcome measurement was time to onset of T2DM. Eligible participants were aged 30 to 60 years, with a BMI > 30 kg/m². All patients had a 75-g oral glucose tolerance test and were required to have normal glucose tolerance or impaired glucose tolerance, but not T2DM. The double-blind randomized controlled trial included 3,305 subjects and compared a group taking 120 mg orlistat 3 times daily vs placebo. All patients were prescribed a reduced-calorie diet (800 kcal/d deficit) containing 30% of calories from fat. Patients were also encouraged to walk at least 1 kilometer daily in addition to their usual physical activity. Incidence of T2DM after 4 years was 6.2% in the orlistat group and 9.0% in the placebo group, reflecting a 37.3% risk reduction in the orlistat group (P = .0032).25,26

Lorcaserin

In 2012, lorcaserin HCl was FDA approved as a schedule IV drug for use as a weight loss medication as an adjunct to a reduced-calorie diet and increased physical activity. Lorcaserin is thought to act on 5-hydroxytryptamine-2c (5HT2c) receptors on the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, causing release of alpha-melanocortin-stimulating hormone (alpha-MSH), which in turn acts on melanocortin-4 receptors in the paraventricular nucleus to suppress appetite. At the maximum suggested dose of 10 mg twice daily, lorcaserin binds with 15 to 100 times greater affinity to 5HT2c receptors compared with 5HT2a and 5HT2b receptors respectively.

Indications for lorcaserin include patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² or greater with a weight-related comorbid condition such as hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea.

The efficacy of lorcaserin for weight loss has been evaluated in 3 separate trials. The trials were randomized, double blinded and placebo controlled. The BLOOM trial, which included 3,182 patients with a mean BMI of 36.2 kg/m², evaluated the efficacy of lorcaserin as a weight loss adjunct.27 Patients with pre-existing valvular disease, uncontrolled hypertension, or a major psychiatric condition were excluded. After initial randomization, patients were assigned to receive either lorcaserin 10 mg twice daily or a placebo. The primary endpoint was a 5% weight reduction from baseline by the end of 2 years. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost ≥ 5% of their body weight (P <.001). The average loss for the lorcaserin group was 5.8 ± 0.2 kg and 2.2 ± 0.1 kg for the placebo group at 1 year (P < .001).

The BLOSSOM trial was a 1-year study of 4,008 patients aged 18 to 65 years. The trial evaluated the effects of lorcaserin on body weight, CVD risk factors, and safety in obese and overweight patients.28 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. The primary endpoint was the proportion of patients achieving at least 5% reduction in body weight. Completer analysis showed weight reduction in the placebo group was 4.0% and 7.9% in the lorcaserin group (P < .001). In the modified intent-to-treat/last observation carried forward analysis (MITT/LOCF), a statistically significant 47.2% of patients receiving lorcaserin 10 mg twice daily and 40.2% of patients receiving lorcaserin 10 mg once daily lost at least 5% of baseline body weight; compared with 25% of patients receiving placebo (P < .001). Weight loss of at least 10% was achieved by 22.6% of patients receiving lorcaserin 10 mg twice daily, and 17.4% of patients receiving 10 mg daily compared with 9.7% of patients in the placebo group (P < .001).

The most common AEs noted were headache, nausea, and dizziness. Echocardiographic evidence of valvulopathy occurred in 2% of patients taking lorcaserin 10 mg twice daily and those taking the placebo. Lorcaserin administered in conjunction with a diet and exercise program was associated with an overall reduction in baseline BMI when compared with placebo over the year.

The BLOOM-DM study evaluated efficacy and safety of lorcaserin for weight loss in 604 patients with T2DM over the course of 1 year.²⁹ Patients had a hemoglobin A_1c (A_1c) of 7% to 10% and were treated with metformin, a sulfonylurea, or both. The primary endpoint was a 5% weight reduction from baseline at the end of 1 year. Patients were randomized into 3 groups: 1 group received lorcaserin 10 mg twice daily, 1 group took lorcaserin 10 mg daily, and 1 group received the placebo. A statistically significant 37.5% of patients taking lorcaserin 10 mg twice daily achieved > 5% body weight reduction, compared with 44.7% in the lorcaserin 10 mg daily group, and 16.1% in the placebo group. Overall reductions in A_1c and fasting glucose were observed in both lorcaserin groups taking as compared with placebo. Patient A_1c decreased 0.9 ± 0.06 with lorcaserin 10 mg bid, 1.0 ± 0.09 with lorcaserin 10 mg qd, and 0.4 ± 0.06 with the placebo (P < .001). Fasting glucose in the lorcaserin bid, lorcaserin qd, and placebo groups decreased 27.4 ± 2.5 mg/dL, 28.4 ± 3.8 mg/dL, and 11.9 ± 2.5 mg/dL, respectively (P < .001). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin bid, 10.5% on lorcaserin qd, and 6.3% on placebo. Headache, back pain, nasopharyngitis, and nausea were among the most commonly reported AEs.

As lorcaserin is a serotonergic agonist, potential interactions exist when used with other medications affecting serotonin. Most notably, serotonin syndrome and neuroleptic malignant syndrome-like reactions may occur. Because of this, it is recommended to avoid selective serotonin re-uptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors, tricyclic antidepressants, bupropion, triptans, monoamine oxidase inhibitors, lithium, dextromethorphan, and dopamine agonists. Lorcaserin seems to be safe in those patient populations with mild hepatic as well as mild renal impairment; however, it is not recommended for those with severe renal impairment. Given the multiple enzymatic pathways used to metabolize lorcaserin, there is a low probability for cytochrome drug interactions. Safety has not been well evaluated in patients aged < 18 years and those that are pregnant (pregnancy category X).

Adverse events include headache, dizziness, fatigue, nausea, and dry mouth. Other notable AEs include nasopharyngitis and URI. Hypoglycemia appeared to be more common in patients with DM taking lorcaserin. Cognitive impairment and psychiatric disorders including euphoria and hallucinations were also reported. Notably, valvular heart disease has been reported in patients who take medications with 5HT2b activity. In a 1-year clinical trial, a small number of patients were found to develop valvular regurgitation. Furthermore, bradycardia, priapism, leucopenia, elevated prolactin, and pulmonary hypertension have also been observed. Caution is recommended if symptoms of any of the aforementioned conditions are noticed.

Qsymia

The schedule IV controlled substance Qsymia (Vivus, Mountain View, CA) is a combination of phentermine, an anorexigenic agent, and topiramate extended-release, an antiepileptic drug. In July of 2012 it was approved for chronic weight management as an addition to a reduced-calorie diet and exercise. The drug is approved for adults with a BMI ≥ 30 kg/m² or adults with a BMI ≥ 27 kg/m² who have at least 1 weight-related condition such as hypertension, T2DM, or dyslipidemia.³⁰

In 1996 topiramate was approved by the FDA for the treatment of seizure disorders and was also approved for migraine prophylaxis in 2004. In patients who were treated with topiramate for seizure disorders and migraines, weight loss and a reduction in visceral body fat has been observed.³¹ The precise MOA of topiramate in regards to weight loss is not fully understood. It may be due to its effects on both appetite suppression and satiety enhancement. Topiramate exhibits a combination of properties including modulatory effects on sodium channels, enhancement of GABA-activated chloride channels, inhibition of excitatory neurotransmission through actions on kainite and AMPA receptors, and inhibition of carbonic anhydrase (CA) isoenzymes in particular CA II and IV.¹⁴

The combination of phentermine and topiramate is a once-daily formulation that is designed to provide an immediate release of phentermine and a delayed release of topiramate, allowing a peak exposure of the phentermine in the morning and a peak concentration of topiramate in the evening. It should be taken in the morning in order to avoid the possibility of insomnia that can occur if taken in the evening. It can be taken with or without food. The recommended dose is as follows: Start treatment with Qsymia 3.75 mg/23 mg extended-release daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg once daily.

Weight loss should be evaluated after 12 weeks at the higher dose. If at least 3% of baseline body weight has not been lost at that time, discontinue or escalate the dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg daily for 14 days; followed by Qsymia 15 mg/92 mg daily. Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If at least 5% of baseline body weight has not been lost on Qsymia 15 mg/92 mg, discontinue as directed. It is important not to suddenly discontinue, as this may cause seizures. Patients should be slowly titrated off the medication.

In vitro studies of phentermine and topiramate indicate that these drugs are not likely to cause clinically significant interactions with drugs using the cytochrome P450 enzyme pathways, or those involved in plasma protein binding displacement; however there is evidence suggesting that ethinyl estradiol levels may be decreased by 16%, thus raising a concern about the possibility of decreased contraceptive efficacy.³¹ In patients with moderate (creatine clearance ≥ 30 mL/min to < 50 mL/min) and severe renal dysfunction (< 30 mL/min), the maximum dose of should not exceed 7.5 mg/46 mg.

Qsymia was evaluated in 3 phase 3 trials for its long-term efficacy and safety. In all trials, diet and lifestyle counseling were provided for all patients. The first of these studies was OB-301, a 28-week confirmatory trial with a factorial design involving 7 treatment arms, tested 2 fixed-dose Qsymia combinations—regular dose (7.5 mg/46 mg) and maximum dose (15 mg/92 mg)—as well as regular and maximum doses of the individual constituent drugs vs placebo.³² The study randomized 756 obese patients with a BMI range of 30 kg/m² to 45 kg/m² to 1 of the 7 treatment arms for 28 weeks. Patients treated with maximum-dose Qsymia achieved an average weight change of -9.0%, vs -1.5% with placebo (P < .0001). Weight change with regular-dose Qsymia was -8.2%. Weight changes with monotherapies were: -6.1% with topiramate 92 mg, -4.9% with topiramate 46 mg, -5.8% with phentermine 15 mg, and -5.2% with phentermine 7.5 mg.

OB-302 was a 56-week trial that randomized 1,267 morbidly obese patients with a BMI ≥ 35 kg/m² without significant comorbidities to low-dose Qsymia (3.7 mg/23 mg), maximum-dose Qsymia (15 mg/92 mg), or placebo.33 At baseline, the mean BMI for the entire study cohort was 42 kg/m². Mean weight changes were -1.6% with placebo, -5.1% with low-dose Qsymia, and -10.9% with maximum-dose Qsymia. The proportions of patients achieving ≥ 5% weight loss were: 17% with placebo, 45% with low-dose Qsymia, and 67% with maximum-dose Qsymia.

CONQUER was the largest of the phase 3 trials. It randomized 2,487 overweight or obese patients with a BMI of 27 kg/m² to 45 kg/m² and ≥ 2 obesity-related comorbidities (hypertension, dyslipidemia, T2DM, prediabetes or abdominal obesity) to receive a placebo, regular-dose Qsymia, or maximum-dose Qsymia for 56 weeks.34 In the completer population, mean weight changes in the placebo, regular dose Qsymia, and maximum-dose Qsymia groups were -1.6%, -9.6% (P <.0001), and -12.4% (P < .0001); and weight loss of ≥ 5% was achieved by 21%, 62%, and 70%, respectively. Relative to placebo, there were greater reductions in systolic BP, triglycerides, and fasting insulin with both doses of Qsymia.

Patients should not take Qsymia if they are pregnant, planning to become pregnant, or become pregnant during Qsymia treatment as there is an increased risk of birth defects, namely cleft lip and cleft palate. Women who can become pregnant should have a negative pregnancy test before taking Qsymia and every month while on the medication. They should use effective birth control consistently while taking Qsymia.

Qsymia is contraindicated in patients with glaucoma and patients who have hyperthyroidism. Qsymia can cause an increase in resting heart rate and regular monitoring of resting heart rate is recommended, especially in patients with cardiac or cerebrovascular disease. It has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended.

Qsymia can cause mood disorders such as anxiety and depression and can increase the risk of suicidal thoughts. Patients should be monitored for worsening depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. It is not recommended in patients with a history of suicidal attempts or active suicidal ideation. Qsymia can cause cognitive dysfunction. It can cause confusion, problems with concentration, attention, memory, or speech. Patients should be cautioned about operating automobiles and hazardous machinery.

Normal anion gap hyperchloremic metabolic acidosis has been reported in patients treated with Qsymia. If this does develop and persists, consideration should be given to either reduce the dose or discontinue Qsymia.

Weight loss may increase the risk of hypoglycemia in patients with T2DM treated with insulin and/or insulin secretagogues (eg, sulfonylureas). Qsymia has not been studied in combination with insulin. A reduction in the dose of antidiabetic medications, which are nonglucose dependent, should be considered to reduce the risk of hypoglycemia.

The most common AEs in controlled clinical studies (≥ 5% and at least 1.5 times placebo) included paraesthesia in the hands, arms, feet or face, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Contrave

In 2014, the FDA approved Contrave (Takeda, Deerfield, IL) as treatment option for chronic weight management in addition to reduced-calorie diet and physical activity. The combination of naltrexone hydrochloride and bupropion hydrochloride was originally introduced for the treatment of opioid addiction and later expanded to include the treatment of alcoholism. The antidepressant bupropion was approved in the U.S. in 1989. It is structurally different from all other marketed antidepressants (ie, tricyclics, tetracyclics, and SSRIs), but closely resembles the structure of diethylpropion, an appetite depressant with minimal CNS effects.³⁵

This drug is approved for adults with BMI ≥ 30 kg/m²  and for adults with BMI ≥ 27 kg/m2 with at least 1 weight-related risk factors such as hypertension, T2DM, or dyslipidemia. It should be used as an adjunct to diet and exercise and is not approved for use for depression even though it contains bupropion.

Naltrexone is a pure opioid antagonist with high affinity to μ-opioid receptor, which is implicated in eating behavior. Naltrexone is rapidly and nearly completely absorbed from the GI tract after oral administration. The time to peak plasma concentration is about 1 hour. Naltrexone is well absorbed but first pass extraction and metabolism by the liver decreases oral bioavailability to between 5% to 40%. Primary elimination of naltrexone and its metabolites is renal excretion.

Bupropion is a weak inhibitor of neuronal reuptake of dopamine and norepinephrine. This drug is used to treat depression and seasonal affective disorder, and aid in smoking cessation. Bupropion is absorbed rapidly after oral administration, but the absolute oral bioavailability of bupropion is not known because an IV preparation is not available. The time to peak plasma concentrations of bupropion is within 2 hours of oral administration. Bupropion is extensively metabolized by the liver to multiple metabolites. Primary elimination of bupropion is urinary excretion. However, hepatic and renal impairment may affect the elimination of bupropion and its metabolites. Patients with hepatic or renal impairment should use a reduced dosage.

Combination therapy has been found to have complementary actions on CNS to reduce food intake. They are believed to dampen CNS reward pathways, taking away the compulsive feeding behavior and pleasure of feeding, ultimately leading to weight loss. Bupropion stimulates hypothalamic pro-opiomelanocortin neurons (POMC), which results in reduced food intake and increased energy expenditure. Naltrexone blocks opioid-receptor mediated POMC auto-inhibition, blocks the increase in dopamine in nucleus accumbens that occurs when eating, and acting synergistically with bupropion in augmenting POMC firing.

The COR-I and COR-II trials compared Contrave to diet and exercise in patients who did not have DM. The COR-Diabetes trial included the same study design but focused on patients with DM. In all the studies the participants had a 4-week titration to Contrave (naltrexone 8 mg/bupropion 90 mg) to decrease nausea. The first week dosing was 1 tablet in the morning. Week 2 was 1 tablet in morning and 1 tablet in the evening. In week 3, patients took 2 tablets in the morning and 1 tablet in the evening. The final titration step was 2 tablets in the morning and 2 tablets in the evening.

The COR-1 study was a 56-week randomized, double-blind, placebo-controlled study. It compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁶ To be included adults must be aged 18 to 65 years with a BMI 30 kg/m² to 45 kg/m² or a BMI 27 kg/m² to 45 kg/m² with dyslipidemia or hypertension. Patients were instructed on a hypocaloric diet that was a 500 kcal per day deficit based on World Health Organization algorithm for calculating metabolic rate and they were urged to increase physical activity.

The completer population results showed 8.0% weight loss in the NB32/360 group and 1.9% weight loss in the placebo group (P < .001). For the NB32/360 and placebo groups, weight loss of ≥ 5% was achieved by 48% and 16% (P <.001), respectively; and weight loss of ≥ 10% by 25% and 7% (P < .001), respectively. The most common AE was nausea—29.8% with NB32/360 vs 5.3% with placebo. Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (6.3%) then the overall reported nausea rates.

Contrave was also studied in patients with T2DM. The COR-Diabetes Trial was a 56-week randomized, double blind, placebo-controlled study. The trial compared Contrave 32 mg naltrexone/360 mg bupropion (NB32/360) with an active placebo of diet and exercise.³⁷ Inclusion criteria for the trial were patients aged 18 to 70 years with T2DM and a BMI from 27 kg/m² to 45 kg/m², A_1c between 7% and 10%, and fasting blood glucose < 270 mg/dL. Participants either were not taking a DM medication or were on stable doses of oral antidiabetes drugs ≥ 3 months prior to randomization. Patients were placed on a 500 kcal hypocaloric diet and advised to increase physical activity.

The results showed 5.0% weight loss in the NB32/360 group and 1.8% weight loss in the placebo group (P < .001). Weight loss of ≥ 5% and ≥ 10% was achieved by 44.5% and 18.5% of the NB32/360 group, respectively, and 18.9% and 5.7%, respectively (P < .001) of the placebo group. The NB32/360 and placebo showed a reduction of A_1c of 0.6% and 0.1% respectively (P < .001). The most common AE was nausea (42.3% with NB32/360 vs 7.1% with placebo). Nausea generally occurred early and then diminished and the discontinuation rate from nausea was significantly lower (9.6%) then the overall reported nausea rates.³⁷

Due to potential nausea caused by naltrexone, Contrave should be titrated over 4 weeks as described earlier. At maintenance dose, patients should be evaluated after 12 weeks to determine treatment benefits. If a patient has not lost at least 5% of baseline body weight, Contrave should be discontinued, because it would be unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. Contrave should not be taken with high-fat meals that may result in significant increase in bupropion and naltrexone systemic exposure.

Since Contrave contains the antidepressant bupropion, it has a boxed warning similar to other antidepressants in its class of increased risk of suicidal thoughts and behaviors, especially in children, adolescents, and young adults.³⁸Contrave can lower the seizure threshold; therefore it should not be used in people with a seizure disorder. It can also raise BP and heart rate; however the clinical significance of hypertension and elevated heart rate observed with Contrave treatment is unclear. Blood pressure rose on average by 1 point during the first 8 weeks of treatment and then returned to baseline.³⁸ The heart rate also increased by about 1.7 beats per minute.³⁸ Patients with uncontrolled hypertension should avoid Contrave.

Contrave should not be taken with products contain bupropion or naltrexone. It should not be taken by patient who are regularly taking opioids or who are opioid dependent, or who are experiencing opiate withdrawal. Pregnant women should also avoid Contrave. In patients with renal impairment the maximum dose is 1 tablet twice a day and in patients with hepatic impairment the maximum dose is 1 tablet a day.

Liraglutide

Liraglutide is the newest weight loss medication to be approved by the FDA for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity in adult patients with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with hypertension, diabetes, or dyslipidemia. The recommended dose of liraglutide is 3 mg daily. The initial dose is 0.6 mg daily for the first week, then titrated up by 0.6 each week for 4 weeks, until reaching 3 mg daily.

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) receptor agonist, which are expressed in the brain and is involved in the control of appetite. It is also found in the beta cells of the pancreas, where GLP-1 receptors stimulate insulin release in response to elevated blood glucose concentrations and suppress glucagon secretion. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the DDP-4 enzyme, but liraglutide is stable against degradation by peptidases and has a half- life of 13 hours.

Liraglutide was studied in a 56-week randomized, double-blind, placebo-controlled trial, which compared liraglutide 3 mg with an active placebo of diet and physical activity.³⁹ Inclusion criteria were adults aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. Both groups received lifestyle modification counseling. Patients were excluded if they had DM.

In the trial, 3,731 participants enrolled, 2,487 in the liraglutide group and 1,244 in the placebo group; 78.7% of the participants were female and the average age was 45 years. Subjects in the liraglutide group had a weekly titration regimen. The starting dose at week 1 was 0.6 mg, week 2 was 1.2 mg, week 3 was 1.8 mg, week 4 was 2.4 mg, and week 5 was 3.0 kg.

The completer population showed 9.2% weight loss in the liraglutide group and 3.0% weight loss in the control group.39 Weight loss of ≥ 5% was seen in 63.2% and 27.1% of the liraglutide and placebo groups, respectively. Weight loss rates of ≥ 10% was seen by 33.1% and 10.6%, respectively. The most common AEs were nausea, diarrhea, and constipation. Nausea generally occurred early during the titration period and then diminished.

A second clinically relevant study was performed with liraglutide. Often patients are able to lose weight with diet and exercise and then plateau. This study examined participants who lost 5% percent of their initial body weight and then were randomized to liraglutide or placebo.40 Key inclusion criteria were people aged ≥ 18 years old with a BMI 30 kg/m² to 45 kg/m² or BMI 27 kg/m² to 45 kg/m² with dyslipidemia and/or hypertension. In order to be randomized, participants were required to lose at least 5% of their initial body weight on a 1,200 kcal to 1,400 kcal diet with increased physical activity during a 4 to 12 week run-in period.

Four hundred twenty-two participants were enrolled, 212 in the liraglutide group and 210 in the placebo group. Most of the participants were female (81%). The average BMI in the study was 35.6 kg/m². Subjects in the liraglutide group had a weekly titration regimen.

After an average weight loss of 6% using a low calorie diet and increased physical activity the participants were randomized to continue diet and increased activity alone (placebo) or with liraglutide. At week 56 the results showed an additional 6.2% weight loss in the liraglutide group and 0.2% weight gain in the placebo group. The liraglutide group had a greater number of participants with ≥ 5% weight loss compared to placebo, 50.5% vs 21.8% (P < .0001).40 In the pooled data set from the registration trials the 3 most common GI AEs were nausea, diarrhea, and constipation occurring in 39.3%, 20.9%, and 19.4% of participants respectively. Discontinuation due to nausea for liraglutide was 2.9%.⁴¹

Clinicians should be aware that medications that can cause hypoglycemia such as sulfonylureas and insulin must be tapered as patients lose weight with liraglutide. Documented symptomatic hypoglycemia in patients with T2DM and with sulfonylurea background therapy was 43.6% with liraglutide vs 27.3% with placebo.

