In this issue of JFP, MacLaughlin and colleagues echo the recommendations of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on high blood pressure (BP).¹

This guideline, however, is not endorsed by primary care organizations. Both the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their own evidence-based guideline in 2017.² (The European Society of Cardiology also declined to endorse the ACC/AHA guideline.³) So how do we make sense of the different recommendations? And how do we decide which guideline is most trustworthy?⁴

Evidence based vs evidence informed

Both guideline writing groups are highly respected and affiliated with influential organizations. Both claim their guidelines are based on scientific evidence and are crafted with the intention to improve health. The 2 guidelines, however, differ in their fidelity to the evidence-based process and in their willingness to generalize disease-centered interventions to non-diseased populations.

Evidence-based guidelines differ from evidence-informed guidelines.

Evidence-based guidelines differ from evidence-informed guidelines. Evidence-based guidelines have an established methodology that includes well-designed specific critical questions, a literature review with clearly defined inclusion and exclusion criteria, an evidence grading system, and a systematic approach to creating recommendations. Evidence-based guidelines are limited in scope and are often controversial because the evidence may not comport with the narrative promulgated by experts. Indeed, the controversy surrounding the 2014 Eighth Joint National Committee (JNC 8) guideline that I co-chaired focused on the one recommendation with the strongest evidence.^5,6

Comprehensive guidelines written by experts are by their very nature evidence-informed guidelines. The ACC/AHA guidelines are comprehensive, providing a panoply of recommendations. When such guidelines are written for primary care, the generalizability of specialized disease-centered knowledge is limited,⁷ and the risk of overdiagnosis and overtreatment rises,⁸ especially when the primary care community is not invited as equal partners in the guideline development process.

Trustworthy guidelines require management of conflicts of interests. A hidden contributor to guideline panel membership and content is organizational sponsorship. Advocacy organizations and specialty societies have governing boards that have fiduciary responsibilities to their organizations. Such responsibilities may supersede the responsibilities of guideline panel members and influence content. JNC 8’s appointed panel members chose to release the 2014 guideline independently, so as not to cede editorial authority to governing boards of associations with potential conflicts of interest.

As Paul Frame said, “An ounce of prevention is a ton of work.”⁹

Dr. Frame, a family medicine pioneer who applied evidence-based medicine to preventive practice, encouraged us to ask critical questions that must be supported by scientific evidence before implementing these practices in healthy populations.¹⁰ The ACC/AHA guidelines advocate recommendations based on untested assumptions: that improved health results from earlier “diagnosis” and disease labeling of individuals with risks (healthy patients), and that such patients should receive aggressive “prevention” with daily and lifelong medications requiring physician monitoring.¹¹ To support their new diagnostic standards, the authors cite similar relative risk (RR) reductions (an outcome-based measure), while discounting the smaller absolute risk (AR) reductions (a population-based measure) in studies supporting lower BP goals.

Continue to: Let's examine what this means

Let’s examine what this means

In 1967, a study of 143 hypertensive patients showed that treating high BP (average diastolic BP between 115 and 129 mm Hg) dramatically improved important health outcomes.¹² The number needed to treat (NNT) after about 1.5 years showed that for every 1.4 people treated, 1 benefited.⁸ This is strong and effective medicine.

We must all advocate for better guideline processes.

Successive randomized controlled trials of lower BP goals showed consistent RR reductions; however, AR reductions were much lower, reflecting a higher NNT.⁸ To prove BP-lowering benefits were not a random effect, higher numbers of participants were needed (SPRINT required over 9300 participants).¹³ The AR reduction in SPRINT was 1.6% (meaning no benefit was seen in 98.4% receiving the intensive intervention). One participant with high cardiovascular disease risk benefited for every 63 subjects given the intensive therapy compared with usual care (BP goal of 120 mm Hg vs 140 mm Hg).^13,14 The researchers noted serious harms in 1 of 22 subjects treated. Treating younger patients to lower BP goals labels healthy people with risk factors as “sick” and commits them to lifelong medications. It exposes them to more frequent harms than benefits. For healthy patients who are unlikely to benefit from taking more antihypertensive medication, these harms matter.

Interpreting the benefits of BP Tx when the benefit to individuals appears small

If only there were a biomarker that could tell us who is most likely to benefit from antihypertensive medication treatment, FPs could ensure that the correct patients are treated. The ACP/AAFP guideline points the way. There is a biomarker, and it is called BP. Systolic BP above 150 mm Hg signals urgency to treat with medications.

A call to advocate. We must all advocate for better guideline processes. The status quo in guideline development and its reliance on special interest funding requires ongoing vigilance to advocate on behalf of our patients. High-value medical care is expensive and hard work. When it is applied to the wrong people at the wrong time, we don’t deliver on our promises.

In this issue of JFP, MacLaughlin and colleagues echo the recommendations of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on high blood pressure (BP).¹

This guideline, however, is not endorsed by primary care organizations. Both the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their own evidence-based guideline in 2017.² (The European Society of Cardiology also declined to endorse the ACC/AHA guideline.³) So how do we make sense of the different recommendations? And how do we decide which guideline is most trustworthy?⁴

Evidence based vs evidence informed

Both guideline writing groups are highly respected and affiliated with influential organizations. Both claim their guidelines are based on scientific evidence and are crafted with the intention to improve health. The 2 guidelines, however, differ in their fidelity to the evidence-based process and in their willingness to generalize disease-centered interventions to non-diseased populations.

Evidence-based guidelines differ from evidence-informed guidelines.

Evidence-based guidelines differ from evidence-informed guidelines. Evidence-based guidelines have an established methodology that includes well-designed specific critical questions, a literature review with clearly defined inclusion and exclusion criteria, an evidence grading system, and a systematic approach to creating recommendations. Evidence-based guidelines are limited in scope and are often controversial because the evidence may not comport with the narrative promulgated by experts. Indeed, the controversy surrounding the 2014 Eighth Joint National Committee (JNC 8) guideline that I co-chaired focused on the one recommendation with the strongest evidence.^5,6

Comprehensive guidelines written by experts are by their very nature evidence-informed guidelines. The ACC/AHA guidelines are comprehensive, providing a panoply of recommendations. When such guidelines are written for primary care, the generalizability of specialized disease-centered knowledge is limited,⁷ and the risk of overdiagnosis and overtreatment rises,⁸ especially when the primary care community is not invited as equal partners in the guideline development process.

Trustworthy guidelines require management of conflicts of interests. A hidden contributor to guideline panel membership and content is organizational sponsorship. Advocacy organizations and specialty societies have governing boards that have fiduciary responsibilities to their organizations. Such responsibilities may supersede the responsibilities of guideline panel members and influence content. JNC 8’s appointed panel members chose to release the 2014 guideline independently, so as not to cede editorial authority to governing boards of associations with potential conflicts of interest.

As Paul Frame said, “An ounce of prevention is a ton of work.”⁹

Dr. Frame, a family medicine pioneer who applied evidence-based medicine to preventive practice, encouraged us to ask critical questions that must be supported by scientific evidence before implementing these practices in healthy populations.¹⁰ The ACC/AHA guidelines advocate recommendations based on untested assumptions: that improved health results from earlier “diagnosis” and disease labeling of individuals with risks (healthy patients), and that such patients should receive aggressive “prevention” with daily and lifelong medications requiring physician monitoring.¹¹ To support their new diagnostic standards, the authors cite similar relative risk (RR) reductions (an outcome-based measure), while discounting the smaller absolute risk (AR) reductions (a population-based measure) in studies supporting lower BP goals.

Continue to: Let's examine what this means

Let’s examine what this means

In 1967, a study of 143 hypertensive patients showed that treating high BP (average diastolic BP between 115 and 129 mm Hg) dramatically improved important health outcomes.¹² The number needed to treat (NNT) after about 1.5 years showed that for every 1.4 people treated, 1 benefited.⁸ This is strong and effective medicine.

We must all advocate for better guideline processes.

Successive randomized controlled trials of lower BP goals showed consistent RR reductions; however, AR reductions were much lower, reflecting a higher NNT.⁸ To prove BP-lowering benefits were not a random effect, higher numbers of participants were needed (SPRINT required over 9300 participants).¹³ The AR reduction in SPRINT was 1.6% (meaning no benefit was seen in 98.4% receiving the intensive intervention). One participant with high cardiovascular disease risk benefited for every 63 subjects given the intensive therapy compared with usual care (BP goal of 120 mm Hg vs 140 mm Hg).^13,14 The researchers noted serious harms in 1 of 22 subjects treated. Treating younger patients to lower BP goals labels healthy people with risk factors as “sick” and commits them to lifelong medications. It exposes them to more frequent harms than benefits. For healthy patients who are unlikely to benefit from taking more antihypertensive medication, these harms matter.

Interpreting the benefits of BP Tx when the benefit to individuals appears small

If only there were a biomarker that could tell us who is most likely to benefit from antihypertensive medication treatment, FPs could ensure that the correct patients are treated. The ACP/AAFP guideline points the way. There is a biomarker, and it is called BP. Systolic BP above 150 mm Hg signals urgency to treat with medications.

A call to advocate. We must all advocate for better guideline processes. The status quo in guideline development and its reliance on special interest funding requires ongoing vigilance to advocate on behalf of our patients. High-value medical care is expensive and hard work. When it is applied to the wrong people at the wrong time, we don’t deliver on our promises.

In this issue of JFP, MacLaughlin and colleagues echo the recommendations of the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on high blood pressure (BP).¹

This guideline, however, is not endorsed by primary care organizations. Both the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) released their own evidence-based guideline in 2017.² (The European Society of Cardiology also declined to endorse the ACC/AHA guideline.³) So how do we make sense of the different recommendations? And how do we decide which guideline is most trustworthy?⁴

Evidence based vs evidence informed

Both guideline writing groups are highly respected and affiliated with influential organizations. Both claim their guidelines are based on scientific evidence and are crafted with the intention to improve health. The 2 guidelines, however, differ in their fidelity to the evidence-based process and in their willingness to generalize disease-centered interventions to non-diseased populations.

Evidence-based guidelines differ from evidence-informed guidelines.

Evidence-based guidelines differ from evidence-informed guidelines. Evidence-based guidelines have an established methodology that includes well-designed specific critical questions, a literature review with clearly defined inclusion and exclusion criteria, an evidence grading system, and a systematic approach to creating recommendations. Evidence-based guidelines are limited in scope and are often controversial because the evidence may not comport with the narrative promulgated by experts. Indeed, the controversy surrounding the 2014 Eighth Joint National Committee (JNC 8) guideline that I co-chaired focused on the one recommendation with the strongest evidence.^5,6

Comprehensive guidelines written by experts are by their very nature evidence-informed guidelines. The ACC/AHA guidelines are comprehensive, providing a panoply of recommendations. When such guidelines are written for primary care, the generalizability of specialized disease-centered knowledge is limited,⁷ and the risk of overdiagnosis and overtreatment rises,⁸ especially when the primary care community is not invited as equal partners in the guideline development process.

Trustworthy guidelines require management of conflicts of interests. A hidden contributor to guideline panel membership and content is organizational sponsorship. Advocacy organizations and specialty societies have governing boards that have fiduciary responsibilities to their organizations. Such responsibilities may supersede the responsibilities of guideline panel members and influence content. JNC 8’s appointed panel members chose to release the 2014 guideline independently, so as not to cede editorial authority to governing boards of associations with potential conflicts of interest.

As Paul Frame said, “An ounce of prevention is a ton of work.”⁹

Dr. Frame, a family medicine pioneer who applied evidence-based medicine to preventive practice, encouraged us to ask critical questions that must be supported by scientific evidence before implementing these practices in healthy populations.¹⁰ The ACC/AHA guidelines advocate recommendations based on untested assumptions: that improved health results from earlier “diagnosis” and disease labeling of individuals with risks (healthy patients), and that such patients should receive aggressive “prevention” with daily and lifelong medications requiring physician monitoring.¹¹ To support their new diagnostic standards, the authors cite similar relative risk (RR) reductions (an outcome-based measure), while discounting the smaller absolute risk (AR) reductions (a population-based measure) in studies supporting lower BP goals.

Continue to: Let's examine what this means

Let’s examine what this means

In 1967, a study of 143 hypertensive patients showed that treating high BP (average diastolic BP between 115 and 129 mm Hg) dramatically improved important health outcomes.¹² The number needed to treat (NNT) after about 1.5 years showed that for every 1.4 people treated, 1 benefited.⁸ This is strong and effective medicine.

We must all advocate for better guideline processes.

Successive randomized controlled trials of lower BP goals showed consistent RR reductions; however, AR reductions were much lower, reflecting a higher NNT.⁸ To prove BP-lowering benefits were not a random effect, higher numbers of participants were needed (SPRINT required over 9300 participants).¹³ The AR reduction in SPRINT was 1.6% (meaning no benefit was seen in 98.4% receiving the intensive intervention). One participant with high cardiovascular disease risk benefited for every 63 subjects given the intensive therapy compared with usual care (BP goal of 120 mm Hg vs 140 mm Hg).^13,14 The researchers noted serious harms in 1 of 22 subjects treated. Treating younger patients to lower BP goals labels healthy people with risk factors as “sick” and commits them to lifelong medications. It exposes them to more frequent harms than benefits. For healthy patients who are unlikely to benefit from taking more antihypertensive medication, these harms matter.

Interpreting the benefits of BP Tx when the benefit to individuals appears small

If only there were a biomarker that could tell us who is most likely to benefit from antihypertensive medication treatment, FPs could ensure that the correct patients are treated. The ACP/AAFP guideline points the way. There is a biomarker, and it is called BP. Systolic BP above 150 mm Hg signals urgency to treat with medications.

A call to advocate. We must all advocate for better guideline processes. The status quo in guideline development and its reliance on special interest funding requires ongoing vigilance to advocate on behalf of our patients. High-value medical care is expensive and hard work. When it is applied to the wrong people at the wrong time, we don’t deliver on our promises.

As members of the baby boomer generation (adults ≥65 years) age, the number of people at risk for diabetes increases. Already nearly one-quarter of people over age 65 have type 2 diabetes (T2DM).¹ With a proliferation of new medications to treat diabetes, deciding which ones to use in older patients is becoming complex.

In this article we review the important issues to consider when prescribing and monitoring diabetes medications in older adults. To provide optimal patient-centered care, it’s necessary to assess comorbid conditions as well as the costs, risks, and benefits of each medication. Determining appropriate goals of therapy and selecting agents that minimize the risk of hypoglycemia will help ensure safe and effective management of older patients with diabetes.

What makes elderly patients unique

The pathophysiology of T2DM in the elderly is unique in that it involves not just insulin resistance but also age-related loss of beta-cell function, leading to reduced insulin secretion and altered effectiveness of pharmacotherapy.² The addition of second and third medications may be needed for those with longstanding T2DM, although these agents often reduce the A1C level to a lesser extent than when used as monotherapy in patients whose beta-cell function is still intact. In addition to physiologic changes, older adults with diabetes have varied general health statuses and care support systems. The goal for glycemic management should be personalized based on an individual’s comorbidities and physical and cognitive functional status (TABLE 1^3,4).²

Higher A1C goals can be acceptable for elderly patients with comorbid conditions such as cognitive dysfunction, dementia, or cardiovascular or renal disease. Evaluate cognition when determining appropriate pharmacotherapy. Assess a patient’s awareness of hypoglycemia and ability to adhere to the regimen prescribed. Visual impairment, decreased dexterity, baseline weight, nutritional and functional status, as well as social support, finances, and formulary restrictions should all be considered when determining the most appropriate regimen for a patient. Also take into account patient and family goals of care.² TABLE 2^2-4 summarizes key risks and benefits of the medications we discuss next.