In the setting of renal impairment, patients treated with GLP-1 receptor agonists, including liraglutide, have had reports of acute renal failure and worsening of chronic renal failure usually associated with nausea, vomiting, diarrhea, or dehydration. Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. As the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined liraglutide is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2.

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide in postmarketing reports. After initiation of liraglutide, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, liraglutide should promptly be discontinued.

Conclusion

The treatment of obesity and overweight with comorbidities has always been a challenge. In the past there were few FDA-approved drugs and many drugs had to be used off-label. The toolbox of medications available for medical weight management is more robust than ever. The medications have different MOAs and can be used in a variety of patients. There are differences in the classes and some are controlled substances. Phentermine, lorcaserin, and Qsymia (phentermine/topiramate) are controlled substances whereas orlistat, naltrexone/bupropion and liraglutide are not. Other differences exist including duration of use. The sympathomimetic drugs have a limited window of use whereas orlistat, Qsymia (phentermine/topiramate), lorcaserin, naltrexone/bupropion, and liraglutide do not.

The medications that are available have a wide variety of MOAs. Therefore, if a patient fails one medication, then it is very reasonable to try a medication with a different MOA. In addition, there is the potential for weight regain when weight reduction medications are discontinued. As people lose weight their metabolic rate decreases about 15 kcal per pound of weight reduction.⁴²

Another challenge of using these medications is managing patient expectations. The current metric used for FDA approval is a 5% weight loss that is greater in the study group compared with the diet and physical activity active control. However, many clinicians and patients do not find this weight reduction amount consistent with their expectations. In addition weight loss trajectory may also be too slow for patients and cause early discontinuation. Therefore, patient education and a discussion of reasonable expectations for weight reduction medications are necessary.

Clinicians must acknowledge that there are limitations to the use of these medications. Newer agents do have a higher cost and insurance reimbursement is somewhat limited. However, they offer the opportunity to prevent more expensive, protracted conditions such as diabetes and cardiovascular disease. In summary, clinicians now have a wider variety of medication options to be used with dietary and lifestyle changes in order to improve health and prevent chronic diseases.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.¹ Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.

Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.^2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.

Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.

For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.

Trial Background

The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.⁴

The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.^5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.⁴ Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.

Trial Design

To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.⁷ For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.⁸ One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.

The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.

This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.

Safety Monitoring

As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.

The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.

Trial Results

The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.

The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.

The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.⁹ These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.

In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.

Economic Implications

As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.¹⁰ In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.¹¹ The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.

Summary

The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.

The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.¹ Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.

Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.^2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.

Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.

For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.

Trial Background

The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.⁴

The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.^5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.⁴ Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.

Trial Design

To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.⁷ For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.⁸ One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.

The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.

This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.

Safety Monitoring

As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.

The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.

Trial Results

The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.

The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.

The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.⁹ These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.

In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.

Economic Implications

As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.¹⁰ In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.¹¹ The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.

Summary

The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.

The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints, leading to joint destruction, with significant long-term morbidity and mortality. Over the past quarter century, multiple new therapies and approaches have been introduced, so patients newly diagnosed with RA can realistically expect to be in remission while taking their medications. However, many of the most commonly used medications are costly, making RA care one of the most expensive per patient.¹ Early treatment with disease-modifying antirheumatic drugs (DMARDs) and treating all patients to the target of low-disease activity are critical keys to optimal outcomes.

Methotrexate (MTX) is a highly effective and economical first-line DMARD that is recommended as the initial therapy for most patients.^2,3 Unfortunately, one-half to two-thirds of patients will not have complete responses and, therefore, require additional therapy. Fortunately, there are more than a dozen therapies that, when added to MTX, have been shown to be better than MTX alone. However, since some of these options use conventional DMARDs and others require biologics, there exist very different economic as well as potential toxicity implications. Understanding how best to treat patients with RA with active disease while on an appropriate dose of MTX is important for both medical and economic reasons.

Despite this being a seminal question for the past 15 years, no blinded trial had addressed this issue before the VA Cooperative Studies Program (CSP) Rheumatoid Arthritis: Comparison of Active Therapies (RACAT) trial. This was true for several reasons, likely including the considerable cost of conducting such a trial and the low priority of this research question for the pharmaceutical industry. Industry-funded trials in RA often focus on new indications, and these studies often fail to address the questions most relevant to the day-to-day care of patients.

For example, it is often not particularly helpful to the clinician that patients placed on “therapy A” are doing better or worse than those placed on “therapy B” after 1 year of the same treatment. Such rigid protocols do not mimic what is done in the clinic: A patient’s treatment program is often changed much earlier than 1 year when it is not working. Therefore, RACAT was designed to more closely mirror clinical practice and to test the strategy of starting conventional therapy before biologic therapy, with the option of changing therapy for nonresponders—similar to what most clinicians would do in practice. This article explores the lessons learned from this landmark trial and highlights the critical role that the VA CSP played.

Trial Background

The RACAT trial, a comparative effectiveness, randomized, double-blind, noninferiority trial, originated as a joint effort of investigators from the VA and the Rheumatology and Arthritis Investigational Network (RAIN) and subsequently involved Canadian enrollment sites. The RACAT results were published in the New England Journal of Medicine in 2013, and its investigative team was awarded the 2014 Lee C. Howley Sr. Prize by the Arthritis Foundation for conducting the most important arthritis research worldwide from the previous year.⁴

The RACAT originated with a letter of intent to the VA CSP in 2003. The central question to be addressed was whether biologic therapy should be added first in patients with active RA despite MTX or whether clinicians should first add the much less expensive but very effective combination of conventional therapies, including sulfasalazine (SSZ) and hydroxychloroquine to MTX.^5,6 This led to the 48-week, binational, multicenter, randomized, double-blind, noninferiority trial comparing the strategy of initially adding hydroxychloroquine and SSZ to MTX (triple therapy group) in patients with active disease despite MTX compared with the strategy of first adding etanercept to MTX.⁴ Etanercept is among the most commonly used biologic agents approved for RA. Etanercept works by targeting tumor necrosis factor, a pro-inflammatory cytokine central in disease pathogenesis. Both RACAT treatment groups were switched in a blinded fashion to the other therapy at 24 weeks if they did not have a clinically significant improvement. The primary endpoint was a change in the disease activity score (DAS28) from baseline to 48 weeks. An important secondary endpoint was the comparison of radiographic progression of disease at 48 weeks as measured by the validated modified Sharp scoring method. Additionally, and very importantly, economic and functional outcomes were assessed. To conduct the trial, investigators and patients participated from 16 VA sites in addition to 8 Canadian and 12 RAIN sites. The study was sponsored and primarily funded by the VA CSP, VA Office of Research and Development with additional funding coming from the Canadian Institutes of Health Research (CIHR) and from the National Institutes of Health.

Trial Design

To understand the RACAT trial design, one must appreciate the landscape of RA trials conducted in the early-to-mid 2000s. At that time, there had been an explosion of new biologic therapies for RA. Most of the trials were placebo-controlled studies with nonresponders to MTX being placed on placebo vs active drug.⁷ For ethical and legal reasons, however, clinicians do not treat patients with placebo, especially when highly effective therapies exist, thus limiting the relevance of the classic placebo-controlled trial in RA.⁸ One of the main tenets of RA therapy in this century has been to use effective therapies to treat patients with active RA with the goal of achieving (and maintaining) either low-disease activity or remission as measured by a composite scoring system, most commonly the DAS28. In order to do this in the framework of a designed research trial, therapies commonly need to be escalated when patients are not doing well, similar to what is done in clinical practice.

The RACAT trial was a comparative effectiveness trial. Comparative effectiveness is not a new idea; in fact, it is precisely how many clinicians practice medicine. It is simply comparing 2 or more treatments to determine which is more effective. Since the inception of the RACAT trial, the American Recovery and Reinvestment Act of 2009 provided $1.1 billion for major expansion of comparative effectiveness research. This changing landscape of federally funded research has highlighted the growing national interest in this type of trial.

This trial design posed several barriers as it applies to the study medications. Methotrexate, hydroxychloroquine, and SSZ are generic medications most often taken orally (MTX is available for parenteral administration). In contrast, etanercept is most often given as a subcutaneous injection and currently is not available in a biosimilar (generic) form in the U.S.; thus, the medication and its delivery device are proprietary. Because this was a double-blind, noninferiority trial, the study required both etanercept-active medication and placebo in identical delivery devices. The makers of etanercept donated placebo etanercept to make blinding possible. The VA, along with CIHR, purchased active etanercept for all trial participants, including those from Canada and the RAIN network. The VA research pharmacy in Albuquerque, New Mexico, was responsible for blinding all active and placebo drugs used in the trial and made these drugs available to all patients, even those not eligible for VA care.In a precedent-setting effort for rheumatology research, RACAT culminated from the collaborations among the private sector, the Canadian health system, and VA. The VA CSP was responsible for the collection of the clinical data, data analyses (Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System [VABHS]); the collection of economic data (VA Palo Alto Health Care System); the provision of and payment for the study medications; and the preparation and distribution of active etanercept and placebos (New Mexico VA Health Care System [NMVAHCS]). Through this organizational structure, the trial was successfully completed. In addition to placebo etanercept provided by Amgen (Thousand Oaks, CA), Pharmascience (Montreal, Quebec) provided blinded SSZ and blinded placebo. Neither company was involved in the study design nor did they have an active role in the trial. Hydroxychoroquine and matched placebo were provided by the central pharmacy of the NMVAHCS.

Safety Monitoring

As with any treatment study, patient safety was of paramount importance. Through the aforementioned organizational structure, each participating site had administrative team members who were responsible to the VABHS CSP to ensure research adherence and compliance with best practices. Additionally, an independent data and safety monitoring committee (DSMC) monitored the trial for safety and scientific integrity. At the time that the trial began in 2007, there were questions about the relative efficacy of triple therapy vs MTX plus biologic therapy. Because of this question, the DSMC raised concerns that patients may be placed at a higher risk of joint damage if not placed sooner on biologic therapy. As a response to this concern, the blinded radiographic reviewers were asked to read the hand and feet X-rays as the study progressed, allowing the DSMC to watch for any emerging safety signals. There were none, and in fact, the therapies were essentially identical radiographically.

The consequence of this request was multifold. First, patient safety was maintained; second, the study team was forced to navigate the logistic and technologic challenges posed by the reading and interpretation of the radiographs at an earlier time point than was originally planned; and last, as a result, results became available and were disseminated in a relatively narrow time frame. This third point was very important. One of the major concerns of foregoing biologic therapy was the potential for joint damage. Without the radiographic information, the manuscript could not have been completed in a timely fashion.

Trial Results

The trial was a 48-week, double-blind, noninferiority trial in which 353 patients with RA who had active disease despite MTX therapy were randomized to a triple therapy regimen of DMARDs (baseline MTX, plus SSZ and hydroxychloroquine) or baseline MTX plus etanercept (Figure 1). Patients who did not have a clinically significant improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy.

The primary endpoint, the change between baseline and 48 weeks in the DAS28, was similar; thus the strategy of first starting triple therapy was not inferior to first starting etanercept (the change in DAS28 was -2.12 and -2.29 respectively, P < .0001, supporting noninferiority, Figure 2). Both groups had significant improvement over the course of the first 24 weeks (P = .001). A total of 27% of participants in each group switched at 24 weeks (Figure 3). Patients in both groups who switched therapies had improvement after switching (P < .001), and the response after switching did not differ significantly between the 2 groups. Importantly, there were no significant between-group differences in radiographic progression (P = .43), pain and health-related quality of life (QOL), or in medication-associated major adverse events (AEs), although there were numerically more serious infections with etanercept-MTX therapy (12 vs 4). Gastrointestinal AEs were numerically more frequent with triple therapy; whereas infections and skin and subcutaneous AEs were more frequent with etanercept-MTX therapy.

The cost-effectiveness of adding SSZ and hydroxychloroquine to MTX vs adding etanercept to MTX, using a predetermined measurement of QOL, was assessed in this trial.⁹ These data were initially presented in abstract form at the 2014 American College of Rheumatology national meeting. Considered was the ratio of all the incremental costs between the 2 treatment strategies to the benefits, as measured in quality-adjusted life-years (QALYs), where QOL is measured as an index with 1 being equivalent to full health and 0 being equivalent to death. This incremental cost-effectiveness ratio produces a monetary cost for each QALY, which is an indication of cost-effectiveness and value. Most health care systems currently consider anything that costs < $50,000/QALY to be cost-effective. To be conservative, the trial researchers considered anything up to $100,000 for an additional QALY acceptable.

In the 48-week trial analysis, the use of etanercept first, instead of triple therapy, would incur about $1 million of cost per QALY, far more than the $50,000 to $100,000 deemed to be reasonable value. Biologic therapy use first, had a near-zero chance of being cost-effective and would be cost-effective only after failure of triple therapy; results that were robust to all plausible scenarios.

Economic Implications

As noted in the trial design, economic data were prospectively collected for later analysis. The availability and cost of biologic treatments have become a critical issue. In 2005, it was reported that the U.S. biologics market reached $52 billion and was noted to have an annual growth of 17%.¹⁰ In 2011, 8 of the top 20 drugs sold in the U.S. were biologics, and year-to-year biologics spending has grown by 6.6%. In 2013, the top 100 biologics in the U.S. had combined sales of $66.3 billion.¹¹ The researchers analysis demonstrated that using a strategy of triple therapy first could result in health care cost savings in the tens of billions of dollars. Importantly, these savings would occur at the same time as patients were receiving optimal care.

Summary

The major conclusions from the RACAT trial in RA patients with active disease despite MTX are the following: 1. The strategy of first starting the conventional DMARD triple therapy combination is noninferior to first starting etanercept, based on both clinical and radiographic outcomes. 2. The triple therapy group had more minor gastrointestinal events, whereas the etanercept group had more infections. Patients in either group who did not respond well to the initial treatment and switched (27% in both groups) improved significantly after the switch. 3. The economic implications of these findings are significant. The incremental cost differences approached $1 million per QALY.

The VA CSP should be congratulated for supporting and funding this trial, which will inform therapeutic decisions in RA for years to come. These results allow clinicians to provide not only optimal health care for their RA patients, but also maximize the value of their health care.

More than 52,000 soldiers have been injured and 6,800 have been killed during the wars in Iraq and Afghanistan.¹ Blast injuries from improvised explosive devices (IEDs) account for 70% to 79% of combat-related injuries and deaths in these wars.² Advances in personal body armor, rapid and advanced surgical treatment, and the changing nature of combat in Iraq and Afghanistan have changed injury patterns and survival compared with prior military conflicts such as those in Vietnam and Korea.³

The most common combat-related injuries in the recent wars are extremity, facial, brain, and gastrointestinal injuries. Pelvic and genitourinary injuries are also common, accounting for about 8% of total injuries.² Pelvic and genitourinary injury can cause long-term disability from nerve injury (neurogenic bladder, neurogenic bowel, sexual dysfunction, urethral injury), as well as general loss of genital structures from blast injuries.

The usual care for bladder dysfunction from pelvic or genitourinary injury ranges from the use of chronic indwelling catheters to reconstructive surgery. However, there is no standard of care for long-term treatment of patients with pelvic or genitourinary injury who experience bladder dysfunction. Reconstructive surgery has the potential to improve quality of life (QOL) and eliminate chronic indwelling catheters, which are prone to cause infection and long-term kidney problems in patients with bladder dysfunction from traumatic injury. 

This case report evaluates the efficacy of reconstructive surgery for bladder dysfunction to improve independence and QOL and decrease complications associated with chronic indwelling urinary catheters. The authors hope to raise awareness regarding this option for patients with pelvic, spinal cord, or genitourinary injury who are young and face long-term disability from their injuries.

Case Presentation

A 22-year-old man presented to the George E. Wahlen VAMC Urology Clinic in Salt Lake City, Utah with a complicated history related to combat injuries. During combat operations 3 years earlier, he was injured by an IED blast while on foot patrol. His injuries included bilateral severe extremity injury, perineal and genital blast wounds, a bladder injury, pelvic fracture, colorectal injury, and extensive soft tissue loss. He underwent multiple abdominal explorations, left leg amputation below the knee, multiple skin grafts, soft tissue debridements, left-side orchiectomy, bladder repair, and diverting colostomy. He survived the injuries and was eventually discharged from active military service and returned home.

Upon presentation to the VAMC, the patient had a diverting colostomy, suprapubic bladder catheter, and bladder and bowel function consistent with cauda equina syndrome (pelvic nerve injury). Given the lack of rectal tone, fecal incontinence was likely with colostomy reversal. His bladder had low volume and poor compliance (elasticity). In addition, the patient had no volitional control of urination or defecation.

The patient previously performed intermittent self-catheterization but experienced total urinary incontinence (UI) between catheterizations, due to his bladder dynamics and a lack of urinary sphincter tone. A suprapubic bladder catheter was previously placed to control UI. However, the patient remained incontinent, and urinary leakage, need for diapers, and urinary tract infections (UTIs) negatively impacted QOL. The patient ambulated well and was physically active. His priority was to reduce incontinence and improve QOL.

Catheterizable Ileal Cecocystoplasty

The patient underwent cutaneous catheterizable ileal cecocystoplasty (CCIC) (Figure 1). In this surgery, a segment of the cecum and ascending colon with attached terminal ileum is used to increase the size of the bladder (augmentation cystoplasty) and create a channel for catheterization from the umbilicus. The cecum and colon are detubularized, and a large rectangular plate of large bowel is formed, which is then sewn to the bladder, expanding its volume. About 10 to 15 cm of the terminal ileum is tapered to the diameter of a pencil and brought through the base of the umbilicus, creating a small stoma for intermittent bladder catheterization. The ileocecal valve is tightened and serves as a continence mechanism to prevent urinary leakage through the small stoma in the umbilicus.⁴

A perineal urethral mesh sling was placed at the time of the patient’s surgery to bolster the deinnervated urinary sphincter and prevent urethral leakage. The goal of reconstructive surgery for this patient was to create a small bowel channel connecting the umbilicus and bladder that could be catheterized every 4 to 6 hours, increase bladder capacity, and increase sphincteric resistance to reduce urethral leakage through the penis. Because there can be damage from passing a catheter through mesh slings and the urethra over time, including stenosis or erosion of the sling, an alternative catheterizable channel was needed in this patient.

The patient recovered after the surgery and was able to self-catheterize without difficulty. However, the urethral mesh sling did not place enough pressure on the urethra to prevent leakage, and he had persistent incontinence from the penis. Three months after the original surgery the patient had exploration of the perineum, which revealed that the mesh sling was loose and exerting inadequate pressure on the urethra. It was likely the sling slipped postoperatively—a known complication of urethral slings. An artificial urinary sphincter (AUS) was placed around the urethra during the second surgery to address the patient’s UI.

More than 1 year after the original surgery, the patient self-catheterizes about 4 to 5 times daily via the catheterizable channel using a single-use catheter. His bladder holds at least 500 mL. The patient does not have significant leakage from the channel or the penis. He is no longer dependent on a chronic indwelling catheter and is free of the problems associated with severe UI, including foul odor, UTIs, and social isolation.

Discussion

Patients with spinal cord or pelvic nerve injury often develop spastic bladders with low capacities. This is similar to muscle spasticity that may occur with a neurologic injury, below the level of the injury, such as in the lower extremities. The powerful uncontrolled bladder spasms and small bladder capacity most often lead to incontinence. Additionally, neurologic control of the urinary sphincter is affected, leading to either uncontrolled spasms or poor tone. Patients with these injuries have no volitional control of bladder functions and are forced to catheterize intermittently, use a condom-type catheter, or have a chronic indwelling catheter (a Foley catheter or suprapubic catheter).

Intermittent catheterization is the preferred management option for neurogenic bladder. When compared with chronic indwelling catheters, intermittent catheterization is associated with lower rates of UTI and upper tract abnormalities and with the loss of renal function.⁵ Unfortunately, patients do not often stay on intermittent catheterization. A recent study showed that up to 70% of patients with spinal cord injuries who used clean intermittent catheterization when discharged from acute rehabilitation discontinue use and are subsequently managed by chronic indwelling catheters.⁶ Although the reasons why intermittent catheterization is discontinued are unclear, patient dissatisfaction with catheterization, anatomic problems, such as urethral scarring, or continued leakage despite medical treatments, such as anticholinergic medicines, may be factors.

Uncontrolled leakage and UI significantly impacts QOL and may cause patients to choose chronic indwelling catheters over intermittent catheterization. Several treatments are available to control incontinence associated with intermittent catheterization. Anticholinergic medications and more recently onabotulinum toxin A may help improve bladder spasticity. In 2011, the FDA approved onabotulinum toxin A for transurethral bladder injections. It has been shown to increase functional bladder capacity and decrease spasticity.^7,8 Onabotulinum toxin A treatment will not enlarge a small, contracted bladder.

Onabotulinum toxin A treatment would not be ideal for the patient in this case study. His absolute bladder capacity was 200 mL, and onabotulinum toxin A treatment would not significantly improve capacity or make intermittent catheterization practical. Additionally, the patient had poor urinary sphincter function, and he would continue to leak regardless of improvements in the bladder spasticity or tone.

Augmentation enterocystoplasty is surgical enlargement of the bladder, using a piece of the bowel and is indicated in patients with low bladder volumes. With this procedure the native bladder becomes defunctionalized, and patients experience a dramatic improvement in bladder volumes and a reduction in bladder spasms and leakage. The use of the colon and terminal ileum for bladder augmentation, or CCIC, was first reported by Sarosdy in 2 patients in 1992.⁹ In 1996, King and colleagues demonstrated successful outcomes with CCIC in a cohort of 8 patients after 34 months of follow-up.¹⁰ Seven patients successfully used clean intermittent catheterization, and 1 patient chose an indwelling catheter because of progressive upper extremity weakness. No patients experienced worsened renal function or pyelonephritis suggestive of upper urinary tract deterioration. A single patient had mild stomal stenosis, which was successfully revised under local anesthesia.

In another study, Sutton and colleagues reported at 27 months an improvement of 276 mL in bladder capacity, no metabolic complications, and a 95% continence rate in a cohort of 23 patients with neurogenic bladder who underwent CCIC.⁴ Sutton and colleagues later reported outcomes for 34 patients with a median of 31 months follow-up.¹¹ The most common complications were recurrent UTIs (12%) and stomal stenosis (12%). Only 3 patients (9%) required surgical revisions for stomal stenosis.