Metformin

Metformin is recommended as first-line therapy for those with T2DM for a number of reasons, including its potential to reduce cardiovascular events and mortality.^3,5 It also significantly reduces A1C levels by 1% to 1.5%,⁶ while imparting a low risk of hypoglycemia. Metformin is cost effective and well tolerated, making it an excellent choice for use in older patients.

The most common adverse effects are abdominal discomfort, diarrhea, and weight loss. The use of extended-release preparations, as well as slow titration of dosing, can improve gastrointestinal (GI) tolerance. Weight loss may be an attractive side effect in patients who are overweight or obese, but weight loss and diarrhea are concerning effects in frail older adults who may have poor nutritional reserves.⁶

Monitor renal function frequently in older patients receiving metformin.³ Renal failure is a risk factor for adverse events such as lactic acidosis, and metformin is therefore contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².⁴ With this in mind, metformin should not be started in patients with an eGFR below 45 mL/min/1.73 m². And for patients already taking metformin, reduce the total daily dose if the eGFR falls to between 30 and 45 mL/min/1.73 m².⁴

Metformin can cause a reduction in vitamin B12 levels after long-term use in up to 30% of patients, likely due to decreased absorption from the ileum.⁷ Monitor vitamin B12 serum concentrations periodically with long-term therapy, particularly in patients with peripheral neuropathy or anemia, as these conditions may be exacerbated by vitamin B12 deficiency.^3,4

Continue to: Sulfonylureas

Sulfonylureas

Sulfonylureas increase the secretion of insulin from pancreatic beta cells, significantly lower blood glucose, and reduce A1C levels by 1% to 2%.⁶ Because hypoglycemia is a serious risk with sulfonylureas, they should be used conservatively in the elderly.² Avoid using sulfonylurea formulations with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia.^8,9

Glyburide is broken down into active metabolites that accumulate in patients who have renal insufficiency; it should be avoided in older adults due to the risk of life-threatening hypoglycemic events.¹⁰ Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.^3,10

Thiazolidinediones

Thiazolidinediones (TZDs) reduce insulin resistance and decrease hepatic glucose production without increasing the risk of hypoglycemia. These agents effectively lower A1C levels by 1% to 1.5%.¹¹ Despite their efficacy, TZDs have limited benefit because of adverse effects. Serious complications include fluid retention that can exacerbate or lead to worsening heart failure, weight gain, macular edema, and hepatic failure.

Avoid using sulfonylureas with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia in the elderly.

Specifically, with pioglitazone, there is also a slightly increased risk of bladder cancer.² In one study involving more than 30,000 patients taking pioglitazone, an increase in bladder cancer was noted among those using the medication for more than 2 years.¹² Still, the hazard ratio was only 1.2, with 90 cases diagnosed over the course of the study. A prudent strategy would be to avoid its use in those with high risk of developing bladder cancer. TZDs are contraindicated in patients with New York Heart Association class III or IV heart failure.⁸

Increased fracture risk has been identified in both men and women and is a concerning adverse effect in the elderly.⁸ Fracture risk with TZDs has been approximately twice that of placebo, noted in a study of older women where the fracture rate was 5.1% vs 2.5%, respectively.¹¹ TZDs can be of value in lowering A1C levels without the risk of hypoglycemia. But, due to their adverse effect profile, use TZDs cautiously in older adults at risk for heart failure, falls, or fractures.³

Continue to: DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors work by suppressing the enzyme that degrades 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The resulting enhancement of incretin activity increases glucose-dependent insulin secretion, decreases glucagon secretion, and promotes satiety.⁶ These agents have modest efficacy with the potential to lower A1C by 0.5% to 0.9%.^8,13 Studies show that DPP-4 inhibitors are well tolerated with a minimal risk of hypoglycemia in the elderly.¹³ These agents are ideal for combin­ation therapy or for monotherapy in older patients who are not good candidates for metformin or a sulfonylurea.

The safety profile, neutral effect on weight, and once-daily dosing make these agents advantageous for use in frail and debilitated elderly patients, as well as in patients with cognitive dysfunction, decreased dexterity, inconsistent meal patterns, or adherence issues. Dose adjustment is required in renal impairment, with the exception of linagliptin. High cost or formulary restrictions may impact use of these agents.

The DPP-4 inhibitors were well tolerated in short-term studies, but long-term safety has yet to be established.⁶ Reported post-marketing adverse effects include acute renal failure, allergic reactions, and acute pancreatitis.^6,14 These agents should be avoided in any patient with a history of pancreatitis.¹⁴ In addition, trials investigating the cardiovascular safety and efficacy of DPP-4 inhibitors point to an increased risk of heart failure with the use of saxagliptin and alogliptin, regardless of age.^15,16 The potential for adverse effects warrants increased patient monitoring when using these agents in older patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are injectable agents that potentiate the actions of the naturally occurring incretin GLP-1, which increases glucose-dependent insulin secretion, inhibits glucagon release, reduces hepatic glucose production, and delays gastric emptying. These agents have a pronounced effect on satiety and promote weight loss. The most common adverse effects are nausea, vomiting, and diarrhea, which occur most commonly during treatment initiation and titration. Studies in elderly patients confirm A1C reductions of 1% to 1.5% and a low risk of hypoglycemia when used alone.^17,18

GLP-1 RAs can be used as monotherapy in older patients at risk for hypoglycemia or in those with hypoglycemic unawareness. They can also be used in combination therapy with other agents, including insulin, though concomitant use with insulin or insulin secretagogues increases the risk of hypoglycemia.³ Weight loss and GI adverse effects may limit the use of these agents in frail or undernourished elderly patients.⁶

Continue to: Since these agents are injected...

Since these agents are injected, they require intact visual, motor, and cognitive skills and thus may not be appropriate in older patients with cognitive or visual impairment or decreased dexterity. In addition, the high cost of these agents may limit their use.

Select a GLP-1 RA based on the frequency of administration, type of glucose control required (fasting or post-prandial), and the patient’s ability to use the administration device. Dose adjustment is required in renal impairment, except with dulaglutide and liraglutide. Use with caution in patients with a history of pancreatitis, and stop GLP-1 RAs if pancreatitis is suspected during treatment.⁴ Avoid GLP-1 RAs in patients with a personal or family history of thyroid-related cancers, as these agents have been associated with medullary thyroid tumors in animals.⁴

A new indication. Recent evidence suggests the GLP-1 RAs may offer additional cardiovascular benefit in patients with diabetes.^18,19 In August 2017, liraglutide gained an additional FDA indication to reduce the risk of major adverse cardiovascular events in adults with T2DM and established cardiovascular disease.

This new indication was based on the Novo Nordisk- and National Institutes of Health-sponsored LEADER trial, in which liraglutide reduced the risk of cardiovascular death, nonfatal heart attack, or nonfatal stroke by 13% vs placebo (P=.01) with an absolute risk reduction (ARR) of 1.9%.¹⁹ Liraglutide demonstrated a 22% reduction in cardiovascular death and a 15% reduction in all-cause death (ARR 1.3%, 1.4% respectively).¹⁹ The new cardiovascular indication may impact the choice of add-on therapy to metformin in patients with preexisting cardiovascular conditions.

Continue to: Sodium glucose cotransporter-2 inhibitors

Sodium glucose cotransporter-2 inhibitors

SGLT-2 inhibitors prevent the reabsorption of renal-filtered glucose, resulting in decreased blood glucose levels and increased urinary excretion of glucose without stimulating insulin secretion, and therefore without increasing the risk of hypoglycemia. Additional effects include decreased blood pressure and weight loss.²⁰ Dose adjustment is required in renal impairment.

SGLT-2 inhibitors can be used as monotherapy or in combination with other agents, including insulin, and the relatively low risk of hypoglycemia and moderate A1C lowering potential of 0.5% to 1% provide an oral option for select older patients.²⁰ Common adverse events include hypotension, hyperkalemia, increased low-density lipoprotein (LDL) levels, acute kidney injury, genital mycotic infections, and hypoglycemia when used in combination with insulin or insulin secretagogues.²⁰

DPP-4 agents are ideal for older patients who are not candidates for metformin or a sulfonylurea.

Additional warnings have been issued by the FDA for the risk of urinary tract infection with sepsis, as well as diabetic ketoacidosis associated with SGLT-2 inhibitor use.²¹ The FDA has reported bone fracture risk and decreased bone mineral density with canagliflozin.²¹ Avoid using SGLT-2 inhibitors in patients with osteopenia or osteoporosis, as the risks outweigh the benefits. Drug-specific warnings may further impact individual use of an agent, with canagliflozin most recently having been associated with increased risk of leg and foot amputations.²¹

Given the adverse effect profile of SGLT-2 inhibitors, assess their risks and benefits in older patients on a case-by-case basis. Before initiating therapy, evaluate each patient’s volume status. A higher incidence of adverse effects related to intravascular volume depletion has been reported in those 65 or older, with a more prominent increase seen in patients 75 or older.²² However, the risk of hypoglycemia does not seem to increase with age.²²

Although many adverse effects have been reported with SGLT-2 inhibitors, empagliflozin was associated with significantly lower rates of all-cause and cardiovascular death and lower risk of hospitalization for heart failure in the only SGLT-2 inhibitor cardiovascular outcomes trial reported to date.²³ If this cardiovascular benefit is replicated in additional trials of the other SGLT-2 inhibitors, use of this drug class may increase.

Continue to: Insulin

Many patients will ultimately require insulin due to the progressive loss of beta-cell function that occurs in advanced diabetes. Starting insulin therapy early on in the disease may actually restore beta-cell function and reduce glucotoxicity.²⁴ In elderly patients with uncontrolled diabetes, early treatment with basal insulin results in better glycemic control and less hypoglycemia than continuing to titrate oral agents.²⁵

Despite these benefits, however, insulin use often is not optimized in the elderly due to concerns about hypoglycemia and difficulty of administration. Safe use of insulin requires careful selection of an appropriate insulin regimen, since insulin use has been identified as an independent predictor of severe hypoglycemia in the elderly.^8,26 Before initiating insulin therapy, evaluate whether an older patient is cognitively and physically able to safely use insulin.

Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.

Multiple daily injections may be challenging for some older adults. Limit such insulin regimens to use in high-functioning patients. Although all types of insulin can cause hypoglycemia, regimens that mimic insulin’s normal physiologic pattern introduce less hypoglycemic risk. Using basal insulin that mimics the body’s sustained insulin level throughout the day is associated with a lower frequency of hypoglycemia in older people with diabetes than conventional insulin regimens. Long-acting insulins such as glargine, detemir, and degludec offer a lower risk of hypoglycemia, particularly nocturnal hypoglycemia which may contribute to falls.^2,27

Neutral protamine Hagedorn insulin and regular insulin are not recommended for use in the elderly, as they do not mimic the body’s natural basal-bolus insulin production and thus put patients at higher risk of hypoglycemia.⁴ If insulin intensification is needed after optimizing basal insulin, consider adding mealtime insulin with a bolus of rapid-acting insulin (insulin aspart, insulin lispro, or insulin glulisine). It is important to note that the kidneys are responsible for 30% to 80% of insulin clearance from the body.²⁸ Because insulin action is prolonged in renal insufficiency, prevent hypoglycemia by decreasing basal and bolus doses when the eGFR is below 50 mL/min/1.73m².²⁸

Dosing errors. Whenever possible, use insulin preparations that minimize dosing errors. Insulin pen formulations, if financially feasible, allow more accurate dosing and are more acceptable to older patients compared with syringes and vials.²⁹ Pen formulations are particularly preferable for older patients with impaired vision or dexterity.²⁹ In addition, when patients must mix insulins, errors are more likely to occur. The use of premixed insulin vials has been shown to increase dosing accuracy when used by the elderly.³⁰

Continue to: Combining antidiabetes agents

Combining antidiabetes agents

Combination therapy is often needed as T2DM progresses, even though strict glucose control is generally not recommended for the elderly.³¹ The American Geriatrics Society advises avoiding additional medications other than metformin to achieve an A1C level below 7.5% in most older adults.

However, for older patients already taking metformin who are not at their A1C goal, consider adding a second agent, if not contraindicated. Potential agents include a GLP-1 RA, SGLT-2 inhibitor, DDP-4 inhibitor, or short-acting sulfonylurea (glipizide). Alternatively, basal insulin may be added. However, avoid combining a sulfonylurea with insulin, which greatly increases the risk of hypoglycemia.³² Consider adding a GLP-1 RA or basal insulin if the patient is not at his/her target A1C on oral therapy with multiple agents.³

CORRESPONDENCE
Barbara Keber, MD, Glen Cove Hospital, 101 St. Andrews Lane, Glen Cove, NY; bkeber@northwell.edu.

As members of the baby boomer generation (adults ≥65 years) age, the number of people at risk for diabetes increases. Already nearly one-quarter of people over age 65 have type 2 diabetes (T2DM).¹ With a proliferation of new medications to treat diabetes, deciding which ones to use in older patients is becoming complex.

In this article we review the important issues to consider when prescribing and monitoring diabetes medications in older adults. To provide optimal patient-centered care, it’s necessary to assess comorbid conditions as well as the costs, risks, and benefits of each medication. Determining appropriate goals of therapy and selecting agents that minimize the risk of hypoglycemia will help ensure safe and effective management of older patients with diabetes.

What makes elderly patients unique

The pathophysiology of T2DM in the elderly is unique in that it involves not just insulin resistance but also age-related loss of beta-cell function, leading to reduced insulin secretion and altered effectiveness of pharmacotherapy.² The addition of second and third medications may be needed for those with longstanding T2DM, although these agents often reduce the A1C level to a lesser extent than when used as monotherapy in patients whose beta-cell function is still intact. In addition to physiologic changes, older adults with diabetes have varied general health statuses and care support systems. The goal for glycemic management should be personalized based on an individual’s comorbidities and physical and cognitive functional status (TABLE 1^3,4).²

Higher A1C goals can be acceptable for elderly patients with comorbid conditions such as cognitive dysfunction, dementia, or cardiovascular or renal disease. Evaluate cognition when determining appropriate pharmacotherapy. Assess a patient’s awareness of hypoglycemia and ability to adhere to the regimen prescribed. Visual impairment, decreased dexterity, baseline weight, nutritional and functional status, as well as social support, finances, and formulary restrictions should all be considered when determining the most appropriate regimen for a patient. Also take into account patient and family goals of care.² TABLE 2^2-4 summarizes key risks and benefits of the medications we discuss next.

Metformin

Metformin is recommended as first-line therapy for those with T2DM for a number of reasons, including its potential to reduce cardiovascular events and mortality.^3,5 It also significantly reduces A1C levels by 1% to 1.5%,⁶ while imparting a low risk of hypoglycemia. Metformin is cost effective and well tolerated, making it an excellent choice for use in older patients.

The most common adverse effects are abdominal discomfort, diarrhea, and weight loss. The use of extended-release preparations, as well as slow titration of dosing, can improve gastrointestinal (GI) tolerance. Weight loss may be an attractive side effect in patients who are overweight or obese, but weight loss and diarrhea are concerning effects in frail older adults who may have poor nutritional reserves.⁶

Monitor renal function frequently in older patients receiving metformin.³ Renal failure is a risk factor for adverse events such as lactic acidosis, and metformin is therefore contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².⁴ With this in mind, metformin should not be started in patients with an eGFR below 45 mL/min/1.73 m². And for patients already taking metformin, reduce the total daily dose if the eGFR falls to between 30 and 45 mL/min/1.73 m².⁴

Metformin can cause a reduction in vitamin B12 levels after long-term use in up to 30% of patients, likely due to decreased absorption from the ileum.⁷ Monitor vitamin B12 serum concentrations periodically with long-term therapy, particularly in patients with peripheral neuropathy or anemia, as these conditions may be exacerbated by vitamin B12 deficiency.^3,4

Continue to: Sulfonylureas

Sulfonylureas

Sulfonylureas increase the secretion of insulin from pancreatic beta cells, significantly lower blood glucose, and reduce A1C levels by 1% to 2%.⁶ Because hypoglycemia is a serious risk with sulfonylureas, they should be used conservatively in the elderly.² Avoid using sulfonylurea formulations with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia.^8,9

Glyburide is broken down into active metabolites that accumulate in patients who have renal insufficiency; it should be avoided in older adults due to the risk of life-threatening hypoglycemic events.¹⁰ Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.^3,10

Thiazolidinediones

Thiazolidinediones (TZDs) reduce insulin resistance and decrease hepatic glucose production without increasing the risk of hypoglycemia. These agents effectively lower A1C levels by 1% to 1.5%.¹¹ Despite their efficacy, TZDs have limited benefit because of adverse effects. Serious complications include fluid retention that can exacerbate or lead to worsening heart failure, weight gain, macular edema, and hepatic failure.

Avoid using sulfonylureas with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia in the elderly.

Specifically, with pioglitazone, there is also a slightly increased risk of bladder cancer.² In one study involving more than 30,000 patients taking pioglitazone, an increase in bladder cancer was noted among those using the medication for more than 2 years.¹² Still, the hazard ratio was only 1.2, with 90 cases diagnosed over the course of the study. A prudent strategy would be to avoid its use in those with high risk of developing bladder cancer. TZDs are contraindicated in patients with New York Heart Association class III or IV heart failure.⁸

Increased fracture risk has been identified in both men and women and is a concerning adverse effect in the elderly.⁸ Fracture risk with TZDs has been approximately twice that of placebo, noted in a study of older women where the fracture rate was 5.1% vs 2.5%, respectively.¹¹ TZDs can be of value in lowering A1C levels without the risk of hypoglycemia. But, due to their adverse effect profile, use TZDs cautiously in older adults at risk for heart failure, falls, or fractures.³

Continue to: DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors work by suppressing the enzyme that degrades 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The resulting enhancement of incretin activity increases glucose-dependent insulin secretion, decreases glucagon secretion, and promotes satiety.⁶ These agents have modest efficacy with the potential to lower A1C by 0.5% to 0.9%.^8,13 Studies show that DPP-4 inhibitors are well tolerated with a minimal risk of hypoglycemia in the elderly.¹³ These agents are ideal for combin­ation therapy or for monotherapy in older patients who are not good candidates for metformin or a sulfonylurea.

The safety profile, neutral effect on weight, and once-daily dosing make these agents advantageous for use in frail and debilitated elderly patients, as well as in patients with cognitive dysfunction, decreased dexterity, inconsistent meal patterns, or adherence issues. Dose adjustment is required in renal impairment, with the exception of linagliptin. High cost or formulary restrictions may impact use of these agents.

The DPP-4 inhibitors were well tolerated in short-term studies, but long-term safety has yet to be established.⁶ Reported post-marketing adverse effects include acute renal failure, allergic reactions, and acute pancreatitis.^6,14 These agents should be avoided in any patient with a history of pancreatitis.¹⁴ In addition, trials investigating the cardiovascular safety and efficacy of DPP-4 inhibitors point to an increased risk of heart failure with the use of saxagliptin and alogliptin, regardless of age.^15,16 The potential for adverse effects warrants increased patient monitoring when using these agents in older patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are injectable agents that potentiate the actions of the naturally occurring incretin GLP-1, which increases glucose-dependent insulin secretion, inhibits glucagon release, reduces hepatic glucose production, and delays gastric emptying. These agents have a pronounced effect on satiety and promote weight loss. The most common adverse effects are nausea, vomiting, and diarrhea, which occur most commonly during treatment initiation and titration. Studies in elderly patients confirm A1C reductions of 1% to 1.5% and a low risk of hypoglycemia when used alone.^17,18

GLP-1 RAs can be used as monotherapy in older patients at risk for hypoglycemia or in those with hypoglycemic unawareness. They can also be used in combination therapy with other agents, including insulin, though concomitant use with insulin or insulin secretagogues increases the risk of hypoglycemia.³ Weight loss and GI adverse effects may limit the use of these agents in frail or undernourished elderly patients.⁶

Continue to: Since these agents are injected...

Since these agents are injected, they require intact visual, motor, and cognitive skills and thus may not be appropriate in older patients with cognitive or visual impairment or decreased dexterity. In addition, the high cost of these agents may limit their use.

Select a GLP-1 RA based on the frequency of administration, type of glucose control required (fasting or post-prandial), and the patient’s ability to use the administration device. Dose adjustment is required in renal impairment, except with dulaglutide and liraglutide. Use with caution in patients with a history of pancreatitis, and stop GLP-1 RAs if pancreatitis is suspected during treatment.⁴ Avoid GLP-1 RAs in patients with a personal or family history of thyroid-related cancers, as these agents have been associated with medullary thyroid tumors in animals.⁴

A new indication. Recent evidence suggests the GLP-1 RAs may offer additional cardiovascular benefit in patients with diabetes.^18,19 In August 2017, liraglutide gained an additional FDA indication to reduce the risk of major adverse cardiovascular events in adults with T2DM and established cardiovascular disease.

This new indication was based on the Novo Nordisk- and National Institutes of Health-sponsored LEADER trial, in which liraglutide reduced the risk of cardiovascular death, nonfatal heart attack, or nonfatal stroke by 13% vs placebo (P=.01) with an absolute risk reduction (ARR) of 1.9%.¹⁹ Liraglutide demonstrated a 22% reduction in cardiovascular death and a 15% reduction in all-cause death (ARR 1.3%, 1.4% respectively).¹⁹ The new cardiovascular indication may impact the choice of add-on therapy to metformin in patients with preexisting cardiovascular conditions.

Continue to: Sodium glucose cotransporter-2 inhibitors

Sodium glucose cotransporter-2 inhibitors

SGLT-2 inhibitors prevent the reabsorption of renal-filtered glucose, resulting in decreased blood glucose levels and increased urinary excretion of glucose without stimulating insulin secretion, and therefore without increasing the risk of hypoglycemia. Additional effects include decreased blood pressure and weight loss.²⁰ Dose adjustment is required in renal impairment.

SGLT-2 inhibitors can be used as monotherapy or in combination with other agents, including insulin, and the relatively low risk of hypoglycemia and moderate A1C lowering potential of 0.5% to 1% provide an oral option for select older patients.²⁰ Common adverse events include hypotension, hyperkalemia, increased low-density lipoprotein (LDL) levels, acute kidney injury, genital mycotic infections, and hypoglycemia when used in combination with insulin or insulin secretagogues.²⁰

DPP-4 agents are ideal for older patients who are not candidates for metformin or a sulfonylurea.

Additional warnings have been issued by the FDA for the risk of urinary tract infection with sepsis, as well as diabetic ketoacidosis associated with SGLT-2 inhibitor use.²¹ The FDA has reported bone fracture risk and decreased bone mineral density with canagliflozin.²¹ Avoid using SGLT-2 inhibitors in patients with osteopenia or osteoporosis, as the risks outweigh the benefits. Drug-specific warnings may further impact individual use of an agent, with canagliflozin most recently having been associated with increased risk of leg and foot amputations.²¹

Given the adverse effect profile of SGLT-2 inhibitors, assess their risks and benefits in older patients on a case-by-case basis. Before initiating therapy, evaluate each patient’s volume status. A higher incidence of adverse effects related to intravascular volume depletion has been reported in those 65 or older, with a more prominent increase seen in patients 75 or older.²² However, the risk of hypoglycemia does not seem to increase with age.²²

Although many adverse effects have been reported with SGLT-2 inhibitors, empagliflozin was associated with significantly lower rates of all-cause and cardiovascular death and lower risk of hospitalization for heart failure in the only SGLT-2 inhibitor cardiovascular outcomes trial reported to date.²³ If this cardiovascular benefit is replicated in additional trials of the other SGLT-2 inhibitors, use of this drug class may increase.

Continue to: Insulin

Many patients will ultimately require insulin due to the progressive loss of beta-cell function that occurs in advanced diabetes. Starting insulin therapy early on in the disease may actually restore beta-cell function and reduce glucotoxicity.²⁴ In elderly patients with uncontrolled diabetes, early treatment with basal insulin results in better glycemic control and less hypoglycemia than continuing to titrate oral agents.²⁵

Despite these benefits, however, insulin use often is not optimized in the elderly due to concerns about hypoglycemia and difficulty of administration. Safe use of insulin requires careful selection of an appropriate insulin regimen, since insulin use has been identified as an independent predictor of severe hypoglycemia in the elderly.^8,26 Before initiating insulin therapy, evaluate whether an older patient is cognitively and physically able to safely use insulin.

Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.

Multiple daily injections may be challenging for some older adults. Limit such insulin regimens to use in high-functioning patients. Although all types of insulin can cause hypoglycemia, regimens that mimic insulin’s normal physiologic pattern introduce less hypoglycemic risk. Using basal insulin that mimics the body’s sustained insulin level throughout the day is associated with a lower frequency of hypoglycemia in older people with diabetes than conventional insulin regimens. Long-acting insulins such as glargine, detemir, and degludec offer a lower risk of hypoglycemia, particularly nocturnal hypoglycemia which may contribute to falls.^2,27

Neutral protamine Hagedorn insulin and regular insulin are not recommended for use in the elderly, as they do not mimic the body’s natural basal-bolus insulin production and thus put patients at higher risk of hypoglycemia.⁴ If insulin intensification is needed after optimizing basal insulin, consider adding mealtime insulin with a bolus of rapid-acting insulin (insulin aspart, insulin lispro, or insulin glulisine). It is important to note that the kidneys are responsible for 30% to 80% of insulin clearance from the body.²⁸ Because insulin action is prolonged in renal insufficiency, prevent hypoglycemia by decreasing basal and bolus doses when the eGFR is below 50 mL/min/1.73m².²⁸

Dosing errors. Whenever possible, use insulin preparations that minimize dosing errors. Insulin pen formulations, if financially feasible, allow more accurate dosing and are more acceptable to older patients compared with syringes and vials.²⁹ Pen formulations are particularly preferable for older patients with impaired vision or dexterity.²⁹ In addition, when patients must mix insulins, errors are more likely to occur. The use of premixed insulin vials has been shown to increase dosing accuracy when used by the elderly.³⁰

Continue to: Combining antidiabetes agents

Combining antidiabetes agents

Combination therapy is often needed as T2DM progresses, even though strict glucose control is generally not recommended for the elderly.³¹ The American Geriatrics Society advises avoiding additional medications other than metformin to achieve an A1C level below 7.5% in most older adults.

However, for older patients already taking metformin who are not at their A1C goal, consider adding a second agent, if not contraindicated. Potential agents include a GLP-1 RA, SGLT-2 inhibitor, DDP-4 inhibitor, or short-acting sulfonylurea (glipizide). Alternatively, basal insulin may be added. However, avoid combining a sulfonylurea with insulin, which greatly increases the risk of hypoglycemia.³² Consider adding a GLP-1 RA or basal insulin if the patient is not at his/her target A1C on oral therapy with multiple agents.³

CORRESPONDENCE
Barbara Keber, MD, Glen Cove Hospital, 101 St. Andrews Lane, Glen Cove, NY; bkeber@northwell.edu.

As members of the baby boomer generation (adults ≥65 years) age, the number of people at risk for diabetes increases. Already nearly one-quarter of people over age 65 have type 2 diabetes (T2DM).¹ With a proliferation of new medications to treat diabetes, deciding which ones to use in older patients is becoming complex.

In this article we review the important issues to consider when prescribing and monitoring diabetes medications in older adults. To provide optimal patient-centered care, it’s necessary to assess comorbid conditions as well as the costs, risks, and benefits of each medication. Determining appropriate goals of therapy and selecting agents that minimize the risk of hypoglycemia will help ensure safe and effective management of older patients with diabetes.

What makes elderly patients unique

The pathophysiology of T2DM in the elderly is unique in that it involves not just insulin resistance but also age-related loss of beta-cell function, leading to reduced insulin secretion and altered effectiveness of pharmacotherapy.² The addition of second and third medications may be needed for those with longstanding T2DM, although these agents often reduce the A1C level to a lesser extent than when used as monotherapy in patients whose beta-cell function is still intact. In addition to physiologic changes, older adults with diabetes have varied general health statuses and care support systems. The goal for glycemic management should be personalized based on an individual’s comorbidities and physical and cognitive functional status (TABLE 1^3,4).²

Higher A1C goals can be acceptable for elderly patients with comorbid conditions such as cognitive dysfunction, dementia, or cardiovascular or renal disease. Evaluate cognition when determining appropriate pharmacotherapy. Assess a patient’s awareness of hypoglycemia and ability to adhere to the regimen prescribed. Visual impairment, decreased dexterity, baseline weight, nutritional and functional status, as well as social support, finances, and formulary restrictions should all be considered when determining the most appropriate regimen for a patient. Also take into account patient and family goals of care.² TABLE 2^2-4 summarizes key risks and benefits of the medications we discuss next.

Metformin

Metformin is recommended as first-line therapy for those with T2DM for a number of reasons, including its potential to reduce cardiovascular events and mortality.^3,5 It also significantly reduces A1C levels by 1% to 1.5%,⁶ while imparting a low risk of hypoglycemia. Metformin is cost effective and well tolerated, making it an excellent choice for use in older patients.

The most common adverse effects are abdominal discomfort, diarrhea, and weight loss. The use of extended-release preparations, as well as slow titration of dosing, can improve gastrointestinal (GI) tolerance. Weight loss may be an attractive side effect in patients who are overweight or obese, but weight loss and diarrhea are concerning effects in frail older adults who may have poor nutritional reserves.⁶

Monitor renal function frequently in older patients receiving metformin.³ Renal failure is a risk factor for adverse events such as lactic acidosis, and metformin is therefore contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².⁴ With this in mind, metformin should not be started in patients with an eGFR below 45 mL/min/1.73 m². And for patients already taking metformin, reduce the total daily dose if the eGFR falls to between 30 and 45 mL/min/1.73 m².⁴

Metformin can cause a reduction in vitamin B12 levels after long-term use in up to 30% of patients, likely due to decreased absorption from the ileum.⁷ Monitor vitamin B12 serum concentrations periodically with long-term therapy, particularly in patients with peripheral neuropathy or anemia, as these conditions may be exacerbated by vitamin B12 deficiency.^3,4

Continue to: Sulfonylureas

Sulfonylureas

Sulfonylureas increase the secretion of insulin from pancreatic beta cells, significantly lower blood glucose, and reduce A1C levels by 1% to 2%.⁶ Because hypoglycemia is a serious risk with sulfonylureas, they should be used conservatively in the elderly.² Avoid using sulfonylurea formulations with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia.^8,9

Glyburide is broken down into active metabolites that accumulate in patients who have renal insufficiency; it should be avoided in older adults due to the risk of life-threatening hypoglycemic events.¹⁰ Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.^3,10

Thiazolidinediones

Thiazolidinediones (TZDs) reduce insulin resistance and decrease hepatic glucose production without increasing the risk of hypoglycemia. These agents effectively lower A1C levels by 1% to 1.5%.¹¹ Despite their efficacy, TZDs have limited benefit because of adverse effects. Serious complications include fluid retention that can exacerbate or lead to worsening heart failure, weight gain, macular edema, and hepatic failure.