Altered bowel function and metabolic abnormalities are a concern after bowel resection and reconstruction. However, a study has found no subjective change in bowel function following ileal resection of up to 60 cm for urinary diversion for bladder malignancy.¹² Rates of hyperchloremic hypokalemic metabolic acidosis are low, and most changes in electrolytes are subclinical.^13,14 Long-term vitamin B12 deficiency is seen with larger (> 50 cm) ileal resections but is rare with CCIC, given the small segment used for reconstruction.¹⁵ Overall, CCIC is shown to have excellent surgical outcomes in carefully selected patients with neurogenic bladder.

In addition to low bladder capacity, the case study patient also had intrinsic sphincteric deficiency (very low urinary sphincter tone), which is common with pelvic nerve injury but unusual with spinal cord injury. He initially received a suburethral mesh sling that supported and compressed the urethra and buttressed the natural urinary sphincter. However, patients can develop catheterization issues with a suburethral sling due to mechanical compression of the urethra and traversing the compressed area with a urinary catheter. Given the indication for augmentation cystoplasty in this patient, he additionally elected to undergo catheterization channel creation to avoid long-term issues of urethral catheterization through the urethra compressed by the sling.

Unfortunately, this patient had postoperative issues with his suburethral sling, and a modified AUS was inserted rather than a second sling. Normally, an AUS is attached to a pump mechanism in the scrotum. The pump allows the patient to cycle fluid from the sphincter cuff to a reservoir in the abdomen, removing compression on the urethra and allowing normal urination. Because this patient could not effectively urinate from the penis, the authors wanted to obstruct the urethra to prevent leakage without closing it permanently. The AUS was connected to a tissue expander port placed subcutaneously in the lower abdomen rather than to a pump mechanism. This modified approach used fewer mechanical parts compared with the pump mechanism, possibly reducing rates of mechanical failure. Additionally, a lower cuff pressure could be used to obstruct the urethra and prevent leakage, reducing the likelihood of urethral atrophy. Fewer mechanical parts and a lower cuff pressure could theoretically improve longevity of the AUS (Figure 3). This modified method of AUS placement has been described in patients with sphincteric deficiency and spinal cord injury.¹⁶

These 2 reconstructive surgeries freed the patient from indwelling catheter dependence and significantly improved his incontinence and QOL. Many patients with spinal cord injury or pelvic injury could benefit from similar reconstructive surgeries if conservative measures such as anticholinergic medications or onabotulinum toxin A treatments do not control incontinence.

Conclusion

Blast injuries in soldiers often cause pelvic and genitourinary injuries. These injuries can lead to chronic urinary problems and profound social and physical disability. These young veterans need innovative, individualized approaches to best manage their long-term urinary issues. Reconstructive surgery may improve QOL and decrease disability from bladder dysfunction for carefully selected patients. Clinicians caring for veterans with pelvic and genitourinary injury should strive to create a system where these options are available when they are appropriate.

More than 52,000 soldiers have been injured and 6,800 have been killed during the wars in Iraq and Afghanistan.¹ Blast injuries from improvised explosive devices (IEDs) account for 70% to 79% of combat-related injuries and deaths in these wars.² Advances in personal body armor, rapid and advanced surgical treatment, and the changing nature of combat in Iraq and Afghanistan have changed injury patterns and survival compared with prior military conflicts such as those in Vietnam and Korea.³

The most common combat-related injuries in the recent wars are extremity, facial, brain, and gastrointestinal injuries. Pelvic and genitourinary injuries are also common, accounting for about 8% of total injuries.² Pelvic and genitourinary injury can cause long-term disability from nerve injury (neurogenic bladder, neurogenic bowel, sexual dysfunction, urethral injury), as well as general loss of genital structures from blast injuries.

The usual care for bladder dysfunction from pelvic or genitourinary injury ranges from the use of chronic indwelling catheters to reconstructive surgery. However, there is no standard of care for long-term treatment of patients with pelvic or genitourinary injury who experience bladder dysfunction. Reconstructive surgery has the potential to improve quality of life (QOL) and eliminate chronic indwelling catheters, which are prone to cause infection and long-term kidney problems in patients with bladder dysfunction from traumatic injury. 

This case report evaluates the efficacy of reconstructive surgery for bladder dysfunction to improve independence and QOL and decrease complications associated with chronic indwelling urinary catheters. The authors hope to raise awareness regarding this option for patients with pelvic, spinal cord, or genitourinary injury who are young and face long-term disability from their injuries.

Case Presentation

A 22-year-old man presented to the George E. Wahlen VAMC Urology Clinic in Salt Lake City, Utah with a complicated history related to combat injuries. During combat operations 3 years earlier, he was injured by an IED blast while on foot patrol. His injuries included bilateral severe extremity injury, perineal and genital blast wounds, a bladder injury, pelvic fracture, colorectal injury, and extensive soft tissue loss. He underwent multiple abdominal explorations, left leg amputation below the knee, multiple skin grafts, soft tissue debridements, left-side orchiectomy, bladder repair, and diverting colostomy. He survived the injuries and was eventually discharged from active military service and returned home.

Upon presentation to the VAMC, the patient had a diverting colostomy, suprapubic bladder catheter, and bladder and bowel function consistent with cauda equina syndrome (pelvic nerve injury). Given the lack of rectal tone, fecal incontinence was likely with colostomy reversal. His bladder had low volume and poor compliance (elasticity). In addition, the patient had no volitional control of urination or defecation.

The patient previously performed intermittent self-catheterization but experienced total urinary incontinence (UI) between catheterizations, due to his bladder dynamics and a lack of urinary sphincter tone. A suprapubic bladder catheter was previously placed to control UI. However, the patient remained incontinent, and urinary leakage, need for diapers, and urinary tract infections (UTIs) negatively impacted QOL. The patient ambulated well and was physically active. His priority was to reduce incontinence and improve QOL.

Catheterizable Ileal Cecocystoplasty

The patient underwent cutaneous catheterizable ileal cecocystoplasty (CCIC) (Figure 1). In this surgery, a segment of the cecum and ascending colon with attached terminal ileum is used to increase the size of the bladder (augmentation cystoplasty) and create a channel for catheterization from the umbilicus. The cecum and colon are detubularized, and a large rectangular plate of large bowel is formed, which is then sewn to the bladder, expanding its volume. About 10 to 15 cm of the terminal ileum is tapered to the diameter of a pencil and brought through the base of the umbilicus, creating a small stoma for intermittent bladder catheterization. The ileocecal valve is tightened and serves as a continence mechanism to prevent urinary leakage through the small stoma in the umbilicus.⁴

A perineal urethral mesh sling was placed at the time of the patient’s surgery to bolster the deinnervated urinary sphincter and prevent urethral leakage. The goal of reconstructive surgery for this patient was to create a small bowel channel connecting the umbilicus and bladder that could be catheterized every 4 to 6 hours, increase bladder capacity, and increase sphincteric resistance to reduce urethral leakage through the penis. Because there can be damage from passing a catheter through mesh slings and the urethra over time, including stenosis or erosion of the sling, an alternative catheterizable channel was needed in this patient.

The patient recovered after the surgery and was able to self-catheterize without difficulty. However, the urethral mesh sling did not place enough pressure on the urethra to prevent leakage, and he had persistent incontinence from the penis. Three months after the original surgery the patient had exploration of the perineum, which revealed that the mesh sling was loose and exerting inadequate pressure on the urethra. It was likely the sling slipped postoperatively—a known complication of urethral slings. An artificial urinary sphincter (AUS) was placed around the urethra during the second surgery to address the patient’s UI.

More than 1 year after the original surgery, the patient self-catheterizes about 4 to 5 times daily via the catheterizable channel using a single-use catheter. His bladder holds at least 500 mL. The patient does not have significant leakage from the channel or the penis. He is no longer dependent on a chronic indwelling catheter and is free of the problems associated with severe UI, including foul odor, UTIs, and social isolation.

Discussion

Patients with spinal cord or pelvic nerve injury often develop spastic bladders with low capacities. This is similar to muscle spasticity that may occur with a neurologic injury, below the level of the injury, such as in the lower extremities. The powerful uncontrolled bladder spasms and small bladder capacity most often lead to incontinence. Additionally, neurologic control of the urinary sphincter is affected, leading to either uncontrolled spasms or poor tone. Patients with these injuries have no volitional control of bladder functions and are forced to catheterize intermittently, use a condom-type catheter, or have a chronic indwelling catheter (a Foley catheter or suprapubic catheter).

Intermittent catheterization is the preferred management option for neurogenic bladder. When compared with chronic indwelling catheters, intermittent catheterization is associated with lower rates of UTI and upper tract abnormalities and with the loss of renal function.⁵ Unfortunately, patients do not often stay on intermittent catheterization. A recent study showed that up to 70% of patients with spinal cord injuries who used clean intermittent catheterization when discharged from acute rehabilitation discontinue use and are subsequently managed by chronic indwelling catheters.⁶ Although the reasons why intermittent catheterization is discontinued are unclear, patient dissatisfaction with catheterization, anatomic problems, such as urethral scarring, or continued leakage despite medical treatments, such as anticholinergic medicines, may be factors.

Uncontrolled leakage and UI significantly impacts QOL and may cause patients to choose chronic indwelling catheters over intermittent catheterization. Several treatments are available to control incontinence associated with intermittent catheterization. Anticholinergic medications and more recently onabotulinum toxin A may help improve bladder spasticity. In 2011, the FDA approved onabotulinum toxin A for transurethral bladder injections. It has been shown to increase functional bladder capacity and decrease spasticity.^7,8 Onabotulinum toxin A treatment will not enlarge a small, contracted bladder.

Onabotulinum toxin A treatment would not be ideal for the patient in this case study. His absolute bladder capacity was 200 mL, and onabotulinum toxin A treatment would not significantly improve capacity or make intermittent catheterization practical. Additionally, the patient had poor urinary sphincter function, and he would continue to leak regardless of improvements in the bladder spasticity or tone.

Augmentation enterocystoplasty is surgical enlargement of the bladder, using a piece of the bowel and is indicated in patients with low bladder volumes. With this procedure the native bladder becomes defunctionalized, and patients experience a dramatic improvement in bladder volumes and a reduction in bladder spasms and leakage. The use of the colon and terminal ileum for bladder augmentation, or CCIC, was first reported by Sarosdy in 2 patients in 1992.⁹ In 1996, King and colleagues demonstrated successful outcomes with CCIC in a cohort of 8 patients after 34 months of follow-up.¹⁰ Seven patients successfully used clean intermittent catheterization, and 1 patient chose an indwelling catheter because of progressive upper extremity weakness. No patients experienced worsened renal function or pyelonephritis suggestive of upper urinary tract deterioration. A single patient had mild stomal stenosis, which was successfully revised under local anesthesia.

In another study, Sutton and colleagues reported at 27 months an improvement of 276 mL in bladder capacity, no metabolic complications, and a 95% continence rate in a cohort of 23 patients with neurogenic bladder who underwent CCIC.⁴ Sutton and colleagues later reported outcomes for 34 patients with a median of 31 months follow-up.¹¹ The most common complications were recurrent UTIs (12%) and stomal stenosis (12%). Only 3 patients (9%) required surgical revisions for stomal stenosis.

Altered bowel function and metabolic abnormalities are a concern after bowel resection and reconstruction. However, a study has found no subjective change in bowel function following ileal resection of up to 60 cm for urinary diversion for bladder malignancy.¹² Rates of hyperchloremic hypokalemic metabolic acidosis are low, and most changes in electrolytes are subclinical.^13,14 Long-term vitamin B12 deficiency is seen with larger (> 50 cm) ileal resections but is rare with CCIC, given the small segment used for reconstruction.¹⁵ Overall, CCIC is shown to have excellent surgical outcomes in carefully selected patients with neurogenic bladder.

In addition to low bladder capacity, the case study patient also had intrinsic sphincteric deficiency (very low urinary sphincter tone), which is common with pelvic nerve injury but unusual with spinal cord injury. He initially received a suburethral mesh sling that supported and compressed the urethra and buttressed the natural urinary sphincter. However, patients can develop catheterization issues with a suburethral sling due to mechanical compression of the urethra and traversing the compressed area with a urinary catheter. Given the indication for augmentation cystoplasty in this patient, he additionally elected to undergo catheterization channel creation to avoid long-term issues of urethral catheterization through the urethra compressed by the sling.

Unfortunately, this patient had postoperative issues with his suburethral sling, and a modified AUS was inserted rather than a second sling. Normally, an AUS is attached to a pump mechanism in the scrotum. The pump allows the patient to cycle fluid from the sphincter cuff to a reservoir in the abdomen, removing compression on the urethra and allowing normal urination. Because this patient could not effectively urinate from the penis, the authors wanted to obstruct the urethra to prevent leakage without closing it permanently. The AUS was connected to a tissue expander port placed subcutaneously in the lower abdomen rather than to a pump mechanism. This modified approach used fewer mechanical parts compared with the pump mechanism, possibly reducing rates of mechanical failure. Additionally, a lower cuff pressure could be used to obstruct the urethra and prevent leakage, reducing the likelihood of urethral atrophy. Fewer mechanical parts and a lower cuff pressure could theoretically improve longevity of the AUS (Figure 3). This modified method of AUS placement has been described in patients with sphincteric deficiency and spinal cord injury.¹⁶

These 2 reconstructive surgeries freed the patient from indwelling catheter dependence and significantly improved his incontinence and QOL. Many patients with spinal cord injury or pelvic injury could benefit from similar reconstructive surgeries if conservative measures such as anticholinergic medications or onabotulinum toxin A treatments do not control incontinence.

Conclusion

Blast injuries in soldiers often cause pelvic and genitourinary injuries. These injuries can lead to chronic urinary problems and profound social and physical disability. These young veterans need innovative, individualized approaches to best manage their long-term urinary issues. Reconstructive surgery may improve QOL and decrease disability from bladder dysfunction for carefully selected patients. Clinicians caring for veterans with pelvic and genitourinary injury should strive to create a system where these options are available when they are appropriate.

More than 52,000 soldiers have been injured and 6,800 have been killed during the wars in Iraq and Afghanistan.¹ Blast injuries from improvised explosive devices (IEDs) account for 70% to 79% of combat-related injuries and deaths in these wars.² Advances in personal body armor, rapid and advanced surgical treatment, and the changing nature of combat in Iraq and Afghanistan have changed injury patterns and survival compared with prior military conflicts such as those in Vietnam and Korea.³

The most common combat-related injuries in the recent wars are extremity, facial, brain, and gastrointestinal injuries. Pelvic and genitourinary injuries are also common, accounting for about 8% of total injuries.² Pelvic and genitourinary injury can cause long-term disability from nerve injury (neurogenic bladder, neurogenic bowel, sexual dysfunction, urethral injury), as well as general loss of genital structures from blast injuries.

The usual care for bladder dysfunction from pelvic or genitourinary injury ranges from the use of chronic indwelling catheters to reconstructive surgery. However, there is no standard of care for long-term treatment of patients with pelvic or genitourinary injury who experience bladder dysfunction. Reconstructive surgery has the potential to improve quality of life (QOL) and eliminate chronic indwelling catheters, which are prone to cause infection and long-term kidney problems in patients with bladder dysfunction from traumatic injury. 

This case report evaluates the efficacy of reconstructive surgery for bladder dysfunction to improve independence and QOL and decrease complications associated with chronic indwelling urinary catheters. The authors hope to raise awareness regarding this option for patients with pelvic, spinal cord, or genitourinary injury who are young and face long-term disability from their injuries.

Case Presentation

A 22-year-old man presented to the George E. Wahlen VAMC Urology Clinic in Salt Lake City, Utah with a complicated history related to combat injuries. During combat operations 3 years earlier, he was injured by an IED blast while on foot patrol. His injuries included bilateral severe extremity injury, perineal and genital blast wounds, a bladder injury, pelvic fracture, colorectal injury, and extensive soft tissue loss. He underwent multiple abdominal explorations, left leg amputation below the knee, multiple skin grafts, soft tissue debridements, left-side orchiectomy, bladder repair, and diverting colostomy. He survived the injuries and was eventually discharged from active military service and returned home.

Upon presentation to the VAMC, the patient had a diverting colostomy, suprapubic bladder catheter, and bladder and bowel function consistent with cauda equina syndrome (pelvic nerve injury). Given the lack of rectal tone, fecal incontinence was likely with colostomy reversal. His bladder had low volume and poor compliance (elasticity). In addition, the patient had no volitional control of urination or defecation.

The patient previously performed intermittent self-catheterization but experienced total urinary incontinence (UI) between catheterizations, due to his bladder dynamics and a lack of urinary sphincter tone. A suprapubic bladder catheter was previously placed to control UI. However, the patient remained incontinent, and urinary leakage, need for diapers, and urinary tract infections (UTIs) negatively impacted QOL. The patient ambulated well and was physically active. His priority was to reduce incontinence and improve QOL.

Catheterizable Ileal Cecocystoplasty

The patient underwent cutaneous catheterizable ileal cecocystoplasty (CCIC) (Figure 1). In this surgery, a segment of the cecum and ascending colon with attached terminal ileum is used to increase the size of the bladder (augmentation cystoplasty) and create a channel for catheterization from the umbilicus. The cecum and colon are detubularized, and a large rectangular plate of large bowel is formed, which is then sewn to the bladder, expanding its volume. About 10 to 15 cm of the terminal ileum is tapered to the diameter of a pencil and brought through the base of the umbilicus, creating a small stoma for intermittent bladder catheterization. The ileocecal valve is tightened and serves as a continence mechanism to prevent urinary leakage through the small stoma in the umbilicus.⁴

A perineal urethral mesh sling was placed at the time of the patient’s surgery to bolster the deinnervated urinary sphincter and prevent urethral leakage. The goal of reconstructive surgery for this patient was to create a small bowel channel connecting the umbilicus and bladder that could be catheterized every 4 to 6 hours, increase bladder capacity, and increase sphincteric resistance to reduce urethral leakage through the penis. Because there can be damage from passing a catheter through mesh slings and the urethra over time, including stenosis or erosion of the sling, an alternative catheterizable channel was needed in this patient.

The patient recovered after the surgery and was able to self-catheterize without difficulty. However, the urethral mesh sling did not place enough pressure on the urethra to prevent leakage, and he had persistent incontinence from the penis. Three months after the original surgery the patient had exploration of the perineum, which revealed that the mesh sling was loose and exerting inadequate pressure on the urethra. It was likely the sling slipped postoperatively—a known complication of urethral slings. An artificial urinary sphincter (AUS) was placed around the urethra during the second surgery to address the patient’s UI.

More than 1 year after the original surgery, the patient self-catheterizes about 4 to 5 times daily via the catheterizable channel using a single-use catheter. His bladder holds at least 500 mL. The patient does not have significant leakage from the channel or the penis. He is no longer dependent on a chronic indwelling catheter and is free of the problems associated with severe UI, including foul odor, UTIs, and social isolation.

Discussion

Patients with spinal cord or pelvic nerve injury often develop spastic bladders with low capacities. This is similar to muscle spasticity that may occur with a neurologic injury, below the level of the injury, such as in the lower extremities. The powerful uncontrolled bladder spasms and small bladder capacity most often lead to incontinence. Additionally, neurologic control of the urinary sphincter is affected, leading to either uncontrolled spasms or poor tone. Patients with these injuries have no volitional control of bladder functions and are forced to catheterize intermittently, use a condom-type catheter, or have a chronic indwelling catheter (a Foley catheter or suprapubic catheter).

Intermittent catheterization is the preferred management option for neurogenic bladder. When compared with chronic indwelling catheters, intermittent catheterization is associated with lower rates of UTI and upper tract abnormalities and with the loss of renal function.⁵ Unfortunately, patients do not often stay on intermittent catheterization. A recent study showed that up to 70% of patients with spinal cord injuries who used clean intermittent catheterization when discharged from acute rehabilitation discontinue use and are subsequently managed by chronic indwelling catheters.⁶ Although the reasons why intermittent catheterization is discontinued are unclear, patient dissatisfaction with catheterization, anatomic problems, such as urethral scarring, or continued leakage despite medical treatments, such as anticholinergic medicines, may be factors.

Uncontrolled leakage and UI significantly impacts QOL and may cause patients to choose chronic indwelling catheters over intermittent catheterization. Several treatments are available to control incontinence associated with intermittent catheterization. Anticholinergic medications and more recently onabotulinum toxin A may help improve bladder spasticity. In 2011, the FDA approved onabotulinum toxin A for transurethral bladder injections. It has been shown to increase functional bladder capacity and decrease spasticity.^7,8 Onabotulinum toxin A treatment will not enlarge a small, contracted bladder.

Onabotulinum toxin A treatment would not be ideal for the patient in this case study. His absolute bladder capacity was 200 mL, and onabotulinum toxin A treatment would not significantly improve capacity or make intermittent catheterization practical. Additionally, the patient had poor urinary sphincter function, and he would continue to leak regardless of improvements in the bladder spasticity or tone.

Augmentation enterocystoplasty is surgical enlargement of the bladder, using a piece of the bowel and is indicated in patients with low bladder volumes. With this procedure the native bladder becomes defunctionalized, and patients experience a dramatic improvement in bladder volumes and a reduction in bladder spasms and leakage. The use of the colon and terminal ileum for bladder augmentation, or CCIC, was first reported by Sarosdy in 2 patients in 1992.⁹ In 1996, King and colleagues demonstrated successful outcomes with CCIC in a cohort of 8 patients after 34 months of follow-up.¹⁰ Seven patients successfully used clean intermittent catheterization, and 1 patient chose an indwelling catheter because of progressive upper extremity weakness. No patients experienced worsened renal function or pyelonephritis suggestive of upper urinary tract deterioration. A single patient had mild stomal stenosis, which was successfully revised under local anesthesia.

In another study, Sutton and colleagues reported at 27 months an improvement of 276 mL in bladder capacity, no metabolic complications, and a 95% continence rate in a cohort of 23 patients with neurogenic bladder who underwent CCIC.⁴ Sutton and colleagues later reported outcomes for 34 patients with a median of 31 months follow-up.¹¹ The most common complications were recurrent UTIs (12%) and stomal stenosis (12%). Only 3 patients (9%) required surgical revisions for stomal stenosis.

Altered bowel function and metabolic abnormalities are a concern after bowel resection and reconstruction. However, a study has found no subjective change in bowel function following ileal resection of up to 60 cm for urinary diversion for bladder malignancy.¹² Rates of hyperchloremic hypokalemic metabolic acidosis are low, and most changes in electrolytes are subclinical.^13,14 Long-term vitamin B12 deficiency is seen with larger (> 50 cm) ileal resections but is rare with CCIC, given the small segment used for reconstruction.¹⁵ Overall, CCIC is shown to have excellent surgical outcomes in carefully selected patients with neurogenic bladder.