Avoid using sulfonylureas with long half-lives or active metabolites, which can cause severe and prolonged hypoglycemia in the elderly.

Specifically, with pioglitazone, there is also a slightly increased risk of bladder cancer.² In one study involving more than 30,000 patients taking pioglitazone, an increase in bladder cancer was noted among those using the medication for more than 2 years.¹² Still, the hazard ratio was only 1.2, with 90 cases diagnosed over the course of the study. A prudent strategy would be to avoid its use in those with high risk of developing bladder cancer. TZDs are contraindicated in patients with New York Heart Association class III or IV heart failure.⁸

Increased fracture risk has been identified in both men and women and is a concerning adverse effect in the elderly.⁸ Fracture risk with TZDs has been approximately twice that of placebo, noted in a study of older women where the fracture rate was 5.1% vs 2.5%, respectively.¹¹ TZDs can be of value in lowering A1C levels without the risk of hypoglycemia. But, due to their adverse effect profile, use TZDs cautiously in older adults at risk for heart failure, falls, or fractures.³

Continue to: DPP-4 inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors work by suppressing the enzyme that degrades 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The resulting enhancement of incretin activity increases glucose-dependent insulin secretion, decreases glucagon secretion, and promotes satiety.⁶ These agents have modest efficacy with the potential to lower A1C by 0.5% to 0.9%.^8,13 Studies show that DPP-4 inhibitors are well tolerated with a minimal risk of hypoglycemia in the elderly.¹³ These agents are ideal for combin­ation therapy or for monotherapy in older patients who are not good candidates for metformin or a sulfonylurea.

The safety profile, neutral effect on weight, and once-daily dosing make these agents advantageous for use in frail and debilitated elderly patients, as well as in patients with cognitive dysfunction, decreased dexterity, inconsistent meal patterns, or adherence issues. Dose adjustment is required in renal impairment, with the exception of linagliptin. High cost or formulary restrictions may impact use of these agents.

The DPP-4 inhibitors were well tolerated in short-term studies, but long-term safety has yet to be established.⁶ Reported post-marketing adverse effects include acute renal failure, allergic reactions, and acute pancreatitis.^6,14 These agents should be avoided in any patient with a history of pancreatitis.¹⁴ In addition, trials investigating the cardiovascular safety and efficacy of DPP-4 inhibitors point to an increased risk of heart failure with the use of saxagliptin and alogliptin, regardless of age.^15,16 The potential for adverse effects warrants increased patient monitoring when using these agents in older patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are injectable agents that potentiate the actions of the naturally occurring incretin GLP-1, which increases glucose-dependent insulin secretion, inhibits glucagon release, reduces hepatic glucose production, and delays gastric emptying. These agents have a pronounced effect on satiety and promote weight loss. The most common adverse effects are nausea, vomiting, and diarrhea, which occur most commonly during treatment initiation and titration. Studies in elderly patients confirm A1C reductions of 1% to 1.5% and a low risk of hypoglycemia when used alone.^17,18

GLP-1 RAs can be used as monotherapy in older patients at risk for hypoglycemia or in those with hypoglycemic unawareness. They can also be used in combination therapy with other agents, including insulin, though concomitant use with insulin or insulin secretagogues increases the risk of hypoglycemia.³ Weight loss and GI adverse effects may limit the use of these agents in frail or undernourished elderly patients.⁶

Continue to: Since these agents are injected...

Since these agents are injected, they require intact visual, motor, and cognitive skills and thus may not be appropriate in older patients with cognitive or visual impairment or decreased dexterity. In addition, the high cost of these agents may limit their use.

Select a GLP-1 RA based on the frequency of administration, type of glucose control required (fasting or post-prandial), and the patient’s ability to use the administration device. Dose adjustment is required in renal impairment, except with dulaglutide and liraglutide. Use with caution in patients with a history of pancreatitis, and stop GLP-1 RAs if pancreatitis is suspected during treatment.⁴ Avoid GLP-1 RAs in patients with a personal or family history of thyroid-related cancers, as these agents have been associated with medullary thyroid tumors in animals.⁴

A new indication. Recent evidence suggests the GLP-1 RAs may offer additional cardiovascular benefit in patients with diabetes.^18,19 In August 2017, liraglutide gained an additional FDA indication to reduce the risk of major adverse cardiovascular events in adults with T2DM and established cardiovascular disease.

This new indication was based on the Novo Nordisk- and National Institutes of Health-sponsored LEADER trial, in which liraglutide reduced the risk of cardiovascular death, nonfatal heart attack, or nonfatal stroke by 13% vs placebo (P=.01) with an absolute risk reduction (ARR) of 1.9%.¹⁹ Liraglutide demonstrated a 22% reduction in cardiovascular death and a 15% reduction in all-cause death (ARR 1.3%, 1.4% respectively).¹⁹ The new cardiovascular indication may impact the choice of add-on therapy to metformin in patients with preexisting cardiovascular conditions.

Continue to: Sodium glucose cotransporter-2 inhibitors

Sodium glucose cotransporter-2 inhibitors

SGLT-2 inhibitors prevent the reabsorption of renal-filtered glucose, resulting in decreased blood glucose levels and increased urinary excretion of glucose without stimulating insulin secretion, and therefore without increasing the risk of hypoglycemia. Additional effects include decreased blood pressure and weight loss.²⁰ Dose adjustment is required in renal impairment.

SGLT-2 inhibitors can be used as monotherapy or in combination with other agents, including insulin, and the relatively low risk of hypoglycemia and moderate A1C lowering potential of 0.5% to 1% provide an oral option for select older patients.²⁰ Common adverse events include hypotension, hyperkalemia, increased low-density lipoprotein (LDL) levels, acute kidney injury, genital mycotic infections, and hypoglycemia when used in combination with insulin or insulin secretagogues.²⁰

DPP-4 agents are ideal for older patients who are not candidates for metformin or a sulfonylurea.

Additional warnings have been issued by the FDA for the risk of urinary tract infection with sepsis, as well as diabetic ketoacidosis associated with SGLT-2 inhibitor use.²¹ The FDA has reported bone fracture risk and decreased bone mineral density with canagliflozin.²¹ Avoid using SGLT-2 inhibitors in patients with osteopenia or osteoporosis, as the risks outweigh the benefits. Drug-specific warnings may further impact individual use of an agent, with canagliflozin most recently having been associated with increased risk of leg and foot amputations.²¹

Given the adverse effect profile of SGLT-2 inhibitors, assess their risks and benefits in older patients on a case-by-case basis. Before initiating therapy, evaluate each patient’s volume status. A higher incidence of adverse effects related to intravascular volume depletion has been reported in those 65 or older, with a more prominent increase seen in patients 75 or older.²² However, the risk of hypoglycemia does not seem to increase with age.²²

Although many adverse effects have been reported with SGLT-2 inhibitors, empagliflozin was associated with significantly lower rates of all-cause and cardiovascular death and lower risk of hospitalization for heart failure in the only SGLT-2 inhibitor cardiovascular outcomes trial reported to date.²³ If this cardiovascular benefit is replicated in additional trials of the other SGLT-2 inhibitors, use of this drug class may increase.

Continue to: Insulin

Many patients will ultimately require insulin due to the progressive loss of beta-cell function that occurs in advanced diabetes. Starting insulin therapy early on in the disease may actually restore beta-cell function and reduce glucotoxicity.²⁴ In elderly patients with uncontrolled diabetes, early treatment with basal insulin results in better glycemic control and less hypoglycemia than continuing to titrate oral agents.²⁵

Despite these benefits, however, insulin use often is not optimized in the elderly due to concerns about hypoglycemia and difficulty of administration. Safe use of insulin requires careful selection of an appropriate insulin regimen, since insulin use has been identified as an independent predictor of severe hypoglycemia in the elderly.^8,26 Before initiating insulin therapy, evaluate whether an older patient is cognitively and physically able to safely use insulin.

Glipizide has no active metabolites and has the lowest risk of hypoglycemia in the setting of decreased renal function, making it the preferred sulfonylurea for use in the elderly.

Multiple daily injections may be challenging for some older adults. Limit such insulin regimens to use in high-functioning patients. Although all types of insulin can cause hypoglycemia, regimens that mimic insulin’s normal physiologic pattern introduce less hypoglycemic risk. Using basal insulin that mimics the body’s sustained insulin level throughout the day is associated with a lower frequency of hypoglycemia in older people with diabetes than conventional insulin regimens. Long-acting insulins such as glargine, detemir, and degludec offer a lower risk of hypoglycemia, particularly nocturnal hypoglycemia which may contribute to falls.^2,27

Neutral protamine Hagedorn insulin and regular insulin are not recommended for use in the elderly, as they do not mimic the body’s natural basal-bolus insulin production and thus put patients at higher risk of hypoglycemia.⁴ If insulin intensification is needed after optimizing basal insulin, consider adding mealtime insulin with a bolus of rapid-acting insulin (insulin aspart, insulin lispro, or insulin glulisine). It is important to note that the kidneys are responsible for 30% to 80% of insulin clearance from the body.²⁸ Because insulin action is prolonged in renal insufficiency, prevent hypoglycemia by decreasing basal and bolus doses when the eGFR is below 50 mL/min/1.73m².²⁸

Dosing errors. Whenever possible, use insulin preparations that minimize dosing errors. Insulin pen formulations, if financially feasible, allow more accurate dosing and are more acceptable to older patients compared with syringes and vials.²⁹ Pen formulations are particularly preferable for older patients with impaired vision or dexterity.²⁹ In addition, when patients must mix insulins, errors are more likely to occur. The use of premixed insulin vials has been shown to increase dosing accuracy when used by the elderly.³⁰

Continue to: Combining antidiabetes agents

Combining antidiabetes agents

Combination therapy is often needed as T2DM progresses, even though strict glucose control is generally not recommended for the elderly.³¹ The American Geriatrics Society advises avoiding additional medications other than metformin to achieve an A1C level below 7.5% in most older adults.

However, for older patients already taking metformin who are not at their A1C goal, consider adding a second agent, if not contraindicated. Potential agents include a GLP-1 RA, SGLT-2 inhibitor, DDP-4 inhibitor, or short-acting sulfonylurea (glipizide). Alternatively, basal insulin may be added. However, avoid combining a sulfonylurea with insulin, which greatly increases the risk of hypoglycemia.³² Consider adding a GLP-1 RA or basal insulin if the patient is not at his/her target A1C on oral therapy with multiple agents.³

CORRESPONDENCE
Barbara Keber, MD, Glen Cove Hospital, 101 St. Andrews Lane, Glen Cove, NY; bkeber@northwell.edu.

For more than a century, clinicians have pondered the significance of elevated blood pressure (BP) and its contribution to cardiovascular disease (CVD). While it is widely understood that high BP increases CVD events, and that treatment lowers that risk, the most appropriate BP goal continues to be a subject of debate.

This article briefly summarizes the evidence to support lower BP goals for patients with hypertension who are commonly seen in family practice, including those needing primary prevention, as well as those with, or at high risk for, atherosclerotic cardiovascular disease (ASCVD), patients with diabetes, and those with chronic kidney disease (CKD). Detailed information regarding specific lifestyle and medication treatment recommendations and thresholds for drug therapy is beyond the scope of this review.

A brief history: ACC/AHA guidelines vs JNC 7 and 8

The most recent comprehensive, evidence-based guideline on the prevention, detection, evaluation, and management of high BP in adults was released in late 2017 by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹ It was the first comprehensive BP guideline since the Seventh Report of the Joint National Committee (JNC 7) in 2003.² The new guideline includes several changes, notably in how BP is classified, the threshold for initiation of antihypertensive drug therapy, and target BP.

While widely viewed as positive, the changes in classification, thresholds, and targets for BP therapy have generated controversy and disagreement. Common reasons cited include concern about the data supporting lower thresholds for treatment, the applicability of trial findings to broad patient populations, and the risk of harm with lower BP goals.³ The American Academy of Family Physicians (AAFP) declined to endorse the ACC/AHA guidelines and continues to support the 2014 report by the panel members appointed to the Eighth Joint National Committee (JNC 8) by the National Heart Lung and Blood Institute (NHLBI).⁴ A primary reason cited for the lack of support for the 2017 guideline is that the majority of recommendations made in the ACC/AHA guideline were not “based on a systematic evidence review.”⁴ However, there are significant differences in purpose, structure, and scope between the ACC/AHA and JNC 8.

Evidence supports lower BP goals for a number of different patient populations and groups.

In 2013, the NHLBI announced that it would cease involvement in creating guidelines and transferred responsibility for development to professional organizations.⁵ Of the 5 guidelines that were in the process of creation (cholesterol, lifestyle intervention, obesity, risk assessment, and high BP), all but the high BP guideline were transferred to the ACC/AHA for completion. The panel members appointed to the JNC 8 elected to publish their recommendations independently and focused only on 3 “critical questions” related to hypertension therapy (eg, therapy initiation, BP goals, and choice of initial agent).⁶

[polldaddy:10041785]

The JNC 8 report generated significant controversy with the recommendation to relax the BP goal for patients ≥60 years of age to <150/90 mm Hg. Members of the JNC 8 panel who disagreed with this goal published a "minority view" citing concerns about the negative impact the goal would have on CVD and public health, and the "insufficient and inconsistent" evidence supporting relaxed goals.⁷ The dissenting group cited additional drawbacks of the recommendation, noting that it was highly focused, included data only from randomized controlled trials (RCTs; no meta-analyses or observational data), and did not address or provide guidance on numerous other issues of importance in the care of hypertension.

While the 2017 ACC/AHA guideline also includes formal systematic evidence reviews on major critical questions (ie, optimal BP targets, preferred antihypertensives, the role of home and ambulatory BP monitoring),⁸ it was designed to be comprehensive and useful for clinicians, providing 106 graded recommendations on commonly encountered questions. It would have been unrealistic to do a formal systematic evidence review and meta-analysis on all clinically relevant questions seen in practice. However, available systematic reviews, meta-analyses, and observational data were scrutinized and used to support the recommendations wherever possible.

Continue to: Say "goodbye" to prehypertension; say "hello" to elevated BP

Say “goodbye” to prehypertension; say “hello” to elevated BP

The 2017 ACC/AHA guideline changed the BP classification for adults (TABLE 1^1,2). While “normal” remained respectively.¹ Removal of the “prehypertension” category and use of the term “elevated” instead was meant to better convey the importance of lifestyle interventions to forestall the development of hypertension.

Don’t underestimate the power of BP measurement technique

The importance of appropriate BP measurement technique to confirm a hypertension diagnosis and assist with medication titration is emphasized in the ACC/AHA guidelines.

The importance of appropriate BP measurement technique to confirm the diagnosis of hypertension and assist with medication titration was also emphasized.¹ BP measurement technique in usual clinical practice is frequently suboptimal, most commonly resulting in falsely elevated readings.^9,10 The guideline recommends the use of out-of-office measurements to confirm elevated clinic readings, screen for white-coat and masked hypertension, and assist in medication adjustment decisions. It is critically important that appropriate BP measurement technique is used, which in many cases, will avoid inappropriate treatment. (See “Getting the hypertension Dx right: Patient positioning matters,” JFP. 2018;67:199-207.)

A look at the evidence supporting lower BP goals

The 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for adults with hypertension commonly seen in clinical practice, including those with CVD or an elevated ASCVD risk (10-year risk ≥10% using the Pooled Cohort Equations¹¹), those with hypertension and low ASCVD risk (10-year risk <10%), and those with hypertension who have concomitant diabetes or CKD.¹ The guideline also recommends an SBP goal <130 mm Hg for independently-living, ambulatory older adults (≥65 years) with hypertension.¹ TABLE 2^1,2,6 compares the BP goals in the new 2017 ACC/AHA guidelines to previous recommendations.

SPRINT. Significant new literature has been generated since the publication of JNC 8 that supports these lower BP goals, particularly in patients with CVD or who are at high ASCVD risk.^8,12-15 For example, the Systolic Blood Pressure Intervention Trial (SPRINT) was the largest RCT to assess whether lower BP goals decrease the risk of adverse CVD outcomes.¹⁶ In SPRINT, 9361 patients with an SBP ≥130 mm Hg and an increased risk of CVD, but without diabetes or a history of stroke, were randomized to intensive BP treatment (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). After a median follow-up of 3.26 years, the study was stopped early due to a decreased risk in the primary composite outcome of myocardial infarction (MI), other acute coronary syndromes (ACS), stroke, heart failure, or death from CV causes (number needed to treat [NNT] to prevent one event=61).

Intensive treatment was also associated with a lower risk of all-cause mortality (NNT=90), heart failure (NNT=123), death from CV causes (NNT=172), and the primary outcome or death (NNT=52). While hypotension was higher in the intensive treatment group (number needed to harm [NNH]=106), as was syncope (NNH=173), electrolyte abnormalities (NNH=126), and acute kidney injury or failure (NNH=61), the authors noted that the benefits of lower BP outweighed the risks. Also, there was no increased risk of injurious falls. Therefore, despite the risk of adverse events, SPRINT demonstrated that lower BP goals significantly reduce the risk of adverse CV outcomes.

Continue to: Meta-analyses that have been conducted since SPRINT...

Meta-analyses that have been conducted since SPRINT, and that have incorporated SPRINT data, also support lower BP goals. In the systematic review performed for the 2017 ACC/AHA guideline, an SBP <130 mm Hg compared to a higher BP target was associated with a reduced risk of major CV events, stroke, MI, and heart failure, although not all-cause mortality.⁸ These findings were largely consistent with other recent meta-analyses.^12-15 For example, Bundy et al¹⁵ reported significant CV benefit with more vs less intensive BP lowering, whether or not the data from SPRINT were included, with the greatest reduction in risk seen in the groups with highest baseline BP.

It is important to consider a patient’s baseline level of risk when evaluating the absolute benefit of lower BP targets on CV outcomes. For patients with higher CV risk, the absolute benefit of treatment is greater.^12-14 These findings support the 2017 ACC/AHA guideline, which recommends initiating drug therapy, in addition to lifestyle modification, in adults with hypertension and high ASCVD risk when the average BP is >130/80 mm Hg, with a goal of <130/80 mm Hg. TABLE 3^12-15,17-22 summarizes recent systematic reviews and meta-analyses conducted since the publication of JNC 8 that assess the association between intensity of BP lowering and adverse CV and related outcomes.

Treating patients with low CV risk

The evidence supporting a lower BP goal in patients with low CV risk is less than for patients at elevated risk. There are no large RCTs for this group that have assessed whether an intensive BP lowering strategy decreases CV outcomes more than a standard BP strategy (eg, <140/90 mm Hg). It is likely that absolute benefit is much smaller than for patients with, or at high risk for, ASCVD. 

However, epidemiologic observational studies have indicated a significant log-linear increase in CV mortality starting at an SBP of 115 mm Hg.²³ A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.²³ Decades worth of exposure to “elevated” BP levels would likely result in significant vascular damage, and attenuation of this process would likely be beneficial.^24,25 An RCT specifically designed to test this hypothesis, however, would not be pragmatic considering the substantial number of patient-years that would be required.

Due to insufficient data documenting the value of antihypertensive drug therapy for primary prevention in adults with “elevated” BP and stage 1 hypertension at low risk for CVD, the 2017 ACC/AHA guideline recommends that drug therapy be initiated for all adults only when their BP average is ≥140/90 mm Hg.¹ In contrast, for patients needing secondary prevention and for those with elevated CVD risk, the guideline recommends medication in addition to lifestyle modifications once the average BP is ≥130/80 mm Hg. The recommendation to withhold drug therapy until the BP is ≥140/90 mm Hg in patients needing primary prevention is supported by a new meta-analysis of 74 trials with 306,273 participants that aimed to assess the association between BP-lowering treatment and death and CVD at various BP levels.¹⁷ In this analysis, pharmacologic treatment was associated with a reduced risk of all-cause mortality, major CVD events, and coronary heart disease if the SBP was ≥140 mm Hg.

Continue to: Treating older patients

Significant controversy has existed regarding the optimal BP goal in older patients, particularly once the JNC 8 recommended relaxing the SBP goal to <150 mm Hg for pateints ≥60 years of age.^6,7 This recommendation was consistent with the guideline from the American College of Physicians (ACP)/AAFP,²⁶ which also recommended a lower SBP of <140 mm Hg in patients with a history of stroke or transient ischemic attack and those at high CV risk.²⁶

A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.

Evidence is available, however, supporting more intensive BP goals in older independently-living ambulatory adults. A pre-planned subgroup analysis was conducted in 2636 SPRINT participants ≥75 years of age.²⁷ Similar to the overall experience in SPRINT, lower SBP goals were associated with significant reductions in CV events, including the composite CVD primary outcome (NNT=27), heart failure (NNT=63), nonfatal heart failure (NNT=66), and all-cause mortality (NNT=41). In addition, the relative benefits were approximately equal whether the patients were the most fit, non-fit, or frail, with the absolute benefit being greatest in those who were frail (recognizing that the SPRINT participants were independently-living ambulatory adults). While the absolute rate of serious adverse events was higher in the more intensive BP goal group, there was no statistically significant difference in the incidence of hypotension, orthostatic hypotension, syncope, electrolyte abnormalities, or acute kidney injury or renal failure.

Use of lower BP goals than recommended by JNC 8 was also supported by another recent meta-analysis that compared the outcomes of intensive BP lowering (SBP <140 mm Hg) to a standard BP-lowering strategy (SBP <150 mm Hg).¹⁸ Using a random-effects model, more intensive BP lowering was associated with a significant reduction in major adverse CV events (29%), CV mortality (33%), and heart failure (37%), with no increase in serious adverse events or renal failure. Findings with the fixed-effects model used to confirm results were largely consistent, with the exception of a possible increase in renal failure.

Although the evidence supporting lower BP goals in older, ambulatory, noninstitutionalized patients is sound, it is important to consider a patient’s overall disease burden. For older adults with multiple comorbidities and limited life expectancy, as well as those who are nonambulatory or institutionalized, decisions on the intensity of BP lowering should be made using a team-based approach, weighing the risks and benefits.¹

Continue to: Treating patients with diabetes

Treating patients with diabetes

The most appropriate BP goal for patients with diabetes has been the subject of much debate, with different goals recommended in different guidelines (TABLE 2^1,2,6). The most recent American Diabetes Association guideline recommends a BP goal <140/90 mm Hg for most patients, with lower targets (<130/80 mm Hg) for patients at high CV risk if it is achievable without undue treatment burden,²⁸ whereas the 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for all adults with diabetes.¹

The ACCORD trial. There is limited evidence to suggest which BP goal is most appropriate for patients with diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is the only RCT specifically designed to assess the impact of intensive vs standard BP goals in patients with diabetes.²⁹ In ACCORD, 4733 patients with type 2 diabetes were randomized to either an intensive BP-lowering group (SBP <120 mm Hg) or a standard BP-lowering group (SBP <140 mm Hg). After a mean follow-up of 4.7 years, there was no difference in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from CV causes. However, the risk of stroke was reduced (NNT=89). Interpretation of ACCORD is limited due to its factorial design and because the trial was significantly underpowered.

Systematic reviews and meta-analyses. Literature supporting lower BP goals in patients with diabetes primarily comes from systematic reviews and meta-analyses.³⁰ In the evidence-based review performed for the 2017 ACC/AHA guidelines, more intensive treatment was associated with a decrease in fatal or nonfatal stroke.⁸ The results from the ACCORD trial and SPRINT are consistent,³¹ and a sub-study of SPRINT patients with pre-diabetes showed preservation of CV benefit.³² Also, a meta-analysis of subgroups of trial participants with diabetes showed that more intensive BP lowering in patients is associated with a decrease in major CV events.¹⁴

Treating patients with chronic kidney disease

As with diabetes and older patients, recommended goals for patients with CKD have varied (TABLE 2^1,2,6). The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guideline recommended the same target BP as JNC 7 and the 2017 ACC/AHA guideline: ≤130/80 mm Hg in patients with CKD and urine albumin excretion ≥30 mg/24 hours (or equivalent).^1,2,33 KDIGO recommended a more relaxed target (≤140/90 mm Hg), however, for patients with CKD and urine albumin excretion <30 mg/24 hours.^1,33

Scant data exist from RCTs designed to assess the CV effects of intensive BP targets in patients with CKD. In SPRINT, where 28% of patients had stage 3 or 4 CKD, benefits of more intensive therapy were similar to those observed in the overall cohort.^16,34 While some RCTs have assessed the effect of more intensive BP lowering on progression of CKD, they were not specifically designed or powered to address CV outcomes.^35,36

Continue to: In recent meta-analyses assessing the effects...

In recent meta-analyses assessing the effects of intensive BP lowering on renal and CV events in patients with CKD, a lower BP strategy was not associated with a decrease in CV events.^8,14,19 However, more intensive therapy was associated with a 17% reduced risk of composite kidney failure events and an 18% reduction in end-stage kidney disease.¹⁹ The risk of kidney failure with lower BP goals was 27% lower in patients with baseline proteinuria, but was not significant in patients who did not have proteinuria.¹⁹

Evidence supports lower BP goals, but guidelines should guide

The lower BP goals advised in the 2017 ACC/AHA guideline are supported by substantial new high-quality evidence that was not available at the time of the JNC 8 report.¹ The strongest evidence for lower goals is found in patients with, or at high risk for, CVD, but other patients commonly seen by primary care providers, including those at lower CVD risk, older patients, and those with diabetes or CKD are also likely to benefit.¹

Despite the debates, it is important to remember that guidelines are intended to “guide.” As stated in the guideline, “Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment.”¹ They should be easy to understand and apply, and a consistent, evidence-based BP goal of <130/80 mm Hg for most patients facilitates implementation.

Although more of the US population is categorized as hypertensive under the new guideline, only 1.9% more require drug therapy.

Although more of the US population is categorized as hypertensive under the new guideline (46% now vs 32% before), only 1.9% more require drug therapy, as the vast majority of the newly classified hypertensives are primary prevention patients for whom only lifestyle modification is recommended.³⁷ However, to attain these goals, greater emphasis will be needed on utilizing team-based care, health information technology including electronic medical records and telehealth, performance measures, quality improvement strategies, and financial incentives.¹

Finally, as emphasized in the guidelines, BP monitoring technique matters. Clinicians should not accept flawed BP measurement techniques any more than they would accept flawed results from studies performed incorrectly.

CORRESPONDENCE
Eric J. MacLaughlin, PharmD, BCPS, FASHP, FCCP, Texas Tech University Health Sciences Center,1300 S. Coulter Dr., Amarillo, TX 79106; Eric.MacLaughlin@ttuhsc.edu.

ACKNOWLEDGEMENTS

The authors thank Paul K. Whelton, MB, MD, MSc, FAHA, and Robert M. Carey, MD, FAHA, for their review of this manuscript. 

For more than a century, clinicians have pondered the significance of elevated blood pressure (BP) and its contribution to cardiovascular disease (CVD). While it is widely understood that high BP increases CVD events, and that treatment lowers that risk, the most appropriate BP goal continues to be a subject of debate.

This article briefly summarizes the evidence to support lower BP goals for patients with hypertension who are commonly seen in family practice, including those needing primary prevention, as well as those with, or at high risk for, atherosclerotic cardiovascular disease (ASCVD), patients with diabetes, and those with chronic kidney disease (CKD). Detailed information regarding specific lifestyle and medication treatment recommendations and thresholds for drug therapy is beyond the scope of this review.

A brief history: ACC/AHA guidelines vs JNC 7 and 8

The most recent comprehensive, evidence-based guideline on the prevention, detection, evaluation, and management of high BP in adults was released in late 2017 by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹ It was the first comprehensive BP guideline since the Seventh Report of the Joint National Committee (JNC 7) in 2003.² The new guideline includes several changes, notably in how BP is classified, the threshold for initiation of antihypertensive drug therapy, and target BP.

While widely viewed as positive, the changes in classification, thresholds, and targets for BP therapy have generated controversy and disagreement. Common reasons cited include concern about the data supporting lower thresholds for treatment, the applicability of trial findings to broad patient populations, and the risk of harm with lower BP goals.³ The American Academy of Family Physicians (AAFP) declined to endorse the ACC/AHA guidelines and continues to support the 2014 report by the panel members appointed to the Eighth Joint National Committee (JNC 8) by the National Heart Lung and Blood Institute (NHLBI).⁴ A primary reason cited for the lack of support for the 2017 guideline is that the majority of recommendations made in the ACC/AHA guideline were not “based on a systematic evidence review.”⁴ However, there are significant differences in purpose, structure, and scope between the ACC/AHA and JNC 8.

Evidence supports lower BP goals for a number of different patient populations and groups.

In 2013, the NHLBI announced that it would cease involvement in creating guidelines and transferred responsibility for development to professional organizations.⁵ Of the 5 guidelines that were in the process of creation (cholesterol, lifestyle intervention, obesity, risk assessment, and high BP), all but the high BP guideline were transferred to the ACC/AHA for completion. The panel members appointed to the JNC 8 elected to publish their recommendations independently and focused only on 3 “critical questions” related to hypertension therapy (eg, therapy initiation, BP goals, and choice of initial agent).⁶

[polldaddy:10041785]

The JNC 8 report generated significant controversy with the recommendation to relax the BP goal for patients ≥60 years of age to <150/90 mm Hg. Members of the JNC 8 panel who disagreed with this goal published a "minority view" citing concerns about the negative impact the goal would have on CVD and public health, and the "insufficient and inconsistent" evidence supporting relaxed goals.⁷ The dissenting group cited additional drawbacks of the recommendation, noting that it was highly focused, included data only from randomized controlled trials (RCTs; no meta-analyses or observational data), and did not address or provide guidance on numerous other issues of importance in the care of hypertension.

While the 2017 ACC/AHA guideline also includes formal systematic evidence reviews on major critical questions (ie, optimal BP targets, preferred antihypertensives, the role of home and ambulatory BP monitoring),⁸ it was designed to be comprehensive and useful for clinicians, providing 106 graded recommendations on commonly encountered questions. It would have been unrealistic to do a formal systematic evidence review and meta-analysis on all clinically relevant questions seen in practice. However, available systematic reviews, meta-analyses, and observational data were scrutinized and used to support the recommendations wherever possible.