In addition to low bladder capacity, the case study patient also had intrinsic sphincteric deficiency (very low urinary sphincter tone), which is common with pelvic nerve injury but unusual with spinal cord injury. He initially received a suburethral mesh sling that supported and compressed the urethra and buttressed the natural urinary sphincter. However, patients can develop catheterization issues with a suburethral sling due to mechanical compression of the urethra and traversing the compressed area with a urinary catheter. Given the indication for augmentation cystoplasty in this patient, he additionally elected to undergo catheterization channel creation to avoid long-term issues of urethral catheterization through the urethra compressed by the sling.

Unfortunately, this patient had postoperative issues with his suburethral sling, and a modified AUS was inserted rather than a second sling. Normally, an AUS is attached to a pump mechanism in the scrotum. The pump allows the patient to cycle fluid from the sphincter cuff to a reservoir in the abdomen, removing compression on the urethra and allowing normal urination. Because this patient could not effectively urinate from the penis, the authors wanted to obstruct the urethra to prevent leakage without closing it permanently. The AUS was connected to a tissue expander port placed subcutaneously in the lower abdomen rather than to a pump mechanism. This modified approach used fewer mechanical parts compared with the pump mechanism, possibly reducing rates of mechanical failure. Additionally, a lower cuff pressure could be used to obstruct the urethra and prevent leakage, reducing the likelihood of urethral atrophy. Fewer mechanical parts and a lower cuff pressure could theoretically improve longevity of the AUS (Figure 3). This modified method of AUS placement has been described in patients with sphincteric deficiency and spinal cord injury.¹⁶

These 2 reconstructive surgeries freed the patient from indwelling catheter dependence and significantly improved his incontinence and QOL. Many patients with spinal cord injury or pelvic injury could benefit from similar reconstructive surgeries if conservative measures such as anticholinergic medications or onabotulinum toxin A treatments do not control incontinence.

Conclusion

Blast injuries in soldiers often cause pelvic and genitourinary injuries. These injuries can lead to chronic urinary problems and profound social and physical disability. These young veterans need innovative, individualized approaches to best manage their long-term urinary issues. Reconstructive surgery may improve QOL and decrease disability from bladder dysfunction for carefully selected patients. Clinicians caring for veterans with pelvic and genitourinary injury should strive to create a system where these options are available when they are appropriate.

Health care has become increasingly unaffordable in the U.S., yet it remains ineffective in preventing or effectively treating chronic diseases.^1,2 Given the increasing burden of chronic disease on the American health care system, there is an effort to shift the practice of medicine away from its reactive, disease-oriented approach to a more sustainable proactive model.^3-5

Personalized health care (PHC) is an approach to the practice of medicine where prediction, prevention, intense patient engagement, shared health care decision making, and coordination of care are essential to cost effectively facilitate better outcomes.^3,5-7 Greater collaboration between patient and clinician replaces the traditional clinician-dominated dialogue with more effective patient-clinician partnerships.^8,9 Patients’ knowledge, skills, and confidence to manage their health care have been linked to improved health outcomes, lower costs, and greater satisfaction with health care experiences.^10,11

Personalized health care has been proposed as a means to achieve better patient engagement as part of an aligned, proactive clinical approach. At the heart of PHC is personalized health planning, wherein the patient and clinician develop shared health-related goals and a plan to achieve them.³

The VHA, the largest integrated health care system in the country, is on the vanguard of incorporating tenets of PHC into its delivery model. In 2011, the Office of Patient Centered Care and Cultural Transformation (OPCC&CT) was founded to “oversee the VHA’s cultural transformation to patient-centered care.”¹² This undertaking represents “one of the most massive changes in the philosophy and process for health care delivery ever undertaken by an organized health care system.”¹³

The primary goal of the VHA’s strategic plan for 2013 to 2018 is to provide veterans personalized, proactive, patient-driven health care.¹⁴ The intention of this approach is to engage and inspire veterans to their highest possible level of health and well-being. A personalized approach requires a dynamic customization of care that is specifically relevant to the individual, based on factors such as medical conditions, genome, needs, values, and circumstances. In addition to being personalized, this approach must be proactive, and therefore, preventive and include strategies to strengthen the person’s innate capacity for enhancing health.

The third distinction of this new model health care is that it is patient-driven, rooted in and driven by that which matters most to people in their lives and aligns their health care with their day-to-day and long-term life goals.¹⁵ The latter may be the most critical of the 3 tenets, because a personalized, proactive approach that is not driven by an engaged and inspired individual will be unlikely to achieve adherence, let alone the highest level of health and well-being.

The VHA is uniquely positioned to optimize health and well-being for veterans due in part to a systemwide emphasis on training providers to promote and support behavior change through approaches including health coaching and motivational interviewing. These synergistic approaches used widely by clinicians throughout the VHA are influenced by the transtheoretical model (ie, the stages of change theory), which considers patients holistically and helps them identify intrinsic motivation to improve their health behaviors.^16,17 The transformation occurring in the VHA is intended to shift the current disease-centric medical model to an approach that optimizes the health of veterans through patient-clinician engagement, health risk assessment (HRA), shared health goal creation, and a coordinated plan to attain them.^12,13

Personalized Health Planning

In recognition of the need to deliver care that emphasizes prevention and coordination, the patient-centered medical home, patient-aligned care teams (PACTs), and the chronic care model were developed. All of these embrace concepts of patient engagement, shared decision making, and team-based care. However, none of these approaches have outlined a clinical workflow that systematically and proactively operationalizes these concepts with the creation of a risk-based personalized care approach. Personalized health planning provides a clinical workflow that operationalizes all these features (Figure 1).

Of central importance is the creation of a personalized health plan (PHP), which the patient and clinician develop collaboratively. The plan serves to organize and coordinate care while engaging the patient in the process of care delivery and appropriate self-management of health.^3,5 This approach promotes personalized and proactive care that values the individual and fosters meaningful patient self-awareness and engagement through shared decision making.⁷

The personalized health planning process is composed of several key components (Figure 2).

With this information, the clinician develops a preliminary therapeutic plan to meet these goals and discusses this plan with the patient. The next component is the synthesis of the clinician’s goals and/or treatment plan with the priorities of the patient to establish shared clinician-patient goals. This is followed by the establishment of the PHP, which consists of the agreed upon shared clinician and patient goals, a therapeutic and wellness plan to meet them, metrics for tracking progress, consults and referrals, and a time frame for the patient to achieve the health goals.

Related: The Right Care at the Right Time and in the Right Place: The Role of Technology in the VHA

The final component is coordination of care and a formalized follow-up system in which the health care team monitors the patient’s progress and provides support by revisiting or updating the PHP at intervals determined by the provider, based on the level of monitoring required by the patient’s health status. This approach invites the patient to become an empowered member of the care team by creating a patient-clinician partnership and providing a model for delivering personalized, proactive, patient-driven care to individuals with a diverse range of needs.^4,5,18

Design and Implementation

This project qualified as exempt through the Duke University Institutional Review Board. The primary aim of this pilot was to examine the feasibility of implementing personalized health planning into primary care settings and to develop a workable process that is scalable and customizable to inpatient and outpatient clinics of varying sizes for different patient populations within the VHA. The pilot included 5 clinics in 2 geographic areas that were selected for their facility’s leadership support and desire to participate.

The VA Boston Healthcare System implemented personalized health planning at 3 primary care clinics: Jamaica Plain Primary Care, Jamaica Plain Women’s Health, and Quincy Primary Care. Three distinct PACTs participated in Boston, each composed of a medical doctor or doctor of osteopathy, a registered nurse (RN) or health technician, and a medical support assistant. The Sam Rayburn Memorial Veterans Center in Bonham, Texas, implemented personalized health planning at 2 clinics: the Hypertension Shared Medical Appointment and the Domiciliary Inpatient Primary Care. At Bonham, a medical doctor, pharmacist, RN, and an integrated mental health provider led the shared medical appointment (SMA) with guest presenters for individual appointments, depending on the topic covered. A RN and social worker implemented personalized health planning in the domiciliary.

After receiving training in the personalized health planning process, each of the clinics’ multidisciplinary PACTs incorporated their custom personalized health planning workflow into patient encounters. During the intake process of the clinic visit, the patient received a Personal Health Inventory (PHI) to determine health care priorities. The OPCC&CT developed the PHI as a whole-health self-assessment tool to help patients reflect on their health and lives, including core values, disparities between current and desired states, and preparedness to make behavioral changes to promote health.

The PHI assisted with framing this whole health approach to clinical care by expanding the definition of health to include more holistic elements of well-being, such as spirituality, personal relationships, emotional health, and personal development. A visual representation of the whole health domains termed The Circle of Health introduced this concept to the patient and assisted with goal setting (Figure 3).¹²

The PHI organized the patient’s input and was provided to the clinician to contribute to the development of the shared therapeutic goals and a final treatment plan. The PHP provided the tool to organize the goals, plans, and care following the visit and to connect the patient to additional resources within the VHA to support goal attainment through skill building and support. Each clinical site developed a mechanism to follow up with these patients either telephonically or with additional clinic appointments. The participating clinics implemented their customized version of personalized health planning for an average of 3 months.

Personalized health planning and accompanying tools were used primarily in routine ambulatory care visits. They were also used in the Bonham domiciliary clinic, which provides care for veterans with mental illnesses or addictive disorders who require additional structure and support. The purpose of the pilot was to determine whether personalized health planning could be used within this population. Given the small sample size and incompleteness of data collected, the Bonham domiciliary group was not included in the participating patient total. Across the other 4 clinics a total of 153 patients participated in the 3-month pilot study by establishing shared health goals and plans to meet them.

Results and Evaluation

Using a structured interview guide, a total of 6 small group interviews with participating clinicians were held (3 in Boston and 3 in Bonham, N = 18). Qualitative methods for research and evaluation were used to capture the depth of responses and to provide complex descriptions of the clinicians’ perspectives on the implementation of the personalized health planning process. Two researchers reviewed the transcripts to identify and code themes, and a third researcher reviewed the transcripts to confirm themes and resolve any discrepancies.

Analysis of the interview data revealed 9 core themes related to the feasibility, effectiveness, and future dissemination of personalized health planning. These themes, described below with exemplar data, include (a) patient engagement; (b) clinical assessment; (c) goal setting; (d) clinical workflow; (e) resources and support for veterans and clinicians; (f) Computerized Patient Record System (CPRS) integration; (g) patient-clinician relationship; (h) clinical outcomes; and (i) patient satisfaction.

The purpose of this study was to evaluate the feasibility of introducing personalized health planning within the workflows of the clinics that were participating. As a consequence of this, interviews were held with clinic staff rather than patients. However, the authors did obtain patient satisfaction data from 10 patients who received care from the hypertension SMA and responded to TruthPoint questions after their visit (Table).

Patient Engagement

A central tenant of personalized health planning is to engage patients in their health and health care. Findings revealed that clinicians at both sites perceived the PHP as an effective tool for integrating patients as robust members of the care team. Clinicians noted that by asking patients what was important to them, the patients felt more empowered to actively engage in the clinical encounter and to take responsibility for their health decisions. One pharmacist noted, “Patients are more empowered…when you change how you’re having your conversation with them that helps people start to recognize that they are an active participant [sic] and they can have an impact and can help with minimizing medicines or trying other things.”

Clinicians reported that including patients as active members in their care created a level of buy-in that motivated behavioral changes, because the patients identified behaviors they wanted to change vs the clinician telling them what they should or should not do. A nurse manager reported, “The key is that (the health goal) is coming from the patient…. Once it comes out of their mouth, they’re thinking about it and it’s not the clinician telling them what they should or shouldn’t do, but it’s helping them…identify something that’s important that will keep them into staying the way they want to, for the reasons that they want to.”

Clinical Assessment

The HRA tools are a vital part of the personalized health planning process, as they focus on preventive strategies that are most important for the patient.⁴ Clinicians reported using the PHI and additional HRA tools as part of the pilot program. The PHI is a self-assessment tool designed to identify psychosocial, behavioral, and environmental issues that can impact the patient’s care and health status. Most clinicians found that the PHI helped to solicit patients’ input on what was important to them and their health status while introducing the new approach to care. One nurse commented, “I found [PHI] very effective if I could actually sit down and review it with them to see what it was that was truly important to them and explain that this new approach is for a better understanding.”

Clinicians also found that the PHI helped focus the patient’s attention toward self-care areas that facilitated the shared goal setting process with the clinician. It moved the clinical encounter away from the chief health problems and toward identifying what is important to the patient and leveraging his or her intrinsic motivation to support health promotion via lifestyle modification.

Goal Setting

Shared goal setting is a critical component of personalized health planning. The clinician and patient must agree about realistic goals to improve the patient’s health. Clinicians reported that the goal setting stage was most successful when patients were invited to guide the process and offered the goals themselves; ie, when it was not just patient-centered but patient-driven.

“Setting a goal with a patient is pretty easy because people have an idea of what they should be doing and what they want to be doing,” one clinician reported. “They know their goal. So it’s a matter of just listening, really listening, and seeing what they want…. It’s not incongruous to get the medical goal and the patient goal to match.”

Patients were amenable to this collaborative approach to goal setting, and there was often commonality between the clinician’s goals and what was important to the patient. Occasionally, the patient set goals in seemingly unrelated areas that facilitated chronic disease management.

“One of our hypertensive patients wanted to work on things that are external that they felt are stressors that actually caused their blood pressure to be high,” a pharmacist recalled. “At the end of the day they wanted to control their environment better so that they could see if they could then be off of antihypertensives altogether. It appears that may be the case right now. That this individual has been able to accomplish that, which I thought was amazing, and since it’s still new, I’m still a little bit skeptical.... Is that possible? But if at the end of the day that is an outcome that we see from doing this, I think that’s wonderful.”

Clinicians reported that follow-up with the patient was a critical aspect of goal setting, because it improved accountability and helped track progress and health outcomes. However, due to the 3-month time limit of the pilot, there was insufficient time to get uniform data on the formalized follow-up systems developed by each clinic.

Clinical Workflow

Examining the feasibility of creating a process to incorporate personalized health planning into a busy primary care clinic was one of the major aims of this pilot. As such, issues of time, staff responsibilities, and use of the CPRS and other systems to facilitate the process were challenges that each clinic addressed in slightly different ways and with varying success. One method was to leverage the SMA for a group of patients with a common diagnosis to discuss their goals, provide accountability, and improve access to a medical team.

Another innovative approach was utilizing medical support administrators and health technicians to front-load some of the introductory information and patient education in the waiting room or during the intake process. Despite these efforts, some clinicians thought that the personalized health planning process might take longer than the traditional clinical encounter. One nurse manager commented, “I think it did affect the length of visits…it has made them a little bit longer.”

Resources and Support

The VHA has been undergoing a shift from an emphasis on tertiary care to include a greater focus on primary care. Part of this shift has been an investment in complementary and alternative medicine (CAM). The PHP helped clinicians explore what resources existed at their facility to support veterans in accomplishing their goals, including CAM. One nurse reported, “It made us look into other avenues that were actually available at the VHA that we didn’t even know we had…the acupuncture, the qigong, the voluntary services getting the veterans involved.”

Clinicians also identified the need for patient education in the concepts of whole health, personalized care, and patient involvement as necessary for moving the piloted approach forward. A nurse noted that “for [personalized health planning] to work well, [the patients] need more orientation and education upfront systemwide so that when they get into an appointment with us, we’re not starting at explaining the whole world view of partnership and doing things differently.”

Resources for clinicians were just as critical as resources for patients in facilitating the personalized health planning process. Specifically, most clinicians identified their own education and training in techniques to engage the patient in a meaningful way via motivational interviewing and health coaching complemented the personalized approach to care, particularly for shared goal setting,

CPRS Integration

The CPRS is an integrated, electronic patient record system that provides a single interface for clinicians to manage patient care as well as an efficient means for others to access and use patient information.¹⁹ The most commonly cited challenge in the pilot was the lack of available staff and time in the patient visit to complete the PHP while completing documentation requirements in CPRS.

One clinician stated, “For clinicians, the barriers…it’s time to get through the reminders and preventatives.” Clinicians reported that the process and the CPRS documentation were misaligned and lacked integration to coordinate care or support health planning. Moreover, clinicians reported that the data being collected did not support patient-centered care.

Patient-Clinician Relationship

A significant strength of personalized health planning was that it fostered a beneficial patient-clinician relationship that promoted greater depth of care. One clinician noted, “I think that it adds a more personalized dimension to the whole patient visit.” In addition to experiencing a deeper relationship with their patients, clinicians also expressed having higher levels of job satisfaction and relished the opportunity to connect with their patients in a more personal way.

Clinicians also reported that patients seemed more satisfied with the experience. One nurse commented, “They really respond to it very well when they figure out that you care about them as a whole… it’s not just about the disease process anymore.”

Clinical Outcomes

Clinicians reported a number of positive health outcomes during the pilot. One physician reported, “I have a patient, he had a follow-up today, a 29-year-old veteran, who was 260 pounds 5 months ago, and he’s 230 pounds today. He comes in monthly to see the nurse to let us know he’s doing it.”

The same physician also shared a similar transformation in a patient as a result of personalized health planning. “We had another one yesterday, 4 months ago his [hemoglobin] A_1c was 10.3%. It was 7.2% yesterday, and [his weight was] down 20 pounds.” In addition to positive clinical outcomes, patients made changes in areas of their health that they identified as important through the PHI, although these areas are not typically discussed in a clinical visit.

Patient Satisfaction

Although the overall goal of this pilot was to determine the feasibility of a clinical workflow embracing personalized health planning, data on patient satisfaction were collected from patients receiving care in the Hypertension Shared Medical Appointments Program at Bohnam. Ten patients were seen over the course of 5 visits. At each visit, they were asked to rate their satisfaction (Table).

Overall, patients were highly satisfied with their experience and the care they received: 91.7% reported exploring what they wanted for their health and setting shared goals; 100% reported that their providers truly listened to their needs and treated them with respect and dignity; and 97.2% reported that their experience was better than a traditional office visit. One participating physician noted that higher levels of patient and provider satisfaction are a product of this type of patient engagement. “I also think that looking at patient and provider satisfaction, the visits feel more meaningful, and there’s a better relationship built through this discussion,” he noted. These findings demonstrating increased satisfaction further suggest the benefits of personalized health planning approach.

Discussion

In 2012, the VHA National Leadership Council convened a Strategic Planning Summit to set goals and objectives to help the VHA be at the vanguard of a movement toward a more proactive health care delivery model. The first of 3 goals developed was to provide veterans personalized, proactive, patient-driven health care.¹³ It is becoming increasingly clear that truly affecting health and health outcomes requires motivated, engaged, and informed patients with a care delivery approach that provides ample opportunities for patient involvement and input in health care decision making.^10,11

The OPCC&CT has ongoing initiatives driving innovation, research, education, and deployment across the system to set the stage for personalized, proactive, patient-driven care.²⁰ Some of these innovations include clinician education in the concept of whole health; health coaching; group-based, peer-led approaches; and the expansion of CAM such as mind-body approaches, qi-gong, massage therapy, yoga, and acupuncture.²¹

The primary aim of the Whole Health in Primary Care Project was to determine the feasibility of using personalized health planning as the operational model to deliver personalized, proactive, patient-driven care. The decision was made to integrate personalized health planning into ongoing clinical operations rather than design clinical pilots de novo. This had the advantage of speed in starting the project but limited the ability to create an optimal workflow from scratch. Given the time and resources available for this study, it was not possible to obtain quantitative data particularly as it related to quantifying clinical outcomes.

Despite these limitations, early indications suggest that the personalized health planning process can serve as the operational clinical working model to enable personalized, proactive, patient-driven care in a variety of primary care settings. As noted by one nurse manager, preparing the personalized health plan made the initial visit “a bit longer.” However, after the first visit, monitoring health risk abatement and goal achievement is akin to what is currently done by reviewing problem lists. Thus, although the personalized health planning experience is just beginning, clinicians noted that it fostered a beneficial patient-clinician relationship. This deeper relationship between the patient and the clinician may be the most powerful signal that the process is worthwhile.

This pilot provided valuable information related to the implementation of a clinical workflow redesign, an initial step toward developing an optimized operational model of the PHP process. Additionally, although it is not yet possible to quantify the clinical impact of the personalized health planning, anecdotal evidence suggests its positive potential. Clinicians reported that patients were successful in managing a multitude of common chronic diseases, including weight loss, high blood pressure management, reduction of A_1c, and improved sleep habits.

These findings compare with studies using similar approaches that demonstrated their value in the treatment of congestive heart failure, cardiovascular disease risk, type 2 diabetes, and postpartum weight retention.^22-25 A growing body of evidence continues to affirm that a primary care model designed to deliver individualized care focused on improving health and an augmented patient-clinician relationship results in significant savings, primarily from reduced medical expenditures.²⁶

This pilot provided an important opportunity to learn how to improve the effectiveness of personalized health planning and how to scale it. The experiences in Boston and Bonham demonstrated that personalized health planning can be integrated into diverse primary care settings with PACTs. The authors suggest that the knowledge gained from this project should be incorporated into new pilots at various clinical settings to determine the usefulness of the PHP for clinical indications beyond primary care. Specialty care clinics, home-based primary care services, and telehealth programs would be potential clinical applications for such pilots.

New pilots should be designed de novo and be of sufficient length to gain quantitative data on patient activation and clinical outcomes. Furthermore, future studies of personalized health planning should obtain input from the patient using Likert scales, surveys, and focus groups to gauge and quantify patient satisfaction and outcomes with the approach. Since patient engagement and better understanding of patients’ holistic needs are central to development of the PHP, patients need to be educated about this new approach to care and their active role in it.

The choice of the tools, including the HRA instrument, materials for orienting patients to their more active role in their care, the PHI, the PHP template to document shared goals, and other avenues used to engage patients, require refinement to improve their clarity, effectiveness of conveying the intended information, and ease of use. These studies demonstrated the vital need to address the best means to engage patients in understanding the value of their health to them since the clinician visit is likely to be an opportune teaching moment. Initial observations suggested that patients respond with different degrees of enthusiasm when given the opportunity to be more engaged in their care. Future pilots should clarify whether these differences stem from (a) how the invitation is presented; (b) individual differences in personality and preferences; (c) perceived clinical needs; or (d) unfamiliarity with the collaborative personalized health planning process.