Continue to: Say "goodbye" to prehypertension; say "hello" to elevated BP

Say “goodbye” to prehypertension; say “hello” to elevated BP

The 2017 ACC/AHA guideline changed the BP classification for adults (TABLE 1^1,2). While “normal” remained respectively.¹ Removal of the “prehypertension” category and use of the term “elevated” instead was meant to better convey the importance of lifestyle interventions to forestall the development of hypertension.

Don’t underestimate the power of BP measurement technique

The importance of appropriate BP measurement technique to confirm a hypertension diagnosis and assist with medication titration is emphasized in the ACC/AHA guidelines.

The importance of appropriate BP measurement technique to confirm the diagnosis of hypertension and assist with medication titration was also emphasized.¹ BP measurement technique in usual clinical practice is frequently suboptimal, most commonly resulting in falsely elevated readings.^9,10 The guideline recommends the use of out-of-office measurements to confirm elevated clinic readings, screen for white-coat and masked hypertension, and assist in medication adjustment decisions. It is critically important that appropriate BP measurement technique is used, which in many cases, will avoid inappropriate treatment. (See “Getting the hypertension Dx right: Patient positioning matters,” JFP. 2018;67:199-207.)

A look at the evidence supporting lower BP goals

The 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for adults with hypertension commonly seen in clinical practice, including those with CVD or an elevated ASCVD risk (10-year risk ≥10% using the Pooled Cohort Equations¹¹), those with hypertension and low ASCVD risk (10-year risk <10%), and those with hypertension who have concomitant diabetes or CKD.¹ The guideline also recommends an SBP goal <130 mm Hg for independently-living, ambulatory older adults (≥65 years) with hypertension.¹ TABLE 2^1,2,6 compares the BP goals in the new 2017 ACC/AHA guidelines to previous recommendations.

SPRINT. Significant new literature has been generated since the publication of JNC 8 that supports these lower BP goals, particularly in patients with CVD or who are at high ASCVD risk.^8,12-15 For example, the Systolic Blood Pressure Intervention Trial (SPRINT) was the largest RCT to assess whether lower BP goals decrease the risk of adverse CVD outcomes.¹⁶ In SPRINT, 9361 patients with an SBP ≥130 mm Hg and an increased risk of CVD, but without diabetes or a history of stroke, were randomized to intensive BP treatment (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). After a median follow-up of 3.26 years, the study was stopped early due to a decreased risk in the primary composite outcome of myocardial infarction (MI), other acute coronary syndromes (ACS), stroke, heart failure, or death from CV causes (number needed to treat [NNT] to prevent one event=61).

Intensive treatment was also associated with a lower risk of all-cause mortality (NNT=90), heart failure (NNT=123), death from CV causes (NNT=172), and the primary outcome or death (NNT=52). While hypotension was higher in the intensive treatment group (number needed to harm [NNH]=106), as was syncope (NNH=173), electrolyte abnormalities (NNH=126), and acute kidney injury or failure (NNH=61), the authors noted that the benefits of lower BP outweighed the risks. Also, there was no increased risk of injurious falls. Therefore, despite the risk of adverse events, SPRINT demonstrated that lower BP goals significantly reduce the risk of adverse CV outcomes.

Continue to: Meta-analyses that have been conducted since SPRINT...

Meta-analyses that have been conducted since SPRINT, and that have incorporated SPRINT data, also support lower BP goals. In the systematic review performed for the 2017 ACC/AHA guideline, an SBP <130 mm Hg compared to a higher BP target was associated with a reduced risk of major CV events, stroke, MI, and heart failure, although not all-cause mortality.⁸ These findings were largely consistent with other recent meta-analyses.^12-15 For example, Bundy et al¹⁵ reported significant CV benefit with more vs less intensive BP lowering, whether or not the data from SPRINT were included, with the greatest reduction in risk seen in the groups with highest baseline BP.

It is important to consider a patient’s baseline level of risk when evaluating the absolute benefit of lower BP targets on CV outcomes. For patients with higher CV risk, the absolute benefit of treatment is greater.^12-14 These findings support the 2017 ACC/AHA guideline, which recommends initiating drug therapy, in addition to lifestyle modification, in adults with hypertension and high ASCVD risk when the average BP is >130/80 mm Hg, with a goal of <130/80 mm Hg. TABLE 3^12-15,17-22 summarizes recent systematic reviews and meta-analyses conducted since the publication of JNC 8 that assess the association between intensity of BP lowering and adverse CV and related outcomes.

Treating patients with low CV risk

The evidence supporting a lower BP goal in patients with low CV risk is less than for patients at elevated risk. There are no large RCTs for this group that have assessed whether an intensive BP lowering strategy decreases CV outcomes more than a standard BP strategy (eg, <140/90 mm Hg). It is likely that absolute benefit is much smaller than for patients with, or at high risk for, ASCVD. 

However, epidemiologic observational studies have indicated a significant log-linear increase in CV mortality starting at an SBP of 115 mm Hg.²³ A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.²³ Decades worth of exposure to “elevated” BP levels would likely result in significant vascular damage, and attenuation of this process would likely be beneficial.^24,25 An RCT specifically designed to test this hypothesis, however, would not be pragmatic considering the substantial number of patient-years that would be required.

Due to insufficient data documenting the value of antihypertensive drug therapy for primary prevention in adults with “elevated” BP and stage 1 hypertension at low risk for CVD, the 2017 ACC/AHA guideline recommends that drug therapy be initiated for all adults only when their BP average is ≥140/90 mm Hg.¹ In contrast, for patients needing secondary prevention and for those with elevated CVD risk, the guideline recommends medication in addition to lifestyle modifications once the average BP is ≥130/80 mm Hg. The recommendation to withhold drug therapy until the BP is ≥140/90 mm Hg in patients needing primary prevention is supported by a new meta-analysis of 74 trials with 306,273 participants that aimed to assess the association between BP-lowering treatment and death and CVD at various BP levels.¹⁷ In this analysis, pharmacologic treatment was associated with a reduced risk of all-cause mortality, major CVD events, and coronary heart disease if the SBP was ≥140 mm Hg.

Continue to: Treating older patients

Significant controversy has existed regarding the optimal BP goal in older patients, particularly once the JNC 8 recommended relaxing the SBP goal to <150 mm Hg for pateints ≥60 years of age.^6,7 This recommendation was consistent with the guideline from the American College of Physicians (ACP)/AAFP,²⁶ which also recommended a lower SBP of <140 mm Hg in patients with a history of stroke or transient ischemic attack and those at high CV risk.²⁶

A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.

Evidence is available, however, supporting more intensive BP goals in older independently-living ambulatory adults. A pre-planned subgroup analysis was conducted in 2636 SPRINT participants ≥75 years of age.²⁷ Similar to the overall experience in SPRINT, lower SBP goals were associated with significant reductions in CV events, including the composite CVD primary outcome (NNT=27), heart failure (NNT=63), nonfatal heart failure (NNT=66), and all-cause mortality (NNT=41). In addition, the relative benefits were approximately equal whether the patients were the most fit, non-fit, or frail, with the absolute benefit being greatest in those who were frail (recognizing that the SPRINT participants were independently-living ambulatory adults). While the absolute rate of serious adverse events was higher in the more intensive BP goal group, there was no statistically significant difference in the incidence of hypotension, orthostatic hypotension, syncope, electrolyte abnormalities, or acute kidney injury or renal failure.

Use of lower BP goals than recommended by JNC 8 was also supported by another recent meta-analysis that compared the outcomes of intensive BP lowering (SBP <140 mm Hg) to a standard BP-lowering strategy (SBP <150 mm Hg).¹⁸ Using a random-effects model, more intensive BP lowering was associated with a significant reduction in major adverse CV events (29%), CV mortality (33%), and heart failure (37%), with no increase in serious adverse events or renal failure. Findings with the fixed-effects model used to confirm results were largely consistent, with the exception of a possible increase in renal failure.

Although the evidence supporting lower BP goals in older, ambulatory, noninstitutionalized patients is sound, it is important to consider a patient’s overall disease burden. For older adults with multiple comorbidities and limited life expectancy, as well as those who are nonambulatory or institutionalized, decisions on the intensity of BP lowering should be made using a team-based approach, weighing the risks and benefits.¹

Continue to: Treating patients with diabetes

Treating patients with diabetes

The most appropriate BP goal for patients with diabetes has been the subject of much debate, with different goals recommended in different guidelines (TABLE 2^1,2,6). The most recent American Diabetes Association guideline recommends a BP goal <140/90 mm Hg for most patients, with lower targets (<130/80 mm Hg) for patients at high CV risk if it is achievable without undue treatment burden,²⁸ whereas the 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for all adults with diabetes.¹

The ACCORD trial. There is limited evidence to suggest which BP goal is most appropriate for patients with diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is the only RCT specifically designed to assess the impact of intensive vs standard BP goals in patients with diabetes.²⁹ In ACCORD, 4733 patients with type 2 diabetes were randomized to either an intensive BP-lowering group (SBP <120 mm Hg) or a standard BP-lowering group (SBP <140 mm Hg). After a mean follow-up of 4.7 years, there was no difference in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from CV causes. However, the risk of stroke was reduced (NNT=89). Interpretation of ACCORD is limited due to its factorial design and because the trial was significantly underpowered.

Systematic reviews and meta-analyses. Literature supporting lower BP goals in patients with diabetes primarily comes from systematic reviews and meta-analyses.³⁰ In the evidence-based review performed for the 2017 ACC/AHA guidelines, more intensive treatment was associated with a decrease in fatal or nonfatal stroke.⁸ The results from the ACCORD trial and SPRINT are consistent,³¹ and a sub-study of SPRINT patients with pre-diabetes showed preservation of CV benefit.³² Also, a meta-analysis of subgroups of trial participants with diabetes showed that more intensive BP lowering in patients is associated with a decrease in major CV events.¹⁴

Treating patients with chronic kidney disease

As with diabetes and older patients, recommended goals for patients with CKD have varied (TABLE 2^1,2,6). The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guideline recommended the same target BP as JNC 7 and the 2017 ACC/AHA guideline: ≤130/80 mm Hg in patients with CKD and urine albumin excretion ≥30 mg/24 hours (or equivalent).^1,2,33 KDIGO recommended a more relaxed target (≤140/90 mm Hg), however, for patients with CKD and urine albumin excretion <30 mg/24 hours.^1,33

Scant data exist from RCTs designed to assess the CV effects of intensive BP targets in patients with CKD. In SPRINT, where 28% of patients had stage 3 or 4 CKD, benefits of more intensive therapy were similar to those observed in the overall cohort.^16,34 While some RCTs have assessed the effect of more intensive BP lowering on progression of CKD, they were not specifically designed or powered to address CV outcomes.^35,36

Continue to: In recent meta-analyses assessing the effects...

In recent meta-analyses assessing the effects of intensive BP lowering on renal and CV events in patients with CKD, a lower BP strategy was not associated with a decrease in CV events.^8,14,19 However, more intensive therapy was associated with a 17% reduced risk of composite kidney failure events and an 18% reduction in end-stage kidney disease.¹⁹ The risk of kidney failure with lower BP goals was 27% lower in patients with baseline proteinuria, but was not significant in patients who did not have proteinuria.¹⁹

Evidence supports lower BP goals, but guidelines should guide

The lower BP goals advised in the 2017 ACC/AHA guideline are supported by substantial new high-quality evidence that was not available at the time of the JNC 8 report.¹ The strongest evidence for lower goals is found in patients with, or at high risk for, CVD, but other patients commonly seen by primary care providers, including those at lower CVD risk, older patients, and those with diabetes or CKD are also likely to benefit.¹

Despite the debates, it is important to remember that guidelines are intended to “guide.” As stated in the guideline, “Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment.”¹ They should be easy to understand and apply, and a consistent, evidence-based BP goal of <130/80 mm Hg for most patients facilitates implementation.

Although more of the US population is categorized as hypertensive under the new guideline, only 1.9% more require drug therapy.

Although more of the US population is categorized as hypertensive under the new guideline (46% now vs 32% before), only 1.9% more require drug therapy, as the vast majority of the newly classified hypertensives are primary prevention patients for whom only lifestyle modification is recommended.³⁷ However, to attain these goals, greater emphasis will be needed on utilizing team-based care, health information technology including electronic medical records and telehealth, performance measures, quality improvement strategies, and financial incentives.¹

Finally, as emphasized in the guidelines, BP monitoring technique matters. Clinicians should not accept flawed BP measurement techniques any more than they would accept flawed results from studies performed incorrectly.

CORRESPONDENCE
Eric J. MacLaughlin, PharmD, BCPS, FASHP, FCCP, Texas Tech University Health Sciences Center,1300 S. Coulter Dr., Amarillo, TX 79106; Eric.MacLaughlin@ttuhsc.edu.

ACKNOWLEDGEMENTS

The authors thank Paul K. Whelton, MB, MD, MSc, FAHA, and Robert M. Carey, MD, FAHA, for their review of this manuscript. 

For more than a century, clinicians have pondered the significance of elevated blood pressure (BP) and its contribution to cardiovascular disease (CVD). While it is widely understood that high BP increases CVD events, and that treatment lowers that risk, the most appropriate BP goal continues to be a subject of debate.

This article briefly summarizes the evidence to support lower BP goals for patients with hypertension who are commonly seen in family practice, including those needing primary prevention, as well as those with, or at high risk for, atherosclerotic cardiovascular disease (ASCVD), patients with diabetes, and those with chronic kidney disease (CKD). Detailed information regarding specific lifestyle and medication treatment recommendations and thresholds for drug therapy is beyond the scope of this review.

A brief history: ACC/AHA guidelines vs JNC 7 and 8

The most recent comprehensive, evidence-based guideline on the prevention, detection, evaluation, and management of high BP in adults was released in late 2017 by the American College of Cardiology (ACC) and the American Heart Association (AHA).¹ It was the first comprehensive BP guideline since the Seventh Report of the Joint National Committee (JNC 7) in 2003.² The new guideline includes several changes, notably in how BP is classified, the threshold for initiation of antihypertensive drug therapy, and target BP.

While widely viewed as positive, the changes in classification, thresholds, and targets for BP therapy have generated controversy and disagreement. Common reasons cited include concern about the data supporting lower thresholds for treatment, the applicability of trial findings to broad patient populations, and the risk of harm with lower BP goals.³ The American Academy of Family Physicians (AAFP) declined to endorse the ACC/AHA guidelines and continues to support the 2014 report by the panel members appointed to the Eighth Joint National Committee (JNC 8) by the National Heart Lung and Blood Institute (NHLBI).⁴ A primary reason cited for the lack of support for the 2017 guideline is that the majority of recommendations made in the ACC/AHA guideline were not “based on a systematic evidence review.”⁴ However, there are significant differences in purpose, structure, and scope between the ACC/AHA and JNC 8.

Evidence supports lower BP goals for a number of different patient populations and groups.

In 2013, the NHLBI announced that it would cease involvement in creating guidelines and transferred responsibility for development to professional organizations.⁵ Of the 5 guidelines that were in the process of creation (cholesterol, lifestyle intervention, obesity, risk assessment, and high BP), all but the high BP guideline were transferred to the ACC/AHA for completion. The panel members appointed to the JNC 8 elected to publish their recommendations independently and focused only on 3 “critical questions” related to hypertension therapy (eg, therapy initiation, BP goals, and choice of initial agent).⁶

[polldaddy:10041785]

The JNC 8 report generated significant controversy with the recommendation to relax the BP goal for patients ≥60 years of age to <150/90 mm Hg. Members of the JNC 8 panel who disagreed with this goal published a "minority view" citing concerns about the negative impact the goal would have on CVD and public health, and the "insufficient and inconsistent" evidence supporting relaxed goals.⁷ The dissenting group cited additional drawbacks of the recommendation, noting that it was highly focused, included data only from randomized controlled trials (RCTs; no meta-analyses or observational data), and did not address or provide guidance on numerous other issues of importance in the care of hypertension.