The alignment of personalized health planning with outcomes data in the CPRS is essential for widespread adoption. Importantly, incentives and performance metrics will need to be redesigned to support the intended outcomes of using personalized health planning in clinical care. To that end, further investigation into the potential for cost savings associated with personalized health planning use is warranted, especially given studies that suggest high levels of patient engagement result in lower health care utilization expenditures.²⁷

Additionally, wherever personalized health planning is initiated, employees across all levels of the system would benefit from training in patient engagement techniques and other means of attaining behavioral change. This would facilitate more effective use of time during the clinical visit and improve both the patient’s and the clinician’s satisfaction. Indeed, preliminary data indicate that this approach in a SMA setting is greatly valued by the patients.

Conclusions

The Whole Health in Primary Care Project was conducted to determine the feasibility of personalized health planning as the basis for primary care designed to facilitate personalized, proactive, patient-driven care. The pilot demonstrated that personalized health planning could be operational in VHA clinical settings and used to enhance patient-clinician engagement, establish shared health goals, and increase patient satisfaction. The personalized health planning process also provides a framework for the rational introduction of new capabilities to enhance prediction, clinical tracking, coordination of ancillary services, and clinical data collection. Future research should validate the efficacy of personalized health planning within both the VHA and health systems nationwide. Such research has the potential to refine this process so it becomes a key part of a personalized, proactive, patient-driven delivery approach. 

Acknowledgements
We gratefully acknowledge the assistance of Cindy Mitchell at Duke University Medical Center with the editing and preparation of this manuscript. We also gratefully acknowledge the participation of the providers and patients at VA Boston Healthcare System and Sam Rayburn Memorial Veterans Center. Funding for this project was provided by VA777-12-C-002 to the Pacific Institute for Research and Evaluation through subcontracts to Ralph Snyderman, MD, and to the Duke University School of Nursing (Simmons PI.)

Health care has become increasingly unaffordable in the U.S., yet it remains ineffective in preventing or effectively treating chronic diseases.^1,2 Given the increasing burden of chronic disease on the American health care system, there is an effort to shift the practice of medicine away from its reactive, disease-oriented approach to a more sustainable proactive model.^3-5

Personalized health care (PHC) is an approach to the practice of medicine where prediction, prevention, intense patient engagement, shared health care decision making, and coordination of care are essential to cost effectively facilitate better outcomes.^3,5-7 Greater collaboration between patient and clinician replaces the traditional clinician-dominated dialogue with more effective patient-clinician partnerships.^8,9 Patients’ knowledge, skills, and confidence to manage their health care have been linked to improved health outcomes, lower costs, and greater satisfaction with health care experiences.^10,11

Personalized health care has been proposed as a means to achieve better patient engagement as part of an aligned, proactive clinical approach. At the heart of PHC is personalized health planning, wherein the patient and clinician develop shared health-related goals and a plan to achieve them.³

The VHA, the largest integrated health care system in the country, is on the vanguard of incorporating tenets of PHC into its delivery model. In 2011, the Office of Patient Centered Care and Cultural Transformation (OPCC&CT) was founded to “oversee the VHA’s cultural transformation to patient-centered care.”¹² This undertaking represents “one of the most massive changes in the philosophy and process for health care delivery ever undertaken by an organized health care system.”¹³

The primary goal of the VHA’s strategic plan for 2013 to 2018 is to provide veterans personalized, proactive, patient-driven health care.¹⁴ The intention of this approach is to engage and inspire veterans to their highest possible level of health and well-being. A personalized approach requires a dynamic customization of care that is specifically relevant to the individual, based on factors such as medical conditions, genome, needs, values, and circumstances. In addition to being personalized, this approach must be proactive, and therefore, preventive and include strategies to strengthen the person’s innate capacity for enhancing health.

The third distinction of this new model health care is that it is patient-driven, rooted in and driven by that which matters most to people in their lives and aligns their health care with their day-to-day and long-term life goals.¹⁵ The latter may be the most critical of the 3 tenets, because a personalized, proactive approach that is not driven by an engaged and inspired individual will be unlikely to achieve adherence, let alone the highest level of health and well-being.

The VHA is uniquely positioned to optimize health and well-being for veterans due in part to a systemwide emphasis on training providers to promote and support behavior change through approaches including health coaching and motivational interviewing. These synergistic approaches used widely by clinicians throughout the VHA are influenced by the transtheoretical model (ie, the stages of change theory), which considers patients holistically and helps them identify intrinsic motivation to improve their health behaviors.^16,17 The transformation occurring in the VHA is intended to shift the current disease-centric medical model to an approach that optimizes the health of veterans through patient-clinician engagement, health risk assessment (HRA), shared health goal creation, and a coordinated plan to attain them.^12,13

Personalized Health Planning

In recognition of the need to deliver care that emphasizes prevention and coordination, the patient-centered medical home, patient-aligned care teams (PACTs), and the chronic care model were developed. All of these embrace concepts of patient engagement, shared decision making, and team-based care. However, none of these approaches have outlined a clinical workflow that systematically and proactively operationalizes these concepts with the creation of a risk-based personalized care approach. Personalized health planning provides a clinical workflow that operationalizes all these features (Figure 1).

Of central importance is the creation of a personalized health plan (PHP), which the patient and clinician develop collaboratively. The plan serves to organize and coordinate care while engaging the patient in the process of care delivery and appropriate self-management of health.^3,5 This approach promotes personalized and proactive care that values the individual and fosters meaningful patient self-awareness and engagement through shared decision making.⁷

The personalized health planning process is composed of several key components (Figure 2).

With this information, the clinician develops a preliminary therapeutic plan to meet these goals and discusses this plan with the patient. The next component is the synthesis of the clinician’s goals and/or treatment plan with the priorities of the patient to establish shared clinician-patient goals. This is followed by the establishment of the PHP, which consists of the agreed upon shared clinician and patient goals, a therapeutic and wellness plan to meet them, metrics for tracking progress, consults and referrals, and a time frame for the patient to achieve the health goals.

Related: The Right Care at the Right Time and in the Right Place: The Role of Technology in the VHA

The final component is coordination of care and a formalized follow-up system in which the health care team monitors the patient’s progress and provides support by revisiting or updating the PHP at intervals determined by the provider, based on the level of monitoring required by the patient’s health status. This approach invites the patient to become an empowered member of the care team by creating a patient-clinician partnership and providing a model for delivering personalized, proactive, patient-driven care to individuals with a diverse range of needs.^4,5,18

Design and Implementation

This project qualified as exempt through the Duke University Institutional Review Board. The primary aim of this pilot was to examine the feasibility of implementing personalized health planning into primary care settings and to develop a workable process that is scalable and customizable to inpatient and outpatient clinics of varying sizes for different patient populations within the VHA. The pilot included 5 clinics in 2 geographic areas that were selected for their facility’s leadership support and desire to participate.

The VA Boston Healthcare System implemented personalized health planning at 3 primary care clinics: Jamaica Plain Primary Care, Jamaica Plain Women’s Health, and Quincy Primary Care. Three distinct PACTs participated in Boston, each composed of a medical doctor or doctor of osteopathy, a registered nurse (RN) or health technician, and a medical support assistant. The Sam Rayburn Memorial Veterans Center in Bonham, Texas, implemented personalized health planning at 2 clinics: the Hypertension Shared Medical Appointment and the Domiciliary Inpatient Primary Care. At Bonham, a medical doctor, pharmacist, RN, and an integrated mental health provider led the shared medical appointment (SMA) with guest presenters for individual appointments, depending on the topic covered. A RN and social worker implemented personalized health planning in the domiciliary.

After receiving training in the personalized health planning process, each of the clinics’ multidisciplinary PACTs incorporated their custom personalized health planning workflow into patient encounters. During the intake process of the clinic visit, the patient received a Personal Health Inventory (PHI) to determine health care priorities. The OPCC&CT developed the PHI as a whole-health self-assessment tool to help patients reflect on their health and lives, including core values, disparities between current and desired states, and preparedness to make behavioral changes to promote health.

The PHI assisted with framing this whole health approach to clinical care by expanding the definition of health to include more holistic elements of well-being, such as spirituality, personal relationships, emotional health, and personal development. A visual representation of the whole health domains termed The Circle of Health introduced this concept to the patient and assisted with goal setting (Figure 3).¹²

The PHI organized the patient’s input and was provided to the clinician to contribute to the development of the shared therapeutic goals and a final treatment plan. The PHP provided the tool to organize the goals, plans, and care following the visit and to connect the patient to additional resources within the VHA to support goal attainment through skill building and support. Each clinical site developed a mechanism to follow up with these patients either telephonically or with additional clinic appointments. The participating clinics implemented their customized version of personalized health planning for an average of 3 months.

Personalized health planning and accompanying tools were used primarily in routine ambulatory care visits. They were also used in the Bonham domiciliary clinic, which provides care for veterans with mental illnesses or addictive disorders who require additional structure and support. The purpose of the pilot was to determine whether personalized health planning could be used within this population. Given the small sample size and incompleteness of data collected, the Bonham domiciliary group was not included in the participating patient total. Across the other 4 clinics a total of 153 patients participated in the 3-month pilot study by establishing shared health goals and plans to meet them.

Results and Evaluation

Using a structured interview guide, a total of 6 small group interviews with participating clinicians were held (3 in Boston and 3 in Bonham, N = 18). Qualitative methods for research and evaluation were used to capture the depth of responses and to provide complex descriptions of the clinicians’ perspectives on the implementation of the personalized health planning process. Two researchers reviewed the transcripts to identify and code themes, and a third researcher reviewed the transcripts to confirm themes and resolve any discrepancies.

Analysis of the interview data revealed 9 core themes related to the feasibility, effectiveness, and future dissemination of personalized health planning. These themes, described below with exemplar data, include (a) patient engagement; (b) clinical assessment; (c) goal setting; (d) clinical workflow; (e) resources and support for veterans and clinicians; (f) Computerized Patient Record System (CPRS) integration; (g) patient-clinician relationship; (h) clinical outcomes; and (i) patient satisfaction.

The purpose of this study was to evaluate the feasibility of introducing personalized health planning within the workflows of the clinics that were participating. As a consequence of this, interviews were held with clinic staff rather than patients. However, the authors did obtain patient satisfaction data from 10 patients who received care from the hypertension SMA and responded to TruthPoint questions after their visit (Table).

Patient Engagement

A central tenant of personalized health planning is to engage patients in their health and health care. Findings revealed that clinicians at both sites perceived the PHP as an effective tool for integrating patients as robust members of the care team. Clinicians noted that by asking patients what was important to them, the patients felt more empowered to actively engage in the clinical encounter and to take responsibility for their health decisions. One pharmacist noted, “Patients are more empowered…when you change how you’re having your conversation with them that helps people start to recognize that they are an active participant [sic] and they can have an impact and can help with minimizing medicines or trying other things.”

Clinicians reported that including patients as active members in their care created a level of buy-in that motivated behavioral changes, because the patients identified behaviors they wanted to change vs the clinician telling them what they should or should not do. A nurse manager reported, “The key is that (the health goal) is coming from the patient…. Once it comes out of their mouth, they’re thinking about it and it’s not the clinician telling them what they should or shouldn’t do, but it’s helping them…identify something that’s important that will keep them into staying the way they want to, for the reasons that they want to.”

Clinical Assessment

The HRA tools are a vital part of the personalized health planning process, as they focus on preventive strategies that are most important for the patient.⁴ Clinicians reported using the PHI and additional HRA tools as part of the pilot program. The PHI is a self-assessment tool designed to identify psychosocial, behavioral, and environmental issues that can impact the patient’s care and health status. Most clinicians found that the PHI helped to solicit patients’ input on what was important to them and their health status while introducing the new approach to care. One nurse commented, “I found [PHI] very effective if I could actually sit down and review it with them to see what it was that was truly important to them and explain that this new approach is for a better understanding.”

Clinicians also found that the PHI helped focus the patient’s attention toward self-care areas that facilitated the shared goal setting process with the clinician. It moved the clinical encounter away from the chief health problems and toward identifying what is important to the patient and leveraging his or her intrinsic motivation to support health promotion via lifestyle modification.

Goal Setting

Shared goal setting is a critical component of personalized health planning. The clinician and patient must agree about realistic goals to improve the patient’s health. Clinicians reported that the goal setting stage was most successful when patients were invited to guide the process and offered the goals themselves; ie, when it was not just patient-centered but patient-driven.

“Setting a goal with a patient is pretty easy because people have an idea of what they should be doing and what they want to be doing,” one clinician reported. “They know their goal. So it’s a matter of just listening, really listening, and seeing what they want…. It’s not incongruous to get the medical goal and the patient goal to match.”

Patients were amenable to this collaborative approach to goal setting, and there was often commonality between the clinician’s goals and what was important to the patient. Occasionally, the patient set goals in seemingly unrelated areas that facilitated chronic disease management.

“One of our hypertensive patients wanted to work on things that are external that they felt are stressors that actually caused their blood pressure to be high,” a pharmacist recalled. “At the end of the day they wanted to control their environment better so that they could see if they could then be off of antihypertensives altogether. It appears that may be the case right now. That this individual has been able to accomplish that, which I thought was amazing, and since it’s still new, I’m still a little bit skeptical.... Is that possible? But if at the end of the day that is an outcome that we see from doing this, I think that’s wonderful.”

Clinicians reported that follow-up with the patient was a critical aspect of goal setting, because it improved accountability and helped track progress and health outcomes. However, due to the 3-month time limit of the pilot, there was insufficient time to get uniform data on the formalized follow-up systems developed by each clinic.

Clinical Workflow

Examining the feasibility of creating a process to incorporate personalized health planning into a busy primary care clinic was one of the major aims of this pilot. As such, issues of time, staff responsibilities, and use of the CPRS and other systems to facilitate the process were challenges that each clinic addressed in slightly different ways and with varying success. One method was to leverage the SMA for a group of patients with a common diagnosis to discuss their goals, provide accountability, and improve access to a medical team.

Another innovative approach was utilizing medical support administrators and health technicians to front-load some of the introductory information and patient education in the waiting room or during the intake process. Despite these efforts, some clinicians thought that the personalized health planning process might take longer than the traditional clinical encounter. One nurse manager commented, “I think it did affect the length of visits…it has made them a little bit longer.”

Resources and Support

The VHA has been undergoing a shift from an emphasis on tertiary care to include a greater focus on primary care. Part of this shift has been an investment in complementary and alternative medicine (CAM). The PHP helped clinicians explore what resources existed at their facility to support veterans in accomplishing their goals, including CAM. One nurse reported, “It made us look into other avenues that were actually available at the VHA that we didn’t even know we had…the acupuncture, the qigong, the voluntary services getting the veterans involved.”

Clinicians also identified the need for patient education in the concepts of whole health, personalized care, and patient involvement as necessary for moving the piloted approach forward. A nurse noted that “for [personalized health planning] to work well, [the patients] need more orientation and education upfront systemwide so that when they get into an appointment with us, we’re not starting at explaining the whole world view of partnership and doing things differently.”

Resources for clinicians were just as critical as resources for patients in facilitating the personalized health planning process. Specifically, most clinicians identified their own education and training in techniques to engage the patient in a meaningful way via motivational interviewing and health coaching complemented the personalized approach to care, particularly for shared goal setting,

CPRS Integration

The CPRS is an integrated, electronic patient record system that provides a single interface for clinicians to manage patient care as well as an efficient means for others to access and use patient information.¹⁹ The most commonly cited challenge in the pilot was the lack of available staff and time in the patient visit to complete the PHP while completing documentation requirements in CPRS.

One clinician stated, “For clinicians, the barriers…it’s time to get through the reminders and preventatives.” Clinicians reported that the process and the CPRS documentation were misaligned and lacked integration to coordinate care or support health planning. Moreover, clinicians reported that the data being collected did not support patient-centered care.

Patient-Clinician Relationship

A significant strength of personalized health planning was that it fostered a beneficial patient-clinician relationship that promoted greater depth of care. One clinician noted, “I think that it adds a more personalized dimension to the whole patient visit.” In addition to experiencing a deeper relationship with their patients, clinicians also expressed having higher levels of job satisfaction and relished the opportunity to connect with their patients in a more personal way.

Clinicians also reported that patients seemed more satisfied with the experience. One nurse commented, “They really respond to it very well when they figure out that you care about them as a whole… it’s not just about the disease process anymore.”

Clinical Outcomes

Clinicians reported a number of positive health outcomes during the pilot. One physician reported, “I have a patient, he had a follow-up today, a 29-year-old veteran, who was 260 pounds 5 months ago, and he’s 230 pounds today. He comes in monthly to see the nurse to let us know he’s doing it.”

The same physician also shared a similar transformation in a patient as a result of personalized health planning. “We had another one yesterday, 4 months ago his [hemoglobin] A_1c was 10.3%. It was 7.2% yesterday, and [his weight was] down 20 pounds.” In addition to positive clinical outcomes, patients made changes in areas of their health that they identified as important through the PHI, although these areas are not typically discussed in a clinical visit.

Patient Satisfaction

Although the overall goal of this pilot was to determine the feasibility of a clinical workflow embracing personalized health planning, data on patient satisfaction were collected from patients receiving care in the Hypertension Shared Medical Appointments Program at Bohnam. Ten patients were seen over the course of 5 visits. At each visit, they were asked to rate their satisfaction (Table).

Overall, patients were highly satisfied with their experience and the care they received: 91.7% reported exploring what they wanted for their health and setting shared goals; 100% reported that their providers truly listened to their needs and treated them with respect and dignity; and 97.2% reported that their experience was better than a traditional office visit. One participating physician noted that higher levels of patient and provider satisfaction are a product of this type of patient engagement. “I also think that looking at patient and provider satisfaction, the visits feel more meaningful, and there’s a better relationship built through this discussion,” he noted. These findings demonstrating increased satisfaction further suggest the benefits of personalized health planning approach.

Discussion

In 2012, the VHA National Leadership Council convened a Strategic Planning Summit to set goals and objectives to help the VHA be at the vanguard of a movement toward a more proactive health care delivery model. The first of 3 goals developed was to provide veterans personalized, proactive, patient-driven health care.¹³ It is becoming increasingly clear that truly affecting health and health outcomes requires motivated, engaged, and informed patients with a care delivery approach that provides ample opportunities for patient involvement and input in health care decision making.^10,11

The OPCC&CT has ongoing initiatives driving innovation, research, education, and deployment across the system to set the stage for personalized, proactive, patient-driven care.²⁰ Some of these innovations include clinician education in the concept of whole health; health coaching; group-based, peer-led approaches; and the expansion of CAM such as mind-body approaches, qi-gong, massage therapy, yoga, and acupuncture.²¹

The primary aim of the Whole Health in Primary Care Project was to determine the feasibility of using personalized health planning as the operational model to deliver personalized, proactive, patient-driven care. The decision was made to integrate personalized health planning into ongoing clinical operations rather than design clinical pilots de novo. This had the advantage of speed in starting the project but limited the ability to create an optimal workflow from scratch. Given the time and resources available for this study, it was not possible to obtain quantitative data particularly as it related to quantifying clinical outcomes.

Despite these limitations, early indications suggest that the personalized health planning process can serve as the operational clinical working model to enable personalized, proactive, patient-driven care in a variety of primary care settings. As noted by one nurse manager, preparing the personalized health plan made the initial visit “a bit longer.” However, after the first visit, monitoring health risk abatement and goal achievement is akin to what is currently done by reviewing problem lists. Thus, although the personalized health planning experience is just beginning, clinicians noted that it fostered a beneficial patient-clinician relationship. This deeper relationship between the patient and the clinician may be the most powerful signal that the process is worthwhile.

This pilot provided valuable information related to the implementation of a clinical workflow redesign, an initial step toward developing an optimized operational model of the PHP process. Additionally, although it is not yet possible to quantify the clinical impact of the personalized health planning, anecdotal evidence suggests its positive potential. Clinicians reported that patients were successful in managing a multitude of common chronic diseases, including weight loss, high blood pressure management, reduction of A_1c, and improved sleep habits.

These findings compare with studies using similar approaches that demonstrated their value in the treatment of congestive heart failure, cardiovascular disease risk, type 2 diabetes, and postpartum weight retention.^22-25 A growing body of evidence continues to affirm that a primary care model designed to deliver individualized care focused on improving health and an augmented patient-clinician relationship results in significant savings, primarily from reduced medical expenditures.²⁶

This pilot provided an important opportunity to learn how to improve the effectiveness of personalized health planning and how to scale it. The experiences in Boston and Bonham demonstrated that personalized health planning can be integrated into diverse primary care settings with PACTs. The authors suggest that the knowledge gained from this project should be incorporated into new pilots at various clinical settings to determine the usefulness of the PHP for clinical indications beyond primary care. Specialty care clinics, home-based primary care services, and telehealth programs would be potential clinical applications for such pilots.

New pilots should be designed de novo and be of sufficient length to gain quantitative data on patient activation and clinical outcomes. Furthermore, future studies of personalized health planning should obtain input from the patient using Likert scales, surveys, and focus groups to gauge and quantify patient satisfaction and outcomes with the approach. Since patient engagement and better understanding of patients’ holistic needs are central to development of the PHP, patients need to be educated about this new approach to care and their active role in it.

The choice of the tools, including the HRA instrument, materials for orienting patients to their more active role in their care, the PHI, the PHP template to document shared goals, and other avenues used to engage patients, require refinement to improve their clarity, effectiveness of conveying the intended information, and ease of use. These studies demonstrated the vital need to address the best means to engage patients in understanding the value of their health to them since the clinician visit is likely to be an opportune teaching moment. Initial observations suggested that patients respond with different degrees of enthusiasm when given the opportunity to be more engaged in their care. Future pilots should clarify whether these differences stem from (a) how the invitation is presented; (b) individual differences in personality and preferences; (c) perceived clinical needs; or (d) unfamiliarity with the collaborative personalized health planning process.

The alignment of personalized health planning with outcomes data in the CPRS is essential for widespread adoption. Importantly, incentives and performance metrics will need to be redesigned to support the intended outcomes of using personalized health planning in clinical care. To that end, further investigation into the potential for cost savings associated with personalized health planning use is warranted, especially given studies that suggest high levels of patient engagement result in lower health care utilization expenditures.²⁷

Additionally, wherever personalized health planning is initiated, employees across all levels of the system would benefit from training in patient engagement techniques and other means of attaining behavioral change. This would facilitate more effective use of time during the clinical visit and improve both the patient’s and the clinician’s satisfaction. Indeed, preliminary data indicate that this approach in a SMA setting is greatly valued by the patients.