While the 2017 ACC/AHA guideline also includes formal systematic evidence reviews on major critical questions (ie, optimal BP targets, preferred antihypertensives, the role of home and ambulatory BP monitoring),⁸ it was designed to be comprehensive and useful for clinicians, providing 106 graded recommendations on commonly encountered questions. It would have been unrealistic to do a formal systematic evidence review and meta-analysis on all clinically relevant questions seen in practice. However, available systematic reviews, meta-analyses, and observational data were scrutinized and used to support the recommendations wherever possible.

Continue to: Say "goodbye" to prehypertension; say "hello" to elevated BP

Say “goodbye” to prehypertension; say “hello” to elevated BP

The 2017 ACC/AHA guideline changed the BP classification for adults (TABLE 1^1,2). While “normal” remained respectively.¹ Removal of the “prehypertension” category and use of the term “elevated” instead was meant to better convey the importance of lifestyle interventions to forestall the development of hypertension.

Don’t underestimate the power of BP measurement technique

The importance of appropriate BP measurement technique to confirm a hypertension diagnosis and assist with medication titration is emphasized in the ACC/AHA guidelines.

The importance of appropriate BP measurement technique to confirm the diagnosis of hypertension and assist with medication titration was also emphasized.¹ BP measurement technique in usual clinical practice is frequently suboptimal, most commonly resulting in falsely elevated readings.^9,10 The guideline recommends the use of out-of-office measurements to confirm elevated clinic readings, screen for white-coat and masked hypertension, and assist in medication adjustment decisions. It is critically important that appropriate BP measurement technique is used, which in many cases, will avoid inappropriate treatment. (See “Getting the hypertension Dx right: Patient positioning matters,” JFP. 2018;67:199-207.)

A look at the evidence supporting lower BP goals

The 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for adults with hypertension commonly seen in clinical practice, including those with CVD or an elevated ASCVD risk (10-year risk ≥10% using the Pooled Cohort Equations¹¹), those with hypertension and low ASCVD risk (10-year risk <10%), and those with hypertension who have concomitant diabetes or CKD.¹ The guideline also recommends an SBP goal <130 mm Hg for independently-living, ambulatory older adults (≥65 years) with hypertension.¹ TABLE 2^1,2,6 compares the BP goals in the new 2017 ACC/AHA guidelines to previous recommendations.

SPRINT. Significant new literature has been generated since the publication of JNC 8 that supports these lower BP goals, particularly in patients with CVD or who are at high ASCVD risk.^8,12-15 For example, the Systolic Blood Pressure Intervention Trial (SPRINT) was the largest RCT to assess whether lower BP goals decrease the risk of adverse CVD outcomes.¹⁶ In SPRINT, 9361 patients with an SBP ≥130 mm Hg and an increased risk of CVD, but without diabetes or a history of stroke, were randomized to intensive BP treatment (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). After a median follow-up of 3.26 years, the study was stopped early due to a decreased risk in the primary composite outcome of myocardial infarction (MI), other acute coronary syndromes (ACS), stroke, heart failure, or death from CV causes (number needed to treat [NNT] to prevent one event=61).

Intensive treatment was also associated with a lower risk of all-cause mortality (NNT=90), heart failure (NNT=123), death from CV causes (NNT=172), and the primary outcome or death (NNT=52). While hypotension was higher in the intensive treatment group (number needed to harm [NNH]=106), as was syncope (NNH=173), electrolyte abnormalities (NNH=126), and acute kidney injury or failure (NNH=61), the authors noted that the benefits of lower BP outweighed the risks. Also, there was no increased risk of injurious falls. Therefore, despite the risk of adverse events, SPRINT demonstrated that lower BP goals significantly reduce the risk of adverse CV outcomes.

Continue to: Meta-analyses that have been conducted since SPRINT...

Meta-analyses that have been conducted since SPRINT, and that have incorporated SPRINT data, also support lower BP goals. In the systematic review performed for the 2017 ACC/AHA guideline, an SBP <130 mm Hg compared to a higher BP target was associated with a reduced risk of major CV events, stroke, MI, and heart failure, although not all-cause mortality.⁸ These findings were largely consistent with other recent meta-analyses.^12-15 For example, Bundy et al¹⁵ reported significant CV benefit with more vs less intensive BP lowering, whether or not the data from SPRINT were included, with the greatest reduction in risk seen in the groups with highest baseline BP.

It is important to consider a patient’s baseline level of risk when evaluating the absolute benefit of lower BP targets on CV outcomes. For patients with higher CV risk, the absolute benefit of treatment is greater.^12-14 These findings support the 2017 ACC/AHA guideline, which recommends initiating drug therapy, in addition to lifestyle modification, in adults with hypertension and high ASCVD risk when the average BP is >130/80 mm Hg, with a goal of <130/80 mm Hg. TABLE 3^12-15,17-22 summarizes recent systematic reviews and meta-analyses conducted since the publication of JNC 8 that assess the association between intensity of BP lowering and adverse CV and related outcomes.

Treating patients with low CV risk

The evidence supporting a lower BP goal in patients with low CV risk is less than for patients at elevated risk. There are no large RCTs for this group that have assessed whether an intensive BP lowering strategy decreases CV outcomes more than a standard BP strategy (eg, <140/90 mm Hg). It is likely that absolute benefit is much smaller than for patients with, or at high risk for, ASCVD. 

However, epidemiologic observational studies have indicated a significant log-linear increase in CV mortality starting at an SBP of 115 mm Hg.²³ A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.²³ Decades worth of exposure to “elevated” BP levels would likely result in significant vascular damage, and attenuation of this process would likely be beneficial.^24,25 An RCT specifically designed to test this hypothesis, however, would not be pragmatic considering the substantial number of patient-years that would be required.

Due to insufficient data documenting the value of antihypertensive drug therapy for primary prevention in adults with “elevated” BP and stage 1 hypertension at low risk for CVD, the 2017 ACC/AHA guideline recommends that drug therapy be initiated for all adults only when their BP average is ≥140/90 mm Hg.¹ In contrast, for patients needing secondary prevention and for those with elevated CVD risk, the guideline recommends medication in addition to lifestyle modifications once the average BP is ≥130/80 mm Hg. The recommendation to withhold drug therapy until the BP is ≥140/90 mm Hg in patients needing primary prevention is supported by a new meta-analysis of 74 trials with 306,273 participants that aimed to assess the association between BP-lowering treatment and death and CVD at various BP levels.¹⁷ In this analysis, pharmacologic treatment was associated with a reduced risk of all-cause mortality, major CVD events, and coronary heart disease if the SBP was ≥140 mm Hg.

Continue to: Treating older patients

Significant controversy has existed regarding the optimal BP goal in older patients, particularly once the JNC 8 recommended relaxing the SBP goal to <150 mm Hg for pateints ≥60 years of age.^6,7 This recommendation was consistent with the guideline from the American College of Physicians (ACP)/AAFP,²⁶ which also recommended a lower SBP of <140 mm Hg in patients with a history of stroke or transient ischemic attack and those at high CV risk.²⁶

A 20-mm Hg increase in SBP above 115 mm Hg is associated with an approximate doubling of stroke and ischemic heart disease mortality risk.

Evidence is available, however, supporting more intensive BP goals in older independently-living ambulatory adults. A pre-planned subgroup analysis was conducted in 2636 SPRINT participants ≥75 years of age.²⁷ Similar to the overall experience in SPRINT, lower SBP goals were associated with significant reductions in CV events, including the composite CVD primary outcome (NNT=27), heart failure (NNT=63), nonfatal heart failure (NNT=66), and all-cause mortality (NNT=41). In addition, the relative benefits were approximately equal whether the patients were the most fit, non-fit, or frail, with the absolute benefit being greatest in those who were frail (recognizing that the SPRINT participants were independently-living ambulatory adults). While the absolute rate of serious adverse events was higher in the more intensive BP goal group, there was no statistically significant difference in the incidence of hypotension, orthostatic hypotension, syncope, electrolyte abnormalities, or acute kidney injury or renal failure.

Use of lower BP goals than recommended by JNC 8 was also supported by another recent meta-analysis that compared the outcomes of intensive BP lowering (SBP <140 mm Hg) to a standard BP-lowering strategy (SBP <150 mm Hg).¹⁸ Using a random-effects model, more intensive BP lowering was associated with a significant reduction in major adverse CV events (29%), CV mortality (33%), and heart failure (37%), with no increase in serious adverse events or renal failure. Findings with the fixed-effects model used to confirm results were largely consistent, with the exception of a possible increase in renal failure.

Although the evidence supporting lower BP goals in older, ambulatory, noninstitutionalized patients is sound, it is important to consider a patient’s overall disease burden. For older adults with multiple comorbidities and limited life expectancy, as well as those who are nonambulatory or institutionalized, decisions on the intensity of BP lowering should be made using a team-based approach, weighing the risks and benefits.¹

Continue to: Treating patients with diabetes

Treating patients with diabetes

The most appropriate BP goal for patients with diabetes has been the subject of much debate, with different goals recommended in different guidelines (TABLE 2^1,2,6). The most recent American Diabetes Association guideline recommends a BP goal <140/90 mm Hg for most patients, with lower targets (<130/80 mm Hg) for patients at high CV risk if it is achievable without undue treatment burden,²⁸ whereas the 2017 ACC/AHA guideline recommends a BP goal <130/80 mm Hg for all adults with diabetes.¹

The ACCORD trial. There is limited evidence to suggest which BP goal is most appropriate for patients with diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is the only RCT specifically designed to assess the impact of intensive vs standard BP goals in patients with diabetes.²⁹ In ACCORD, 4733 patients with type 2 diabetes were randomized to either an intensive BP-lowering group (SBP <120 mm Hg) or a standard BP-lowering group (SBP <140 mm Hg). After a mean follow-up of 4.7 years, there was no difference in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from CV causes. However, the risk of stroke was reduced (NNT=89). Interpretation of ACCORD is limited due to its factorial design and because the trial was significantly underpowered.

Systematic reviews and meta-analyses. Literature supporting lower BP goals in patients with diabetes primarily comes from systematic reviews and meta-analyses.³⁰ In the evidence-based review performed for the 2017 ACC/AHA guidelines, more intensive treatment was associated with a decrease in fatal or nonfatal stroke.⁸ The results from the ACCORD trial and SPRINT are consistent,³¹ and a sub-study of SPRINT patients with pre-diabetes showed preservation of CV benefit.³² Also, a meta-analysis of subgroups of trial participants with diabetes showed that more intensive BP lowering in patients is associated with a decrease in major CV events.¹⁴

Treating patients with chronic kidney disease

As with diabetes and older patients, recommended goals for patients with CKD have varied (TABLE 2^1,2,6). The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guideline recommended the same target BP as JNC 7 and the 2017 ACC/AHA guideline: ≤130/80 mm Hg in patients with CKD and urine albumin excretion ≥30 mg/24 hours (or equivalent).^1,2,33 KDIGO recommended a more relaxed target (≤140/90 mm Hg), however, for patients with CKD and urine albumin excretion <30 mg/24 hours.^1,33

Scant data exist from RCTs designed to assess the CV effects of intensive BP targets in patients with CKD. In SPRINT, where 28% of patients had stage 3 or 4 CKD, benefits of more intensive therapy were similar to those observed in the overall cohort.^16,34 While some RCTs have assessed the effect of more intensive BP lowering on progression of CKD, they were not specifically designed or powered to address CV outcomes.^35,36

Continue to: In recent meta-analyses assessing the effects...

In recent meta-analyses assessing the effects of intensive BP lowering on renal and CV events in patients with CKD, a lower BP strategy was not associated with a decrease in CV events.^8,14,19 However, more intensive therapy was associated with a 17% reduced risk of composite kidney failure events and an 18% reduction in end-stage kidney disease.¹⁹ The risk of kidney failure with lower BP goals was 27% lower in patients with baseline proteinuria, but was not significant in patients who did not have proteinuria.¹⁹

Evidence supports lower BP goals, but guidelines should guide

The lower BP goals advised in the 2017 ACC/AHA guideline are supported by substantial new high-quality evidence that was not available at the time of the JNC 8 report.¹ The strongest evidence for lower goals is found in patients with, or at high risk for, CVD, but other patients commonly seen by primary care providers, including those at lower CVD risk, older patients, and those with diabetes or CKD are also likely to benefit.¹

Despite the debates, it is important to remember that guidelines are intended to “guide.” As stated in the guideline, “Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances and should not replace clinical judgment.”¹ They should be easy to understand and apply, and a consistent, evidence-based BP goal of <130/80 mm Hg for most patients facilitates implementation.

Although more of the US population is categorized as hypertensive under the new guideline, only 1.9% more require drug therapy.

Although more of the US population is categorized as hypertensive under the new guideline (46% now vs 32% before), only 1.9% more require drug therapy, as the vast majority of the newly classified hypertensives are primary prevention patients for whom only lifestyle modification is recommended.³⁷ However, to attain these goals, greater emphasis will be needed on utilizing team-based care, health information technology including electronic medical records and telehealth, performance measures, quality improvement strategies, and financial incentives.¹

Finally, as emphasized in the guidelines, BP monitoring technique matters. Clinicians should not accept flawed BP measurement techniques any more than they would accept flawed results from studies performed incorrectly.

CORRESPONDENCE
Eric J. MacLaughlin, PharmD, BCPS, FASHP, FCCP, Texas Tech University Health Sciences Center,1300 S. Coulter Dr., Amarillo, TX 79106; Eric.MacLaughlin@ttuhsc.edu.

ACKNOWLEDGEMENTS

The authors thank Paul K. Whelton, MB, MD, MSc, FAHA, and Robert M. Carey, MD, FAHA, for their review of this manuscript. 

Resources

Rosenberg R, Lindsey NP, Fischer M, et al. Vital Signs: Trends in reported vectorborne disease cases—United States and territories, 2004-2016. MMWR Morb Mortal Wkly Rep. 2018;67:496-501.

US Environmental Protection Agency. Repellents: protection against mosquitoes, ticks, and other arthropods. Available at: https://www.epa.gov/insect-repellents. Accessed June 6, 2018.

Centers for Disease Control and Prevention. Zika virus: prevent mosquito bites. Available at: https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html. Accessed June 6, 2018.

Resources

Rosenberg R, Lindsey NP, Fischer M, et al. Vital Signs: Trends in reported vectorborne disease cases—United States and territories, 2004-2016. MMWR Morb Mortal Wkly Rep. 2018;67:496-501.

US Environmental Protection Agency. Repellents: protection against mosquitoes, ticks, and other arthropods. Available at: https://www.epa.gov/insect-repellents. Accessed June 6, 2018.

Centers for Disease Control and Prevention. Zika virus: prevent mosquito bites. Available at: https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html. Accessed June 6, 2018.

Resources

Rosenberg R, Lindsey NP, Fischer M, et al. Vital Signs: Trends in reported vectorborne disease cases—United States and territories, 2004-2016. MMWR Morb Mortal Wkly Rep. 2018;67:496-501.

US Environmental Protection Agency. Repellents: protection against mosquitoes, ticks, and other arthropods. Available at: https://www.epa.gov/insect-repellents. Accessed June 6, 2018.