Conclusions

The Whole Health in Primary Care Project was conducted to determine the feasibility of personalized health planning as the basis for primary care designed to facilitate personalized, proactive, patient-driven care. The pilot demonstrated that personalized health planning could be operational in VHA clinical settings and used to enhance patient-clinician engagement, establish shared health goals, and increase patient satisfaction. The personalized health planning process also provides a framework for the rational introduction of new capabilities to enhance prediction, clinical tracking, coordination of ancillary services, and clinical data collection. Future research should validate the efficacy of personalized health planning within both the VHA and health systems nationwide. Such research has the potential to refine this process so it becomes a key part of a personalized, proactive, patient-driven delivery approach. 

Acknowledgements
We gratefully acknowledge the assistance of Cindy Mitchell at Duke University Medical Center with the editing and preparation of this manuscript. We also gratefully acknowledge the participation of the providers and patients at VA Boston Healthcare System and Sam Rayburn Memorial Veterans Center. Funding for this project was provided by VA777-12-C-002 to the Pacific Institute for Research and Evaluation through subcontracts to Ralph Snyderman, MD, and to the Duke University School of Nursing (Simmons PI.)

Health care has become increasingly unaffordable in the U.S., yet it remains ineffective in preventing or effectively treating chronic diseases.^1,2 Given the increasing burden of chronic disease on the American health care system, there is an effort to shift the practice of medicine away from its reactive, disease-oriented approach to a more sustainable proactive model.^3-5

Personalized health care (PHC) is an approach to the practice of medicine where prediction, prevention, intense patient engagement, shared health care decision making, and coordination of care are essential to cost effectively facilitate better outcomes.^3,5-7 Greater collaboration between patient and clinician replaces the traditional clinician-dominated dialogue with more effective patient-clinician partnerships.^8,9 Patients’ knowledge, skills, and confidence to manage their health care have been linked to improved health outcomes, lower costs, and greater satisfaction with health care experiences.^10,11

Personalized health care has been proposed as a means to achieve better patient engagement as part of an aligned, proactive clinical approach. At the heart of PHC is personalized health planning, wherein the patient and clinician develop shared health-related goals and a plan to achieve them.³

The VHA, the largest integrated health care system in the country, is on the vanguard of incorporating tenets of PHC into its delivery model. In 2011, the Office of Patient Centered Care and Cultural Transformation (OPCC&CT) was founded to “oversee the VHA’s cultural transformation to patient-centered care.”¹² This undertaking represents “one of the most massive changes in the philosophy and process for health care delivery ever undertaken by an organized health care system.”¹³

The primary goal of the VHA’s strategic plan for 2013 to 2018 is to provide veterans personalized, proactive, patient-driven health care.¹⁴ The intention of this approach is to engage and inspire veterans to their highest possible level of health and well-being. A personalized approach requires a dynamic customization of care that is specifically relevant to the individual, based on factors such as medical conditions, genome, needs, values, and circumstances. In addition to being personalized, this approach must be proactive, and therefore, preventive and include strategies to strengthen the person’s innate capacity for enhancing health.

The third distinction of this new model health care is that it is patient-driven, rooted in and driven by that which matters most to people in their lives and aligns their health care with their day-to-day and long-term life goals.¹⁵ The latter may be the most critical of the 3 tenets, because a personalized, proactive approach that is not driven by an engaged and inspired individual will be unlikely to achieve adherence, let alone the highest level of health and well-being.

The VHA is uniquely positioned to optimize health and well-being for veterans due in part to a systemwide emphasis on training providers to promote and support behavior change through approaches including health coaching and motivational interviewing. These synergistic approaches used widely by clinicians throughout the VHA are influenced by the transtheoretical model (ie, the stages of change theory), which considers patients holistically and helps them identify intrinsic motivation to improve their health behaviors.^16,17 The transformation occurring in the VHA is intended to shift the current disease-centric medical model to an approach that optimizes the health of veterans through patient-clinician engagement, health risk assessment (HRA), shared health goal creation, and a coordinated plan to attain them.^12,13

Personalized Health Planning

In recognition of the need to deliver care that emphasizes prevention and coordination, the patient-centered medical home, patient-aligned care teams (PACTs), and the chronic care model were developed. All of these embrace concepts of patient engagement, shared decision making, and team-based care. However, none of these approaches have outlined a clinical workflow that systematically and proactively operationalizes these concepts with the creation of a risk-based personalized care approach. Personalized health planning provides a clinical workflow that operationalizes all these features (Figure 1).

Of central importance is the creation of a personalized health plan (PHP), which the patient and clinician develop collaboratively. The plan serves to organize and coordinate care while engaging the patient in the process of care delivery and appropriate self-management of health.^3,5 This approach promotes personalized and proactive care that values the individual and fosters meaningful patient self-awareness and engagement through shared decision making.⁷

The personalized health planning process is composed of several key components (Figure 2).

With this information, the clinician develops a preliminary therapeutic plan to meet these goals and discusses this plan with the patient. The next component is the synthesis of the clinician’s goals and/or treatment plan with the priorities of the patient to establish shared clinician-patient goals. This is followed by the establishment of the PHP, which consists of the agreed upon shared clinician and patient goals, a therapeutic and wellness plan to meet them, metrics for tracking progress, consults and referrals, and a time frame for the patient to achieve the health goals.

Related: The Right Care at the Right Time and in the Right Place: The Role of Technology in the VHA

The final component is coordination of care and a formalized follow-up system in which the health care team monitors the patient’s progress and provides support by revisiting or updating the PHP at intervals determined by the provider, based on the level of monitoring required by the patient’s health status. This approach invites the patient to become an empowered member of the care team by creating a patient-clinician partnership and providing a model for delivering personalized, proactive, patient-driven care to individuals with a diverse range of needs.^4,5,18

Design and Implementation

This project qualified as exempt through the Duke University Institutional Review Board. The primary aim of this pilot was to examine the feasibility of implementing personalized health planning into primary care settings and to develop a workable process that is scalable and customizable to inpatient and outpatient clinics of varying sizes for different patient populations within the VHA. The pilot included 5 clinics in 2 geographic areas that were selected for their facility’s leadership support and desire to participate.

The VA Boston Healthcare System implemented personalized health planning at 3 primary care clinics: Jamaica Plain Primary Care, Jamaica Plain Women’s Health, and Quincy Primary Care. Three distinct PACTs participated in Boston, each composed of a medical doctor or doctor of osteopathy, a registered nurse (RN) or health technician, and a medical support assistant. The Sam Rayburn Memorial Veterans Center in Bonham, Texas, implemented personalized health planning at 2 clinics: the Hypertension Shared Medical Appointment and the Domiciliary Inpatient Primary Care. At Bonham, a medical doctor, pharmacist, RN, and an integrated mental health provider led the shared medical appointment (SMA) with guest presenters for individual appointments, depending on the topic covered. A RN and social worker implemented personalized health planning in the domiciliary.

After receiving training in the personalized health planning process, each of the clinics’ multidisciplinary PACTs incorporated their custom personalized health planning workflow into patient encounters. During the intake process of the clinic visit, the patient received a Personal Health Inventory (PHI) to determine health care priorities. The OPCC&CT developed the PHI as a whole-health self-assessment tool to help patients reflect on their health and lives, including core values, disparities between current and desired states, and preparedness to make behavioral changes to promote health.

The PHI assisted with framing this whole health approach to clinical care by expanding the definition of health to include more holistic elements of well-being, such as spirituality, personal relationships, emotional health, and personal development. A visual representation of the whole health domains termed The Circle of Health introduced this concept to the patient and assisted with goal setting (Figure 3).¹²

The PHI organized the patient’s input and was provided to the clinician to contribute to the development of the shared therapeutic goals and a final treatment plan. The PHP provided the tool to organize the goals, plans, and care following the visit and to connect the patient to additional resources within the VHA to support goal attainment through skill building and support. Each clinical site developed a mechanism to follow up with these patients either telephonically or with additional clinic appointments. The participating clinics implemented their customized version of personalized health planning for an average of 3 months.

Personalized health planning and accompanying tools were used primarily in routine ambulatory care visits. They were also used in the Bonham domiciliary clinic, which provides care for veterans with mental illnesses or addictive disorders who require additional structure and support. The purpose of the pilot was to determine whether personalized health planning could be used within this population. Given the small sample size and incompleteness of data collected, the Bonham domiciliary group was not included in the participating patient total. Across the other 4 clinics a total of 153 patients participated in the 3-month pilot study by establishing shared health goals and plans to meet them.

Results and Evaluation

Using a structured interview guide, a total of 6 small group interviews with participating clinicians were held (3 in Boston and 3 in Bonham, N = 18). Qualitative methods for research and evaluation were used to capture the depth of responses and to provide complex descriptions of the clinicians’ perspectives on the implementation of the personalized health planning process. Two researchers reviewed the transcripts to identify and code themes, and a third researcher reviewed the transcripts to confirm themes and resolve any discrepancies.

Analysis of the interview data revealed 9 core themes related to the feasibility, effectiveness, and future dissemination of personalized health planning. These themes, described below with exemplar data, include (a) patient engagement; (b) clinical assessment; (c) goal setting; (d) clinical workflow; (e) resources and support for veterans and clinicians; (f) Computerized Patient Record System (CPRS) integration; (g) patient-clinician relationship; (h) clinical outcomes; and (i) patient satisfaction.

The purpose of this study was to evaluate the feasibility of introducing personalized health planning within the workflows of the clinics that were participating. As a consequence of this, interviews were held with clinic staff rather than patients. However, the authors did obtain patient satisfaction data from 10 patients who received care from the hypertension SMA and responded to TruthPoint questions after their visit (Table).

Patient Engagement

A central tenant of personalized health planning is to engage patients in their health and health care. Findings revealed that clinicians at both sites perceived the PHP as an effective tool for integrating patients as robust members of the care team. Clinicians noted that by asking patients what was important to them, the patients felt more empowered to actively engage in the clinical encounter and to take responsibility for their health decisions. One pharmacist noted, “Patients are more empowered…when you change how you’re having your conversation with them that helps people start to recognize that they are an active participant [sic] and they can have an impact and can help with minimizing medicines or trying other things.”

Clinicians reported that including patients as active members in their care created a level of buy-in that motivated behavioral changes, because the patients identified behaviors they wanted to change vs the clinician telling them what they should or should not do. A nurse manager reported, “The key is that (the health goal) is coming from the patient…. Once it comes out of their mouth, they’re thinking about it and it’s not the clinician telling them what they should or shouldn’t do, but it’s helping them…identify something that’s important that will keep them into staying the way they want to, for the reasons that they want to.”

Clinical Assessment

The HRA tools are a vital part of the personalized health planning process, as they focus on preventive strategies that are most important for the patient.⁴ Clinicians reported using the PHI and additional HRA tools as part of the pilot program. The PHI is a self-assessment tool designed to identify psychosocial, behavioral, and environmental issues that can impact the patient’s care and health status. Most clinicians found that the PHI helped to solicit patients’ input on what was important to them and their health status while introducing the new approach to care. One nurse commented, “I found [PHI] very effective if I could actually sit down and review it with them to see what it was that was truly important to them and explain that this new approach is for a better understanding.”

Clinicians also found that the PHI helped focus the patient’s attention toward self-care areas that facilitated the shared goal setting process with the clinician. It moved the clinical encounter away from the chief health problems and toward identifying what is important to the patient and leveraging his or her intrinsic motivation to support health promotion via lifestyle modification.

Goal Setting

Shared goal setting is a critical component of personalized health planning. The clinician and patient must agree about realistic goals to improve the patient’s health. Clinicians reported that the goal setting stage was most successful when patients were invited to guide the process and offered the goals themselves; ie, when it was not just patient-centered but patient-driven.

“Setting a goal with a patient is pretty easy because people have an idea of what they should be doing and what they want to be doing,” one clinician reported. “They know their goal. So it’s a matter of just listening, really listening, and seeing what they want…. It’s not incongruous to get the medical goal and the patient goal to match.”

Patients were amenable to this collaborative approach to goal setting, and there was often commonality between the clinician’s goals and what was important to the patient. Occasionally, the patient set goals in seemingly unrelated areas that facilitated chronic disease management.

“One of our hypertensive patients wanted to work on things that are external that they felt are stressors that actually caused their blood pressure to be high,” a pharmacist recalled. “At the end of the day they wanted to control their environment better so that they could see if they could then be off of antihypertensives altogether. It appears that may be the case right now. That this individual has been able to accomplish that, which I thought was amazing, and since it’s still new, I’m still a little bit skeptical.... Is that possible? But if at the end of the day that is an outcome that we see from doing this, I think that’s wonderful.”

Clinicians reported that follow-up with the patient was a critical aspect of goal setting, because it improved accountability and helped track progress and health outcomes. However, due to the 3-month time limit of the pilot, there was insufficient time to get uniform data on the formalized follow-up systems developed by each clinic.

Clinical Workflow

Examining the feasibility of creating a process to incorporate personalized health planning into a busy primary care clinic was one of the major aims of this pilot. As such, issues of time, staff responsibilities, and use of the CPRS and other systems to facilitate the process were challenges that each clinic addressed in slightly different ways and with varying success. One method was to leverage the SMA for a group of patients with a common diagnosis to discuss their goals, provide accountability, and improve access to a medical team.

Another innovative approach was utilizing medical support administrators and health technicians to front-load some of the introductory information and patient education in the waiting room or during the intake process. Despite these efforts, some clinicians thought that the personalized health planning process might take longer than the traditional clinical encounter. One nurse manager commented, “I think it did affect the length of visits…it has made them a little bit longer.”

Resources and Support

The VHA has been undergoing a shift from an emphasis on tertiary care to include a greater focus on primary care. Part of this shift has been an investment in complementary and alternative medicine (CAM). The PHP helped clinicians explore what resources existed at their facility to support veterans in accomplishing their goals, including CAM. One nurse reported, “It made us look into other avenues that were actually available at the VHA that we didn’t even know we had…the acupuncture, the qigong, the voluntary services getting the veterans involved.”

Clinicians also identified the need for patient education in the concepts of whole health, personalized care, and patient involvement as necessary for moving the piloted approach forward. A nurse noted that “for [personalized health planning] to work well, [the patients] need more orientation and education upfront systemwide so that when they get into an appointment with us, we’re not starting at explaining the whole world view of partnership and doing things differently.”

Resources for clinicians were just as critical as resources for patients in facilitating the personalized health planning process. Specifically, most clinicians identified their own education and training in techniques to engage the patient in a meaningful way via motivational interviewing and health coaching complemented the personalized approach to care, particularly for shared goal setting,

CPRS Integration

The CPRS is an integrated, electronic patient record system that provides a single interface for clinicians to manage patient care as well as an efficient means for others to access and use patient information.¹⁹ The most commonly cited challenge in the pilot was the lack of available staff and time in the patient visit to complete the PHP while completing documentation requirements in CPRS.

One clinician stated, “For clinicians, the barriers…it’s time to get through the reminders and preventatives.” Clinicians reported that the process and the CPRS documentation were misaligned and lacked integration to coordinate care or support health planning. Moreover, clinicians reported that the data being collected did not support patient-centered care.

Patient-Clinician Relationship

A significant strength of personalized health planning was that it fostered a beneficial patient-clinician relationship that promoted greater depth of care. One clinician noted, “I think that it adds a more personalized dimension to the whole patient visit.” In addition to experiencing a deeper relationship with their patients, clinicians also expressed having higher levels of job satisfaction and relished the opportunity to connect with their patients in a more personal way.

Clinicians also reported that patients seemed more satisfied with the experience. One nurse commented, “They really respond to it very well when they figure out that you care about them as a whole… it’s not just about the disease process anymore.”

Clinical Outcomes

Clinicians reported a number of positive health outcomes during the pilot. One physician reported, “I have a patient, he had a follow-up today, a 29-year-old veteran, who was 260 pounds 5 months ago, and he’s 230 pounds today. He comes in monthly to see the nurse to let us know he’s doing it.”

The same physician also shared a similar transformation in a patient as a result of personalized health planning. “We had another one yesterday, 4 months ago his [hemoglobin] A_1c was 10.3%. It was 7.2% yesterday, and [his weight was] down 20 pounds.” In addition to positive clinical outcomes, patients made changes in areas of their health that they identified as important through the PHI, although these areas are not typically discussed in a clinical visit.

Patient Satisfaction

Although the overall goal of this pilot was to determine the feasibility of a clinical workflow embracing personalized health planning, data on patient satisfaction were collected from patients receiving care in the Hypertension Shared Medical Appointments Program at Bohnam. Ten patients were seen over the course of 5 visits. At each visit, they were asked to rate their satisfaction (Table).

Overall, patients were highly satisfied with their experience and the care they received: 91.7% reported exploring what they wanted for their health and setting shared goals; 100% reported that their providers truly listened to their needs and treated them with respect and dignity; and 97.2% reported that their experience was better than a traditional office visit. One participating physician noted that higher levels of patient and provider satisfaction are a product of this type of patient engagement. “I also think that looking at patient and provider satisfaction, the visits feel more meaningful, and there’s a better relationship built through this discussion,” he noted. These findings demonstrating increased satisfaction further suggest the benefits of personalized health planning approach.

Discussion

In 2012, the VHA National Leadership Council convened a Strategic Planning Summit to set goals and objectives to help the VHA be at the vanguard of a movement toward a more proactive health care delivery model. The first of 3 goals developed was to provide veterans personalized, proactive, patient-driven health care.¹³ It is becoming increasingly clear that truly affecting health and health outcomes requires motivated, engaged, and informed patients with a care delivery approach that provides ample opportunities for patient involvement and input in health care decision making.^10,11

The OPCC&CT has ongoing initiatives driving innovation, research, education, and deployment across the system to set the stage for personalized, proactive, patient-driven care.²⁰ Some of these innovations include clinician education in the concept of whole health; health coaching; group-based, peer-led approaches; and the expansion of CAM such as mind-body approaches, qi-gong, massage therapy, yoga, and acupuncture.²¹

The primary aim of the Whole Health in Primary Care Project was to determine the feasibility of using personalized health planning as the operational model to deliver personalized, proactive, patient-driven care. The decision was made to integrate personalized health planning into ongoing clinical operations rather than design clinical pilots de novo. This had the advantage of speed in starting the project but limited the ability to create an optimal workflow from scratch. Given the time and resources available for this study, it was not possible to obtain quantitative data particularly as it related to quantifying clinical outcomes.

Despite these limitations, early indications suggest that the personalized health planning process can serve as the operational clinical working model to enable personalized, proactive, patient-driven care in a variety of primary care settings. As noted by one nurse manager, preparing the personalized health plan made the initial visit “a bit longer.” However, after the first visit, monitoring health risk abatement and goal achievement is akin to what is currently done by reviewing problem lists. Thus, although the personalized health planning experience is just beginning, clinicians noted that it fostered a beneficial patient-clinician relationship. This deeper relationship between the patient and the clinician may be the most powerful signal that the process is worthwhile.

This pilot provided valuable information related to the implementation of a clinical workflow redesign, an initial step toward developing an optimized operational model of the PHP process. Additionally, although it is not yet possible to quantify the clinical impact of the personalized health planning, anecdotal evidence suggests its positive potential. Clinicians reported that patients were successful in managing a multitude of common chronic diseases, including weight loss, high blood pressure management, reduction of A_1c, and improved sleep habits.

These findings compare with studies using similar approaches that demonstrated their value in the treatment of congestive heart failure, cardiovascular disease risk, type 2 diabetes, and postpartum weight retention.^22-25 A growing body of evidence continues to affirm that a primary care model designed to deliver individualized care focused on improving health and an augmented patient-clinician relationship results in significant savings, primarily from reduced medical expenditures.²⁶

This pilot provided an important opportunity to learn how to improve the effectiveness of personalized health planning and how to scale it. The experiences in Boston and Bonham demonstrated that personalized health planning can be integrated into diverse primary care settings with PACTs. The authors suggest that the knowledge gained from this project should be incorporated into new pilots at various clinical settings to determine the usefulness of the PHP for clinical indications beyond primary care. Specialty care clinics, home-based primary care services, and telehealth programs would be potential clinical applications for such pilots.

New pilots should be designed de novo and be of sufficient length to gain quantitative data on patient activation and clinical outcomes. Furthermore, future studies of personalized health planning should obtain input from the patient using Likert scales, surveys, and focus groups to gauge and quantify patient satisfaction and outcomes with the approach. Since patient engagement and better understanding of patients’ holistic needs are central to development of the PHP, patients need to be educated about this new approach to care and their active role in it.

The choice of the tools, including the HRA instrument, materials for orienting patients to their more active role in their care, the PHI, the PHP template to document shared goals, and other avenues used to engage patients, require refinement to improve their clarity, effectiveness of conveying the intended information, and ease of use. These studies demonstrated the vital need to address the best means to engage patients in understanding the value of their health to them since the clinician visit is likely to be an opportune teaching moment. Initial observations suggested that patients respond with different degrees of enthusiasm when given the opportunity to be more engaged in their care. Future pilots should clarify whether these differences stem from (a) how the invitation is presented; (b) individual differences in personality and preferences; (c) perceived clinical needs; or (d) unfamiliarity with the collaborative personalized health planning process.

The alignment of personalized health planning with outcomes data in the CPRS is essential for widespread adoption. Importantly, incentives and performance metrics will need to be redesigned to support the intended outcomes of using personalized health planning in clinical care. To that end, further investigation into the potential for cost savings associated with personalized health planning use is warranted, especially given studies that suggest high levels of patient engagement result in lower health care utilization expenditures.²⁷

Additionally, wherever personalized health planning is initiated, employees across all levels of the system would benefit from training in patient engagement techniques and other means of attaining behavioral change. This would facilitate more effective use of time during the clinical visit and improve both the patient’s and the clinician’s satisfaction. Indeed, preliminary data indicate that this approach in a SMA setting is greatly valued by the patients.

Conclusions

The Whole Health in Primary Care Project was conducted to determine the feasibility of personalized health planning as the basis for primary care designed to facilitate personalized, proactive, patient-driven care. The pilot demonstrated that personalized health planning could be operational in VHA clinical settings and used to enhance patient-clinician engagement, establish shared health goals, and increase patient satisfaction. The personalized health planning process also provides a framework for the rational introduction of new capabilities to enhance prediction, clinical tracking, coordination of ancillary services, and clinical data collection. Future research should validate the efficacy of personalized health planning within both the VHA and health systems nationwide. Such research has the potential to refine this process so it becomes a key part of a personalized, proactive, patient-driven delivery approach. 

Acknowledgements
We gratefully acknowledge the assistance of Cindy Mitchell at Duke University Medical Center with the editing and preparation of this manuscript. We also gratefully acknowledge the participation of the providers and patients at VA Boston Healthcare System and Sam Rayburn Memorial Veterans Center. Funding for this project was provided by VA777-12-C-002 to the Pacific Institute for Research and Evaluation through subcontracts to Ralph Snyderman, MD, and to the Duke University School of Nursing (Simmons PI.)

Gout is an extremely painful arthritis initiated by innate immune responses to monosodium urate crystals that accumulate in affected joints and surrounding tissues. As a result, gout is characterized by painful arthritis flares followed by intervening periods of disease quiescence. Over time, gout can lead to chronic pain, disability, and tophi. Nearly 10% of those aged > 65 years report having gout. The overall prevalence in the U.S. population approaches 4%.¹

Gout treatment has 2 overarching goals: alleviating the pain and inflammation caused by acute gout attacks and long-term management that is focused on lowering serum urate (sUA) levels to reduce the risk of future attacks. Alleviating the pain and inflammation of an acute attack is often complicated by patient characteristics, namely, other chronic health conditions that frequently accompany gout, such as diabetes mellitus (DM), chronic kidney disease (CKD), hypertension, and cardiovascular disease (CVD).

Patients with gout tend to be older and have multiple comorbidities that require the use of many medications.² Because the VA patient population tends to be older, acute gout and attendant complications of treatment are an important consideration for VA health care providers (HCPs).

Recently, the American College of Rheumatology (ACR) released management recommendations for gout, including those for the treatment of acute gout.³ The ACR recommends 3 first-line therapies, but limited guidance is provided for deciding among therapies. This article briefly reviews the relevant ACR recommendations and details important comorbidity and concomitant medication considerations in the treatment of acute gout.

Acute Gout Characteristics

Acute gout attacks are characterized by a rapid onset and escalation with joint pain typically peaking within 24 hours of attack onset. An acute attack often begins to remit after 5 to 12 days without intervention, but complete resolution may take longer in some patients.⁴ In one study, at 24 hours after attack onset, 16% of patients on placebo had > 50% reduction in pain compared with 70% that had no recovery at all.⁵ By 48 hours, one-third of patients on placebo achieved a 50% reduction in pain.⁶

Treatment Recommendations

Therapy for acute gout attacks aims to reduce pain and promote a full, early resolution. The ACR recommends pharmacologic therapy as first-line treatment with adjunctive topical ice and rest as needed.³ Typically, monotherapy is appropriate if the individual is experiencing mild-to-moderate pain affecting ≤ 2 joints of any size. Severe pain or attacks affecting multiple joints may benefit from initial combination therapy. Three first-line therapies are available: nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors, colchicine, or systemic glucocorticoids (Figure 2).

Few studies compare the efficacy of first-line therapeutic categories. There are no clinical trials directly comparing colchicine with NSAIDs or colchicine with glucocorticoids. No difference in mean reduction of pain and no differences in adverse events (AEs) were shown in a trial that compared glucocorticoids with NSAIDs.⁸ Thus, without further study, treatment choices made by HCPs are often guided by factors other than the existence of robust evidence.

Treatment with NSAIDs or COX-2 inhibitors should be initiated at the approved dose and continued until the gout attack has completely resolved. In one study, 73% of patients had pain reduction of ≥ 50% when taking NSAIDs relative to only 27% of patients on placebo.⁸ All available NSAIDs are considered effective, but only 3 NSAIDs are specifically approved for treatment of acute gout (naproxen, indomethacin, and sulindac). There is no evidence supporting one NSAID as being more effective than another; evidence fails to show a meaningful difference.⁸ Limited evidence indicates that selective COX-2 inhibitors, including celexocib, have similar efficacy as nonselective NSAIDs but may have fewer AEs, driven in part by fewer gastrointestinal (GI) events (6% vs 16% for GI events).⁸

Colchicine has long been used as prophylaxis for acute gout attacks and has been endorsed for the treatment of acute attacks. Recent evidence suggests that colchicine initially dosed at 1.2 mg followed by a single 0.6-mg dose 1 hour later is as effective with fewer AEs compared with a traditional regimen of 1.2 mg followed by 0.6 mg every hour for up to 6 hours.⁵ About 40% of patients have 50% pain reduction within 24 hours and a 40% absolute risk reduction in AEs on this low-dose regimen. The efficacy of colchicine relative to other therapies is poorly defined, especially for patients presenting longer after attack onset. The ACR guidelines recommend colchicine only if treatment is initiated within 36 hours of attack onset, but this is based solely on expert consensus. Likewise, the above trial for low-dose colchicine did not provide information about dosing beyond the first 6 hours, leaving little guidance for follow-up treatment of residual pain beyond the 32 hours reported.⁵ Traditionally, one 0.6-mg dose is provided every 12 to 24 hours.³

Systemic glucocorticoids are also commonly used in treating acute gout.⁹ There was a small pain reduction benefit for prednisolone, but the difference was not clinically significant in one clinical trial comparing oral prednisolone 30 mg daily for 5 days vs a combination of indomethacin for 5 days and an initial intramuscular injection of diclofenac 75 mg.¹⁰ The prednisolone group also had fewer patients with AEs, including abdominal pain (0% vs 30%) and GI bleeding (0% vs 11%). The lower incidence of short-term AEs may be a primary benefit of systemic glucocorticoids.¹¹

Intra-articular glucocorticoids are not suggested first-line therapies but are commonly used by rheumatologists.⁹ In an uncontrolled study conducted by Fernández and colleagues, intra-articular glucocorticoid injections helped to quickly resolve 20 out of 20 crystal-proven gout attacks.¹² However, no randomized controlled trials have examined this approach. Although seemingly efficacious, other considerations are important for this modality. Intra-articular glucocorticoids may not be preferred for polyarticular attacks or attacks in difficult-to-aspirate joints. Additionally, intra-articular glucocorticoids have been anecdotally associated with rebound attacks (ie, attacks that occur shortly after resolution without other interventions). However, the Fernández study had no such attacks occur among participants.¹² Finally, septic arthritis must be ruled out as in any case of acute onset monoarticular arthritis.

Biologic agents targeting interleukin-1(IL-1) are not currently approved for gout, although there is burgeoning data suggesting that this strategy may have substantial merit.¹³ Additionally, there is limited evidence that adrenocorticotropic hormone (ACTH) may provide rapid pain relief when other available therapies are ineffective or contraindicated. However, ACTH studies have not provided robust trial designs, and drug costs remain substantial, thus limiting the widespread use of ACTH in acute gout.^14,15 Anti-IL-1 agents and ACTH may both be considered as second-line options if first-line therapies are contraindicated or fail. Careful consideration should be given to AE profiles, patient preferences, and cost.

Comorbidities

Acute gout care, especially in the context of comorbidities, has been identified as a critical treatment concern by an international panel of rheumatologists as part of the 3e (Evidence, Expertise, Exchange) Initiative.¹⁶ However, regular clinical trial exclusion criteria have limited data necessary to guide treatment when comorbidities are present. Therefore, studies of acute gout treatment in the context of disease comorbidity represents a major unmet need in understanding and optimizing gout care.

Chronic Kidney Disease

Chronic kidney disease is common in gout; 20% of patients with gout have an estimated glomerular filtration rate (eGFR) of < 30 mL/min.² Thus, CKD is an important consideration when deciding the best treatment for acute gout. The ACR recommendations do not provide specific guidance on NSAID use in CKD but suggest the potential option of tapering the dose as pain begins to resolve. There is mixed evidence that NSAIDs accelerate CKD progression with the best evidence for high-dose NSAID use.¹⁷ When prescribing the concomitant use of NSAIDs with other medications affecting kidney function, HCPs should consider CKD.

For colchicine, current labeling and evidence indicate that no dose adjustments are needed for stage 3 or better CKD (eGFR ≥ 60 mL/min) even among the elderly.^18,19 Although labeling indicates that a single unadjusted dose (0.6 mg) can be given once every 2 weeks for those with severe CKD (eGFR < 30 mL/min) or for those who are on dialysis, alternative therapies should be considered, as AEs increase with decreasing renal function.¹⁹ Colchicine should not be used in those with eGFR < 10 mL/min.²⁰ All patients who have CKD and are treated with colchicine should be informed of the AEs and closely observed for signs of toxicity, including blood dyscrasias, neuromyopathy, emesis, or diarrhea.

Considering the potential complications for NSAIDs and colchicine, patients with CKD may be good candidates for glucocorticoid therapy, administered either systemically or as an intra-articular injection. Alternatively, second-line agents such as ACTH or IL-1 inhibition may be considered in such patients.

Hypertension

Hypertension is one of the most common comorbidities among patients with gout. It is important for HCP consideration when deciding treatment. Poorly controlled hypertension is a contraindication for both NSAIDs and systemic glucocorticoids. Patients with hypertension in the absence of significant renal impairment may be good candidates for colchicine.

Diabetes and Hyperlipidemia

Glucocorticoids should be avoided if possible in the setting of inadequately controlled type 2 DM (T2DM) or hyperlipidemia. Glucocorticoids exacerbate insulin resistance and stimulate glucose secretion from the liver. This can create substantial and sometimes dangerous fluctuations in circulating glucose concentrations. Additionally, glucocorticoids may increase serum triglycerides and low-density lipoprotein levels. Thus, patients with T2DM or hyperlipidemia may be good candidates for alternative treatments, such as colchicine or NSAIDs.

Cardiovascular Disease

Cardiovascular disease risk has been shown to increase with the use of COX-2 inhibitors. This risk may be present for all NSAIDs. Current FDA labeling suggests limiting NSAID and COX-2 inhibitor use in patients with a history of myocardial infarction (MI), congestive heart failure, or stroke. Given the potential impact on cardiovascular risk factors, including hypertension, T2DM, and hyperlipidemia, glucocorticoids may not be ideal for patients with known CVD or those at high risk.

Recent evidence has shown that colchicine use is associated with a lower risk of MI among patients with gout.²¹ These results, in addition to a proposed dual role of IL-1 in both gout and CVD, suggest that either colchicine or IL-1 inhibitors may be rational agents in the treatment of acute gout in the context of CVD.²²

Hepatic Impairment and GI Bleeding

Patients with cirrhosis should avoid NSAID use due to the potential increased bleeding risk from underlying coagulopathy. Additionally, colchicine clearance may be reduced in patients with severe liver impairment, mandating close surveillance when this agent is used. If hepatic impairment is mild to moderate, judicious use of any of the first-line therapies may be appropriate.

Patients with GI bleeding or a history of peptic ulcer disease should avoid NSAID use because of increased bleeding risk. If an NSAID is used, proton pump inhibitors decrease the risk of NSAID-associated mucosal damage.

Drug Interactions

Colchicine is metabolized by the cytochrome P450 3A4 enzyme (CYP3A4) and is a substrate for P-glycoprotein (P-gp). Therefore, concomitant use of colchicine with potent inhibitors of CYP3A4 or P-gp should be avoided when possible. These agents include macrolide antibiotics (clarithromyocin), calcium channel blockers (verapamil and diltiazem), and cyclosporine (commonly used in transplant patients who are at high risk for gout). New evidence-based dosing recommendations indicate that no dose reduction is required with azithromyocin.²³

Nonsteroidal anti-inflammatory drugs are contraindicated with the concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics. Prostaglandin production is decreased while using NSAIDs, resulting in increased constriction of afferent renal arterioles and decreased glomerular filtration pressure. This physiologic effect of NSAIDs can be exacerbated when used in combination with ACE inhibitors or diuretics, both of which can also reduce glomerular filtration pressures. Combination therapy with either ACE inhibitors or diuretics increases the risk for NSAID-mediated acute kidney injury. Additionally, NSAID use should be avoided in patients taking anticoagulants such as warfarin or heparin due to increased bleeding risk.

Diagnosis

Diagnosis is a key component of proper treatment of acute gout. A gout diagnosis is usually made based on clinical signs and symptoms, including sudden onset of pain that peaks within 24 hours, past history of acute self-limited attacks of arthritis, first MTP involvement, and an elevated sUA. However, not all these factors must be present. In a study conducted by Janssens and colleagues, these factors plus additional demographics had a sensitivity of 90% and specificity of 65% when compared with crystal diagnosis.²⁴ However, a normal sUA level does not exclude gout as a diagnosis due to the uricosuric effect of the inflammatory process.²⁵ In fact, one observational cohort recorded an average sUA decrease from baseline of 2 mg/dL during an acute gout attack.²⁶

Alternative diagnoses, including septic arthritis, should be considered, particularly in the context of treatment failure (< 50% reduction in pain) within the first 24 to 48 hours. A definitive diagnosis is made by identifying negatively birefringent crystals in the synovial fluid of the affected joint (using polarized microscopy) with negative cultures. In the absence of crystal confirmation, there is an emerging role for imaging in gout diagnosis, including the use of ultrasound and dual-energy computed tomography.²⁷

Long-term Treatment Considerations

During treatment for acute gout attacks, urate-lowering therapy that was initiated before the attack should not be discontinued.²⁸ There is no evidence to suggest that current urate lowering has any AEs during attacks. However, removing treatment may increase sUA levels, precipitating attacks in other joints by “destabilizing” crystals still present. Current recommendations also state that urate-lowering therapy may be started during an attack despite traditionally being deferred until the attack has resolved.²⁸ In a randomized trial comparing a group starting allopurinol 300 mg during an attack vs a placebo group (with all patients receiving anti-inflammatory treatment for the acute attack), there was no difference in pain outcomes.²⁹ Regardless of the chosen timing, lowering and maintaining sUA ≤ 6.0 mg/dL is the primary method for minimizing long-term risk of gout attacks.²⁸

Health care providers should discuss with patients the likely need for indefinite urate-lowering therapy while noting that attacks related to therapy initiation are relatively common.³⁰ Current guidelines recommend starting urate-lowering therapy in low doses (≤ 100 mg/d for allopurinol) and titrating to achieve and maintain the target sUA level. Along with the judicious use of anti-inflammatory prophylaxis, this may minimize attacks related to therapy initiation.^3,28 By lowering and maintaining sUA below the target level, monosodium urate crystals will dissolve, thereby eliminating the major inciting factor of acute attacks.

Other day-to-day triggers such as alcohol, meat or seafood consumption, and dehydration exist for some patients with gout. Patients should be informed of these inciting factors, as they could potentially be avoided, reducing the risk of future gout attacks. It is important to recognize, however, that dietary or behavioral interventions have generally yielded only modest sUA reductions. For the majority of patients, therefore, reduction and maintenance of sUA ≤ 6.0 mg/dL requires pharmacologic intervention.

Conclusions

Gout attacks should be treated immediately with pharmacologic treatment when contraindications are absent. First-line treatment options include NSAIDs, colchicine, and systemic glucocorticoids. Use of these modalities can be complicated because of comorbidity and concomitant medication use that is prevalent among patients with gout. Comorbidities commonly limiting treatment choice include hypertension (NSAIDs, glucocorticoids), CKD (NSAIDS, colchicine), CVD (NSAIDs, COX-2 inhibitors, glucocorticoids), T2DM (glucocorticoids), and liver disease (NSAIDs, colchicine). Careful consideration must be given to these comorbidities and contraindications as well as patient preferences.

Gout is an extremely painful arthritis initiated by innate immune responses to monosodium urate crystals that accumulate in affected joints and surrounding tissues. As a result, gout is characterized by painful arthritis flares followed by intervening periods of disease quiescence. Over time, gout can lead to chronic pain, disability, and tophi. Nearly 10% of those aged > 65 years report having gout. The overall prevalence in the U.S. population approaches 4%.¹

Gout treatment has 2 overarching goals: alleviating the pain and inflammation caused by acute gout attacks and long-term management that is focused on lowering serum urate (sUA) levels to reduce the risk of future attacks. Alleviating the pain and inflammation of an acute attack is often complicated by patient characteristics, namely, other chronic health conditions that frequently accompany gout, such as diabetes mellitus (DM), chronic kidney disease (CKD), hypertension, and cardiovascular disease (CVD).

Patients with gout tend to be older and have multiple comorbidities that require the use of many medications.² Because the VA patient population tends to be older, acute gout and attendant complications of treatment are an important consideration for VA health care providers (HCPs).

Recently, the American College of Rheumatology (ACR) released management recommendations for gout, including those for the treatment of acute gout.³ The ACR recommends 3 first-line therapies, but limited guidance is provided for deciding among therapies. This article briefly reviews the relevant ACR recommendations and details important comorbidity and concomitant medication considerations in the treatment of acute gout.

Acute Gout Characteristics

Acute gout attacks are characterized by a rapid onset and escalation with joint pain typically peaking within 24 hours of attack onset. An acute attack often begins to remit after 5 to 12 days without intervention, but complete resolution may take longer in some patients.⁴ In one study, at 24 hours after attack onset, 16% of patients on placebo had > 50% reduction in pain compared with 70% that had no recovery at all.⁵ By 48 hours, one-third of patients on placebo achieved a 50% reduction in pain.⁶

Treatment Recommendations

Therapy for acute gout attacks aims to reduce pain and promote a full, early resolution. The ACR recommends pharmacologic therapy as first-line treatment with adjunctive topical ice and rest as needed.³ Typically, monotherapy is appropriate if the individual is experiencing mild-to-moderate pain affecting ≤ 2 joints of any size. Severe pain or attacks affecting multiple joints may benefit from initial combination therapy. Three first-line therapies are available: nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors, colchicine, or systemic glucocorticoids (Figure 2).

Few studies compare the efficacy of first-line therapeutic categories. There are no clinical trials directly comparing colchicine with NSAIDs or colchicine with glucocorticoids. No difference in mean reduction of pain and no differences in adverse events (AEs) were shown in a trial that compared glucocorticoids with NSAIDs.⁸ Thus, without further study, treatment choices made by HCPs are often guided by factors other than the existence of robust evidence.

Treatment with NSAIDs or COX-2 inhibitors should be initiated at the approved dose and continued until the gout attack has completely resolved. In one study, 73% of patients had pain reduction of ≥ 50% when taking NSAIDs relative to only 27% of patients on placebo.⁸ All available NSAIDs are considered effective, but only 3 NSAIDs are specifically approved for treatment of acute gout (naproxen, indomethacin, and sulindac). There is no evidence supporting one NSAID as being more effective than another; evidence fails to show a meaningful difference.⁸ Limited evidence indicates that selective COX-2 inhibitors, including celexocib, have similar efficacy as nonselective NSAIDs but may have fewer AEs, driven in part by fewer gastrointestinal (GI) events (6% vs 16% for GI events).⁸

Colchicine has long been used as prophylaxis for acute gout attacks and has been endorsed for the treatment of acute attacks. Recent evidence suggests that colchicine initially dosed at 1.2 mg followed by a single 0.6-mg dose 1 hour later is as effective with fewer AEs compared with a traditional regimen of 1.2 mg followed by 0.6 mg every hour for up to 6 hours.⁵ About 40% of patients have 50% pain reduction within 24 hours and a 40% absolute risk reduction in AEs on this low-dose regimen. The efficacy of colchicine relative to other therapies is poorly defined, especially for patients presenting longer after attack onset. The ACR guidelines recommend colchicine only if treatment is initiated within 36 hours of attack onset, but this is based solely on expert consensus. Likewise, the above trial for low-dose colchicine did not provide information about dosing beyond the first 6 hours, leaving little guidance for follow-up treatment of residual pain beyond the 32 hours reported.⁵ Traditionally, one 0.6-mg dose is provided every 12 to 24 hours.³

Systemic glucocorticoids are also commonly used in treating acute gout.⁹ There was a small pain reduction benefit for prednisolone, but the difference was not clinically significant in one clinical trial comparing oral prednisolone 30 mg daily for 5 days vs a combination of indomethacin for 5 days and an initial intramuscular injection of diclofenac 75 mg.¹⁰ The prednisolone group also had fewer patients with AEs, including abdominal pain (0% vs 30%) and GI bleeding (0% vs 11%). The lower incidence of short-term AEs may be a primary benefit of systemic glucocorticoids.¹¹

Intra-articular glucocorticoids are not suggested first-line therapies but are commonly used by rheumatologists.⁹ In an uncontrolled study conducted by Fernández and colleagues, intra-articular glucocorticoid injections helped to quickly resolve 20 out of 20 crystal-proven gout attacks.¹² However, no randomized controlled trials have examined this approach. Although seemingly efficacious, other considerations are important for this modality. Intra-articular glucocorticoids may not be preferred for polyarticular attacks or attacks in difficult-to-aspirate joints. Additionally, intra-articular glucocorticoids have been anecdotally associated with rebound attacks (ie, attacks that occur shortly after resolution without other interventions). However, the Fernández study had no such attacks occur among participants.¹² Finally, septic arthritis must be ruled out as in any case of acute onset monoarticular arthritis.

Biologic agents targeting interleukin-1(IL-1) are not currently approved for gout, although there is burgeoning data suggesting that this strategy may have substantial merit.¹³ Additionally, there is limited evidence that adrenocorticotropic hormone (ACTH) may provide rapid pain relief when other available therapies are ineffective or contraindicated. However, ACTH studies have not provided robust trial designs, and drug costs remain substantial, thus limiting the widespread use of ACTH in acute gout.^14,15 Anti-IL-1 agents and ACTH may both be considered as second-line options if first-line therapies are contraindicated or fail. Careful consideration should be given to AE profiles, patient preferences, and cost.

Comorbidities

Acute gout care, especially in the context of comorbidities, has been identified as a critical treatment concern by an international panel of rheumatologists as part of the 3e (Evidence, Expertise, Exchange) Initiative.¹⁶ However, regular clinical trial exclusion criteria have limited data necessary to guide treatment when comorbidities are present. Therefore, studies of acute gout treatment in the context of disease comorbidity represents a major unmet need in understanding and optimizing gout care.

Chronic Kidney Disease

Chronic kidney disease is common in gout; 20% of patients with gout have an estimated glomerular filtration rate (eGFR) of < 30 mL/min.² Thus, CKD is an important consideration when deciding the best treatment for acute gout. The ACR recommendations do not provide specific guidance on NSAID use in CKD but suggest the potential option of tapering the dose as pain begins to resolve. There is mixed evidence that NSAIDs accelerate CKD progression with the best evidence for high-dose NSAID use.¹⁷ When prescribing the concomitant use of NSAIDs with other medications affecting kidney function, HCPs should consider CKD.

For colchicine, current labeling and evidence indicate that no dose adjustments are needed for stage 3 or better CKD (eGFR ≥ 60 mL/min) even among the elderly.^18,19 Although labeling indicates that a single unadjusted dose (0.6 mg) can be given once every 2 weeks for those with severe CKD (eGFR < 30 mL/min) or for those who are on dialysis, alternative therapies should be considered, as AEs increase with decreasing renal function.¹⁹ Colchicine should not be used in those with eGFR < 10 mL/min.²⁰ All patients who have CKD and are treated with colchicine should be informed of the AEs and closely observed for signs of toxicity, including blood dyscrasias, neuromyopathy, emesis, or diarrhea.

Considering the potential complications for NSAIDs and colchicine, patients with CKD may be good candidates for glucocorticoid therapy, administered either systemically or as an intra-articular injection. Alternatively, second-line agents such as ACTH or IL-1 inhibition may be considered in such patients.

Hypertension

Hypertension is one of the most common comorbidities among patients with gout. It is important for HCP consideration when deciding treatment. Poorly controlled hypertension is a contraindication for both NSAIDs and systemic glucocorticoids. Patients with hypertension in the absence of significant renal impairment may be good candidates for colchicine.

Diabetes and Hyperlipidemia

Glucocorticoids should be avoided if possible in the setting of inadequately controlled type 2 DM (T2DM) or hyperlipidemia. Glucocorticoids exacerbate insulin resistance and stimulate glucose secretion from the liver. This can create substantial and sometimes dangerous fluctuations in circulating glucose concentrations. Additionally, glucocorticoids may increase serum triglycerides and low-density lipoprotein levels. Thus, patients with T2DM or hyperlipidemia may be good candidates for alternative treatments, such as colchicine or NSAIDs.

Cardiovascular Disease

Cardiovascular disease risk has been shown to increase with the use of COX-2 inhibitors. This risk may be present for all NSAIDs. Current FDA labeling suggests limiting NSAID and COX-2 inhibitor use in patients with a history of myocardial infarction (MI), congestive heart failure, or stroke. Given the potential impact on cardiovascular risk factors, including hypertension, T2DM, and hyperlipidemia, glucocorticoids may not be ideal for patients with known CVD or those at high risk.

Recent evidence has shown that colchicine use is associated with a lower risk of MI among patients with gout.²¹ These results, in addition to a proposed dual role of IL-1 in both gout and CVD, suggest that either colchicine or IL-1 inhibitors may be rational agents in the treatment of acute gout in the context of CVD.²²

Hepatic Impairment and GI Bleeding

Patients with cirrhosis should avoid NSAID use due to the potential increased bleeding risk from underlying coagulopathy. Additionally, colchicine clearance may be reduced in patients with severe liver impairment, mandating close surveillance when this agent is used. If hepatic impairment is mild to moderate, judicious use of any of the first-line therapies may be appropriate.

Patients with GI bleeding or a history of peptic ulcer disease should avoid NSAID use because of increased bleeding risk. If an NSAID is used, proton pump inhibitors decrease the risk of NSAID-associated mucosal damage.

Drug Interactions

Colchicine is metabolized by the cytochrome P450 3A4 enzyme (CYP3A4) and is a substrate for P-glycoprotein (P-gp). Therefore, concomitant use of colchicine with potent inhibitors of CYP3A4 or P-gp should be avoided when possible. These agents include macrolide antibiotics (clarithromyocin), calcium channel blockers (verapamil and diltiazem), and cyclosporine (commonly used in transplant patients who are at high risk for gout). New evidence-based dosing recommendations indicate that no dose reduction is required with azithromyocin.²³

Nonsteroidal anti-inflammatory drugs are contraindicated with the concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics. Prostaglandin production is decreased while using NSAIDs, resulting in increased constriction of afferent renal arterioles and decreased glomerular filtration pressure. This physiologic effect of NSAIDs can be exacerbated when used in combination with ACE inhibitors or diuretics, both of which can also reduce glomerular filtration pressures. Combination therapy with either ACE inhibitors or diuretics increases the risk for NSAID-mediated acute kidney injury. Additionally, NSAID use should be avoided in patients taking anticoagulants such as warfarin or heparin due to increased bleeding risk.

Diagnosis

Diagnosis is a key component of proper treatment of acute gout. A gout diagnosis is usually made based on clinical signs and symptoms, including sudden onset of pain that peaks within 24 hours, past history of acute self-limited attacks of arthritis, first MTP involvement, and an elevated sUA. However, not all these factors must be present. In a study conducted by Janssens and colleagues, these factors plus additional demographics had a sensitivity of 90% and specificity of 65% when compared with crystal diagnosis.²⁴ However, a normal sUA level does not exclude gout as a diagnosis due to the uricosuric effect of the inflammatory process.²⁵ In fact, one observational cohort recorded an average sUA decrease from baseline of 2 mg/dL during an acute gout attack.²⁶

Alternative diagnoses, including septic arthritis, should be considered, particularly in the context of treatment failure (< 50% reduction in pain) within the first 24 to 48 hours. A definitive diagnosis is made by identifying negatively birefringent crystals in the synovial fluid of the affected joint (using polarized microscopy) with negative cultures. In the absence of crystal confirmation, there is an emerging role for imaging in gout diagnosis, including the use of ultrasound and dual-energy computed tomography.²⁷

Long-term Treatment Considerations

During treatment for acute gout attacks, urate-lowering therapy that was initiated before the attack should not be discontinued.²⁸ There is no evidence to suggest that current urate lowering has any AEs during attacks. However, removing treatment may increase sUA levels, precipitating attacks in other joints by “destabilizing” crystals still present. Current recommendations also state that urate-lowering therapy may be started during an attack despite traditionally being deferred until the attack has resolved.²⁸ In a randomized trial comparing a group starting allopurinol 300 mg during an attack vs a placebo group (with all patients receiving anti-inflammatory treatment for the acute attack), there was no difference in pain outcomes.²⁹ Regardless of the chosen timing, lowering and maintaining sUA ≤ 6.0 mg/dL is the primary method for minimizing long-term risk of gout attacks.²⁸

Health care providers should discuss with patients the likely need for indefinite urate-lowering therapy while noting that attacks related to therapy initiation are relatively common.³⁰ Current guidelines recommend starting urate-lowering therapy in low doses (≤ 100 mg/d for allopurinol) and titrating to achieve and maintain the target sUA level. Along with the judicious use of anti-inflammatory prophylaxis, this may minimize attacks related to therapy initiation.^3,28 By lowering and maintaining sUA below the target level, monosodium urate crystals will dissolve, thereby eliminating the major inciting factor of acute attacks.

Other day-to-day triggers such as alcohol, meat or seafood consumption, and dehydration exist for some patients with gout. Patients should be informed of these inciting factors, as they could potentially be avoided, reducing the risk of future gout attacks. It is important to recognize, however, that dietary or behavioral interventions have generally yielded only modest sUA reductions. For the majority of patients, therefore, reduction and maintenance of sUA ≤ 6.0 mg/dL requires pharmacologic intervention.

Conclusions

Gout attacks should be treated immediately with pharmacologic treatment when contraindications are absent. First-line treatment options include NSAIDs, colchicine, and systemic glucocorticoids. Use of these modalities can be complicated because of comorbidity and concomitant medication use that is prevalent among patients with gout. Comorbidities commonly limiting treatment choice include hypertension (NSAIDs, glucocorticoids), CKD (NSAIDS, colchicine), CVD (NSAIDs, COX-2 inhibitors, glucocorticoids), T2DM (glucocorticoids), and liver disease (NSAIDs, colchicine). Careful consideration must be given to these comorbidities and contraindications as well as patient preferences.

Gout is an extremely painful arthritis initiated by innate immune responses to monosodium urate crystals that accumulate in affected joints and surrounding tissues. As a result, gout is characterized by painful arthritis flares followed by intervening periods of disease quiescence. Over time, gout can lead to chronic pain, disability, and tophi. Nearly 10% of those aged > 65 years report having gout. The overall prevalence in the U.S. population approaches 4%.¹

Gout treatment has 2 overarching goals: alleviating the pain and inflammation caused by acute gout attacks and long-term management that is focused on lowering serum urate (sUA) levels to reduce the risk of future attacks. Alleviating the pain and inflammation of an acute attack is often complicated by patient characteristics, namely, other chronic health conditions that frequently accompany gout, such as diabetes mellitus (DM), chronic kidney disease (CKD), hypertension, and cardiovascular disease (CVD).

Patients with gout tend to be older and have multiple comorbidities that require the use of many medications.² Because the VA patient population tends to be older, acute gout and attendant complications of treatment are an important consideration for VA health care providers (HCPs).

Recently, the American College of Rheumatology (ACR) released management recommendations for gout, including those for the treatment of acute gout.³ The ACR recommends 3 first-line therapies, but limited guidance is provided for deciding among therapies. This article briefly reviews the relevant ACR recommendations and details important comorbidity and concomitant medication considerations in the treatment of acute gout.

Acute Gout Characteristics

Acute gout attacks are characterized by a rapid onset and escalation with joint pain typically peaking within 24 hours of attack onset. An acute attack often begins to remit after 5 to 12 days without intervention, but complete resolution may take longer in some patients.⁴ In one study, at 24 hours after attack onset, 16% of patients on placebo had > 50% reduction in pain compared with 70% that had no recovery at all.⁵ By 48 hours, one-third of patients on placebo achieved a 50% reduction in pain.⁶

Treatment Recommendations

Therapy for acute gout attacks aims to reduce pain and promote a full, early resolution. The ACR recommends pharmacologic therapy as first-line treatment with adjunctive topical ice and rest as needed.³ Typically, monotherapy is appropriate if the individual is experiencing mild-to-moderate pain affecting ≤ 2 joints of any size. Severe pain or attacks affecting multiple joints may benefit from initial combination therapy. Three first-line therapies are available: nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors, colchicine, or systemic glucocorticoids (Figure 2).

Few studies compare the efficacy of first-line therapeutic categories. There are no clinical trials directly comparing colchicine with NSAIDs or colchicine with glucocorticoids. No difference in mean reduction of pain and no differences in adverse events (AEs) were shown in a trial that compared glucocorticoids with NSAIDs.⁸ Thus, without further study, treatment choices made by HCPs are often guided by factors other than the existence of robust evidence.

Treatment with NSAIDs or COX-2 inhibitors should be initiated at the approved dose and continued until the gout attack has completely resolved. In one study, 73% of patients had pain reduction of ≥ 50% when taking NSAIDs relative to only 27% of patients on placebo.⁸ All available NSAIDs are considered effective, but only 3 NSAIDs are specifically approved for treatment of acute gout (naproxen, indomethacin, and sulindac). There is no evidence supporting one NSAID as being more effective than another; evidence fails to show a meaningful difference.⁸ Limited evidence indicates that selective COX-2 inhibitors, including celexocib, have similar efficacy as nonselective NSAIDs but may have fewer AEs, driven in part by fewer gastrointestinal (GI) events (6% vs 16% for GI events).⁸

Colchicine has long been used as prophylaxis for acute gout attacks and has been endorsed for the treatment of acute attacks. Recent evidence suggests that colchicine initially dosed at 1.2 mg followed by a single 0.6-mg dose 1 hour later is as effective with fewer AEs compared with a traditional regimen of 1.2 mg followed by 0.6 mg every hour for up to 6 hours.⁵ About 40% of patients have 50% pain reduction within 24 hours and a 40% absolute risk reduction in AEs on this low-dose regimen. The efficacy of colchicine relative to other therapies is poorly defined, especially for patients presenting longer after attack onset. The ACR guidelines recommend colchicine only if treatment is initiated within 36 hours of attack onset, but this is based solely on expert consensus. Likewise, the above trial for low-dose colchicine did not provide information about dosing beyond the first 6 hours, leaving little guidance for follow-up treatment of residual pain beyond the 32 hours reported.⁵ Traditionally, one 0.6-mg dose is provided every 12 to 24 hours.³

Systemic glucocorticoids are also commonly used in treating acute gout.⁹ There was a small pain reduction benefit for prednisolone, but the difference was not clinically significant in one clinical trial comparing oral prednisolone 30 mg daily for 5 days vs a combination of indomethacin for 5 days and an initial intramuscular injection of diclofenac 75 mg.¹⁰ The prednisolone group also had fewer patients with AEs, including abdominal pain (0% vs 30%) and GI bleeding (0% vs 11%). The lower incidence of short-term AEs may be a primary benefit of systemic glucocorticoids.¹¹

Intra-articular glucocorticoids are not suggested first-line therapies but are commonly used by rheumatologists.⁹ In an uncontrolled study conducted by Fernández and colleagues, intra-articular glucocorticoid injections helped to quickly resolve 20 out of 20 crystal-proven gout attacks.¹² However, no randomized controlled trials have examined this approach. Although seemingly efficacious, other considerations are important for this modality. Intra-articular glucocorticoids may not be preferred for polyarticular attacks or attacks in difficult-to-aspirate joints. Additionally, intra-articular glucocorticoids have been anecdotally associated with rebound attacks (ie, attacks that occur shortly after resolution without other interventions). However, the Fernández study had no such attacks occur among participants.¹² Finally, septic arthritis must be ruled out as in any case of acute onset monoarticular arthritis.

Biologic agents targeting interleukin-1(IL-1) are not currently approved for gout, although there is burgeoning data suggesting that this strategy may have substantial merit.¹³ Additionally, there is limited evidence that adrenocorticotropic hormone (ACTH) may provide rapid pain relief when other available therapies are ineffective or contraindicated. However, ACTH studies have not provided robust trial designs, and drug costs remain substantial, thus limiting the widespread use of ACTH in acute gout.^14,15 Anti-IL-1 agents and ACTH may both be considered as second-line options if first-line therapies are contraindicated or fail. Careful consideration should be given to AE profiles, patient preferences, and cost.

Comorbidities

Acute gout care, especially in the context of comorbidities, has been identified as a critical treatment concern by an international panel of rheumatologists as part of the 3e (Evidence, Expertise, Exchange) Initiative.¹⁶ However, regular clinical trial exclusion criteria have limited data necessary to guide treatment when comorbidities are present. Therefore, studies of acute gout treatment in the context of disease comorbidity represents a major unmet need in understanding and optimizing gout care.

Chronic Kidney Disease

Chronic kidney disease is common in gout; 20% of patients with gout have an estimated glomerular filtration rate (eGFR) of < 30 mL/min.² Thus, CKD is an important consideration when deciding the best treatment for acute gout. The ACR recommendations do not provide specific guidance on NSAID use in CKD but suggest the potential option of tapering the dose as pain begins to resolve. There is mixed evidence that NSAIDs accelerate CKD progression with the best evidence for high-dose NSAID use.¹⁷ When prescribing the concomitant use of NSAIDs with other medications affecting kidney function, HCPs should consider CKD.

For colchicine, current labeling and evidence indicate that no dose adjustments are needed for stage 3 or better CKD (eGFR ≥ 60 mL/min) even among the elderly.^18,19 Although labeling indicates that a single unadjusted dose (0.6 mg) can be given once every 2 weeks for those with severe CKD (eGFR < 30 mL/min) or for those who are on dialysis, alternative therapies should be considered, as AEs increase with decreasing renal function.¹⁹ Colchicine should not be used in those with eGFR < 10 mL/min.²⁰ All patients who have CKD and are treated with colchicine should be informed of the AEs and closely observed for signs of toxicity, including blood dyscrasias, neuromyopathy, emesis, or diarrhea.

Considering the potential complications for NSAIDs and colchicine, patients with CKD may be good candidates for glucocorticoid therapy, administered either systemically or as an intra-articular injection. Alternatively, second-line agents such as ACTH or IL-1 inhibition may be considered in such patients.

Hypertension

Hypertension is one of the most common comorbidities among patients with gout. It is important for HCP consideration when deciding treatment. Poorly controlled hypertension is a contraindication for both NSAIDs and systemic glucocorticoids. Patients with hypertension in the absence of significant renal impairment may be good candidates for colchicine.

Diabetes and Hyperlipidemia

Glucocorticoids should be avoided if possible in the setting of inadequately controlled type 2 DM (T2DM) or hyperlipidemia. Glucocorticoids exacerbate insulin resistance and stimulate glucose secretion from the liver. This can create substantial and sometimes dangerous fluctuations in circulating glucose concentrations. Additionally, glucocorticoids may increase serum triglycerides and low-density lipoprotein levels. Thus, patients with T2DM or hyperlipidemia may be good candidates for alternative treatments, such as colchicine or NSAIDs.

Cardiovascular Disease

Cardiovascular disease risk has been shown to increase with the use of COX-2 inhibitors. This risk may be present for all NSAIDs. Current FDA labeling suggests limiting NSAID and COX-2 inhibitor use in patients with a history of myocardial infarction (MI), congestive heart failure, or stroke. Given the potential impact on cardiovascular risk factors, including hypertension, T2DM, and hyperlipidemia, glucocorticoids may not be ideal for patients with known CVD or those at high risk.

Recent evidence has shown that colchicine use is associated with a lower risk of MI among patients with gout.²¹ These results, in addition to a proposed dual role of IL-1 in both gout and CVD, suggest that either colchicine or IL-1 inhibitors may be rational agents in the treatment of acute gout in the context of CVD.²²

Hepatic Impairment and GI Bleeding

Patients with cirrhosis should avoid NSAID use due to the potential increased bleeding risk from underlying coagulopathy. Additionally, colchicine clearance may be reduced in patients with severe liver impairment, mandating close surveillance when this agent is used. If hepatic impairment is mild to moderate, judicious use of any of the first-line therapies may be appropriate.

Patients with GI bleeding or a history of peptic ulcer disease should avoid NSAID use because of increased bleeding risk. If an NSAID is used, proton pump inhibitors decrease the risk of NSAID-associated mucosal damage.

Drug Interactions

Colchicine is metabolized by the cytochrome P450 3A4 enzyme (CYP3A4) and is a substrate for P-glycoprotein (P-gp). Therefore, concomitant use of colchicine with potent inhibitors of CYP3A4 or P-gp should be avoided when possible. These agents include macrolide antibiotics (clarithromyocin), calcium channel blockers (verapamil and diltiazem), and cyclosporine (commonly used in transplant patients who are at high risk for gout). New evidence-based dosing recommendations indicate that no dose reduction is required with azithromyocin.²³

Nonsteroidal anti-inflammatory drugs are contraindicated with the concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics. Prostaglandin production is decreased while using NSAIDs, resulting in increased constriction of afferent renal arterioles and decreased glomerular filtration pressure. This physiologic effect of NSAIDs can be exacerbated when used in combination with ACE inhibitors or diuretics, both of which can also reduce glomerular filtration pressures. Combination therapy with either ACE inhibitors or diuretics increases the risk for NSAID-mediated acute kidney injury. Additionally, NSAID use should be avoided in patients taking anticoagulants such as warfarin or heparin due to increased bleeding risk.

Diagnosis

Diagnosis is a key component of proper treatment of acute gout. A gout diagnosis is usually made based on clinical signs and symptoms, including sudden onset of pain that peaks within 24 hours, past history of acute self-limited attacks of arthritis, first MTP involvement, and an elevated sUA. However, not all these factors must be present. In a study conducted by Janssens and colleagues, these factors plus additional demographics had a sensitivity of 90% and specificity of 65% when compared with crystal diagnosis.²⁴ However, a normal sUA level does not exclude gout as a diagnosis due to the uricosuric effect of the inflammatory process.²⁵ In fact, one observational cohort recorded an average sUA decrease from baseline of 2 mg/dL during an acute gout attack.²⁶

Alternative diagnoses, including septic arthritis, should be considered, particularly in the context of treatment failure (< 50% reduction in pain) within the first 24 to 48 hours. A definitive diagnosis is made by identifying negatively birefringent crystals in the synovial fluid of the affected joint (using polarized microscopy) with negative cultures. In the absence of crystal confirmation, there is an emerging role for imaging in gout diagnosis, including the use of ultrasound and dual-energy computed tomography.²⁷

Long-term Treatment Considerations

During treatment for acute gout attacks, urate-lowering therapy that was initiated before the attack should not be discontinued.²⁸ There is no evidence to suggest that current urate lowering has any AEs during attacks. However, removing treatment may increase sUA levels, precipitating attacks in other joints by “destabilizing” crystals still present. Current recommendations also state that urate-lowering therapy may be started during an attack despite traditionally being deferred until the attack has resolved.²⁸ In a randomized trial comparing a group starting allopurinol 300 mg during an attack vs a placebo group (with all patients receiving anti-inflammatory treatment for the acute attack), there was no difference in pain outcomes.²⁹ Regardless of the chosen timing, lowering and maintaining sUA ≤ 6.0 mg/dL is the primary method for minimizing long-term risk of gout attacks.²⁸

Health care providers should discuss with patients the likely need for indefinite urate-lowering therapy while noting that attacks related to therapy initiation are relatively common.³⁰ Current guidelines recommend starting urate-lowering therapy in low doses (≤ 100 mg/d for allopurinol) and titrating to achieve and maintain the target sUA level. Along with the judicious use of anti-inflammatory prophylaxis, this may minimize attacks related to therapy initiation.^3,28 By lowering and maintaining sUA below the target level, monosodium urate crystals will dissolve, thereby eliminating the major inciting factor of acute attacks.

Other day-to-day triggers such as alcohol, meat or seafood consumption, and dehydration exist for some patients with gout. Patients should be informed of these inciting factors, as they could potentially be avoided, reducing the risk of future gout attacks. It is important to recognize, however, that dietary or behavioral interventions have generally yielded only modest sUA reductions. For the majority of patients, therefore, reduction and maintenance of sUA ≤ 6.0 mg/dL requires pharmacologic intervention.

Conclusions

Gout attacks should be treated immediately with pharmacologic treatment when contraindications are absent. First-line treatment options include NSAIDs, colchicine, and systemic glucocorticoids. Use of these modalities can be complicated because of comorbidity and concomitant medication use that is prevalent among patients with gout. Comorbidities commonly limiting treatment choice include hypertension (NSAIDs, glucocorticoids), CKD (NSAIDS, colchicine), CVD (NSAIDs, COX-2 inhibitors, glucocorticoids), T2DM (glucocorticoids), and liver disease (NSAIDs, colchicine). Careful consideration must be given to these comorbidities and contraindications as well as patient preferences.