Centers for Disease Control and Prevention. Zika virus: prevent mosquito bites. Available at: https://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html. Accessed June 6, 2018.

Primarily home-based cognitive-behavioral therapy improved irritable bowel syndrome symptoms at least as much as conventional CBT, cut clinician time by 60%, and significantly outperformed educational sessions in a multicenter clinical trial reported in the July issue of Gastroenterology.

Acutely, primarily home-based CBT produced a mean 61% improvement in self-reported symptoms on the IBS version of the Clinical Global Impressions Scale, versus 44% for the educational control group (P less than .05), wrote Jeffrey M. Lackner, PsyD, of the State University of New York at Buffalo and his associates. Blinded gastroenterologists reported improvements of 56% and 40%, respectively (P less than .05). The superiority of the minimal-contact CBT program held up at 6 months and equivalence tests found it “at least as effective as standard CBT,” the researchers wrote.

IBS is a major area of unmet clinical need that costs the United States some $28 billion annually. Clinicians and patients lack both reliable biomarkers and “uniformly effective” therapies, the investigators noted. In recent years, severe adverse events have greatly restricted the availability of otherwise promising Food and Drug Administration–approved therapies, such as Lotronex (alosetron hydrochlorine), which has been linked to ischemic colitis and fatal cases of ruptured bowel, and Zelnorm (tegaserod maleate), which has been associated with myocardial infarction, stroke, and unstable angina.

In contrast, face-to-face CBT is safe, efficacious, and guideline recommended for IBS. However, uptake is limited by cost, stigma, geography, and a shortage of certified providers, the researchers noted. They enrolled 436 patients with IBS based on Rome III criteria and randomly assigned them to one of three interventions. The standard CBT group received 10 weekly, 60-minute, face-to-face CBT sessions on brain-gut interactions, symptom triggers and monitoring, muscle relaxation, worry control, problem-solving, and relapse prevention. The primarily home-based CBT group covered the same topics but attended only four clinic sessions and was provided home study materials. Finally, the education group attended four sessions with background information on IBS and the role of stress, diet, and exercise.

Baseline characteristics were comparable among groups, as were dropout rates (9% overall). In all, 89% of patients completed at least 8 of 10 standard cognitive-behavioral therapy sessions or at least three of four home-based CBT or educational sessions. Six months after the interventions ended, primarily home-based CBT continued to outperform education (blinded gastroenterologist-reported improvements, 58.4% and 44.8%, respectively; P = .05 for difference between groups).

Equivalence tests indicated that the minimal-CBT intervention was at least as effective as standard CBT, and improvements were not primarily the result of concomitant medications, according to the researchers. Nonetheless, only 42% of patients who benefited from CBT achieved remission, defined as no or mild IBS symptoms on the gastroenterologist-administered Clinical Global Impressions Scale. Unremitted patients might benefit from combining CBT with medical therapies that target both “central and peripheral mechanisms of IBS,” the investigators said.

The three interventions produced comparable acute and longer-term improvements on the IBS Symptom Severity Scale, which emphasizes sensory symptoms and therefore might be a less sensitive endpoint than the Clinical Global Impressions Scale, the researchers noted. Nonetheless, CBT produced some of the strongest absolute symptomatic improvements ever reported for IBS. “To put these data in context, treatment response of FDA-approved pharmacological agents using global IBS symptom improvement scales range from 17% to 40%,” the researchers wrote.

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
 

SOURCE: Lackner JM et al. Gastroenterology. 2018 Apr 24. doi: 10.1053/j.gastro.2018.03.063.

Primarily home-based cognitive-behavioral therapy improved irritable bowel syndrome symptoms at least as much as conventional CBT, cut clinician time by 60%, and significantly outperformed educational sessions in a multicenter clinical trial reported in the July issue of Gastroenterology.

Acutely, primarily home-based CBT produced a mean 61% improvement in self-reported symptoms on the IBS version of the Clinical Global Impressions Scale, versus 44% for the educational control group (P less than .05), wrote Jeffrey M. Lackner, PsyD, of the State University of New York at Buffalo and his associates. Blinded gastroenterologists reported improvements of 56% and 40%, respectively (P less than .05). The superiority of the minimal-contact CBT program held up at 6 months and equivalence tests found it “at least as effective as standard CBT,” the researchers wrote.

IBS is a major area of unmet clinical need that costs the United States some $28 billion annually. Clinicians and patients lack both reliable biomarkers and “uniformly effective” therapies, the investigators noted. In recent years, severe adverse events have greatly restricted the availability of otherwise promising Food and Drug Administration–approved therapies, such as Lotronex (alosetron hydrochlorine), which has been linked to ischemic colitis and fatal cases of ruptured bowel, and Zelnorm (tegaserod maleate), which has been associated with myocardial infarction, stroke, and unstable angina.

In contrast, face-to-face CBT is safe, efficacious, and guideline recommended for IBS. However, uptake is limited by cost, stigma, geography, and a shortage of certified providers, the researchers noted. They enrolled 436 patients with IBS based on Rome III criteria and randomly assigned them to one of three interventions. The standard CBT group received 10 weekly, 60-minute, face-to-face CBT sessions on brain-gut interactions, symptom triggers and monitoring, muscle relaxation, worry control, problem-solving, and relapse prevention. The primarily home-based CBT group covered the same topics but attended only four clinic sessions and was provided home study materials. Finally, the education group attended four sessions with background information on IBS and the role of stress, diet, and exercise.

Baseline characteristics were comparable among groups, as were dropout rates (9% overall). In all, 89% of patients completed at least 8 of 10 standard cognitive-behavioral therapy sessions or at least three of four home-based CBT or educational sessions. Six months after the interventions ended, primarily home-based CBT continued to outperform education (blinded gastroenterologist-reported improvements, 58.4% and 44.8%, respectively; P = .05 for difference between groups).

Equivalence tests indicated that the minimal-CBT intervention was at least as effective as standard CBT, and improvements were not primarily the result of concomitant medications, according to the researchers. Nonetheless, only 42% of patients who benefited from CBT achieved remission, defined as no or mild IBS symptoms on the gastroenterologist-administered Clinical Global Impressions Scale. Unremitted patients might benefit from combining CBT with medical therapies that target both “central and peripheral mechanisms of IBS,” the investigators said.

The three interventions produced comparable acute and longer-term improvements on the IBS Symptom Severity Scale, which emphasizes sensory symptoms and therefore might be a less sensitive endpoint than the Clinical Global Impressions Scale, the researchers noted. Nonetheless, CBT produced some of the strongest absolute symptomatic improvements ever reported for IBS. “To put these data in context, treatment response of FDA-approved pharmacological agents using global IBS symptom improvement scales range from 17% to 40%,” the researchers wrote.

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
 

SOURCE: Lackner JM et al. Gastroenterology. 2018 Apr 24. doi: 10.1053/j.gastro.2018.03.063.

Primarily home-based cognitive-behavioral therapy improved irritable bowel syndrome symptoms at least as much as conventional CBT, cut clinician time by 60%, and significantly outperformed educational sessions in a multicenter clinical trial reported in the July issue of Gastroenterology.

Acutely, primarily home-based CBT produced a mean 61% improvement in self-reported symptoms on the IBS version of the Clinical Global Impressions Scale, versus 44% for the educational control group (P less than .05), wrote Jeffrey M. Lackner, PsyD, of the State University of New York at Buffalo and his associates. Blinded gastroenterologists reported improvements of 56% and 40%, respectively (P less than .05). The superiority of the minimal-contact CBT program held up at 6 months and equivalence tests found it “at least as effective as standard CBT,” the researchers wrote.

IBS is a major area of unmet clinical need that costs the United States some $28 billion annually. Clinicians and patients lack both reliable biomarkers and “uniformly effective” therapies, the investigators noted. In recent years, severe adverse events have greatly restricted the availability of otherwise promising Food and Drug Administration–approved therapies, such as Lotronex (alosetron hydrochlorine), which has been linked to ischemic colitis and fatal cases of ruptured bowel, and Zelnorm (tegaserod maleate), which has been associated with myocardial infarction, stroke, and unstable angina.

In contrast, face-to-face CBT is safe, efficacious, and guideline recommended for IBS. However, uptake is limited by cost, stigma, geography, and a shortage of certified providers, the researchers noted. They enrolled 436 patients with IBS based on Rome III criteria and randomly assigned them to one of three interventions. The standard CBT group received 10 weekly, 60-minute, face-to-face CBT sessions on brain-gut interactions, symptom triggers and monitoring, muscle relaxation, worry control, problem-solving, and relapse prevention. The primarily home-based CBT group covered the same topics but attended only four clinic sessions and was provided home study materials. Finally, the education group attended four sessions with background information on IBS and the role of stress, diet, and exercise.

Baseline characteristics were comparable among groups, as were dropout rates (9% overall). In all, 89% of patients completed at least 8 of 10 standard cognitive-behavioral therapy sessions or at least three of four home-based CBT or educational sessions. Six months after the interventions ended, primarily home-based CBT continued to outperform education (blinded gastroenterologist-reported improvements, 58.4% and 44.8%, respectively; P = .05 for difference between groups).

Equivalence tests indicated that the minimal-CBT intervention was at least as effective as standard CBT, and improvements were not primarily the result of concomitant medications, according to the researchers. Nonetheless, only 42% of patients who benefited from CBT achieved remission, defined as no or mild IBS symptoms on the gastroenterologist-administered Clinical Global Impressions Scale. Unremitted patients might benefit from combining CBT with medical therapies that target both “central and peripheral mechanisms of IBS,” the investigators said.

The three interventions produced comparable acute and longer-term improvements on the IBS Symptom Severity Scale, which emphasizes sensory symptoms and therefore might be a less sensitive endpoint than the Clinical Global Impressions Scale, the researchers noted. Nonetheless, CBT produced some of the strongest absolute symptomatic improvements ever reported for IBS. “To put these data in context, treatment response of FDA-approved pharmacological agents using global IBS symptom improvement scales range from 17% to 40%,” the researchers wrote.

The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
 

SOURCE: Lackner JM et al. Gastroenterology. 2018 Apr 24. doi: 10.1053/j.gastro.2018.03.063.

Research shows the ocean’s cod population is diminishing to dangerously low levels. In response, several countries (the United States, Iceland, and others) have instituted a resource allocation system termed “catch share,” where each fisherman is allotted an annual number of fish. Shares can be leased, bought, and traded. Consequently, there has been horizontal and vertical consolidation within the industry and huge fishing corporations have emerged while independent small-boat fishermen have virtually disappeared. Once consolidation occurred, venture capital entered the market. Parallels to what is happening to independent medical practices should not be ignored.

We have closed the book on DDW^® 2018. Researchers presented new and innovative studies that will directly affect our practices. I was honored to give the “Best of AGA – DDW” lecture where I chose only seven of hundreds of abstracts to present. All DDW lectures are located at https://watch.ondemand.org/ddw. GI & Hepatology News will highlight several high-impact presentations in this and subsequent issues.

John I. Allen, MD, MBA, AGAF

Editor in Chief

Research shows the ocean’s cod population is diminishing to dangerously low levels. In response, several countries (the United States, Iceland, and others) have instituted a resource allocation system termed “catch share,” where each fisherman is allotted an annual number of fish. Shares can be leased, bought, and traded. Consequently, there has been horizontal and vertical consolidation within the industry and huge fishing corporations have emerged while independent small-boat fishermen have virtually disappeared. Once consolidation occurred, venture capital entered the market. Parallels to what is happening to independent medical practices should not be ignored.

We have closed the book on DDW^® 2018. Researchers presented new and innovative studies that will directly affect our practices. I was honored to give the “Best of AGA – DDW” lecture where I chose only seven of hundreds of abstracts to present. All DDW lectures are located at https://watch.ondemand.org/ddw. GI & Hepatology News will highlight several high-impact presentations in this and subsequent issues.

John I. Allen, MD, MBA, AGAF

Editor in Chief

Research shows the ocean’s cod population is diminishing to dangerously low levels. In response, several countries (the United States, Iceland, and others) have instituted a resource allocation system termed “catch share,” where each fisherman is allotted an annual number of fish. Shares can be leased, bought, and traded. Consequently, there has been horizontal and vertical consolidation within the industry and huge fishing corporations have emerged while independent small-boat fishermen have virtually disappeared. Once consolidation occurred, venture capital entered the market. Parallels to what is happening to independent medical practices should not be ignored.

We have closed the book on DDW^® 2018. Researchers presented new and innovative studies that will directly affect our practices. I was honored to give the “Best of AGA – DDW” lecture where I chose only seven of hundreds of abstracts to present. All DDW lectures are located at https://watch.ondemand.org/ddw. GI & Hepatology News will highlight several high-impact presentations in this and subsequent issues.

John I. Allen, MD, MBA, AGAF

Editor in Chief

Older age, male sex, smoking, longer segment length, and low-grade dysplasia were significant risk factors for progression of Barrett’s esophagus in a meta-analysis of 20 studies.

“Individuals with these features should undergo more intensive surveillance or endoscopic therapy,” Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., and his associates wrote in Clinical Gastroenterology and Hepatology. “Smoking is a modifiable risk factor for cancer prevention in patients with BE.”

“Currently, gastrointestinal societies’ guidelines on BE surveillance are solely based on dysplasia grade and do not take into account any of the other risk factors,” the reviewers concluded. Their findings could form the backbone of a risk score that identifies high-risk BE patients with baseline low-grade dysplasia or nondysplastic BE “who would benefit from intensive surveillance or endoscopic therapy.”

Esophageal adenocarcinoma is on the rise and fewer than one in five patients survive 5 years past diagnosis. Endoscopic surveillance for esophageal adenocarcinoma is recommended in Barrett’s esophagus, but only about one in 10 esophageal adenocarcinoma patients has a preceding BE diagnosis. “This ostensible discrepancy has raised concerns about the effectiveness of current screening and surveillance programs,” the reviewers noted. Studies also have yielded conflicting evidence about the value of endoscopic surveillance as currently performed. To help prioritize BE patients for surveillance, the reviewers searched EMBASE, MEDLINE, and Web of Science from inception through May 2016 for cohort studies of risk factors for progression of BE among patients with either no dysplasia or low-grade dysplasia.

The 20 studies covered 1,231 BE progression events among 74,943 patients. In separate pooled estimates, progression of BE correlated significantly with older age (odds ratio, 1.03; 95% CI, 1.01–1.05), male sex (OR, 2.2; 95% CI, 1.8-2.5), current or former smoking (OR, 1.5; 95% CI, 1.09-2.0), and greater BE segment length (OR, 1.3; 95% CI, 1.16-1.36). Results tended to be homogeneous among studies, said the reviewers. Low-grade dysplasia correlated strongly with progression (OR, 4.3; 95% CI, 2.6-7.0), while use of proton pump inhibitors (OR, 0.55; 95% CI, 0.32–0.96) and statins (OR, 0.48; 95% CI, 0.31-0.73) showed the opposite trend. “Alcohol use and obesity did not associate with risk of progression,” the reviewers added.

Thirteen studies in the meta-analysis were from Europe, six were from the United States, and one was from Australia. Ten were multicenter studies, 13 were deemed high-quality, three were deemed medium-quality, and four were deemed low-quality. The reviewers were unable to assess dose-response relationships for relevant factors, such as alcohol, tobacco, and medications, and not all studies accounted for potential confounding.

Only four studies included multivariate analyses to control for the confounding effects of age, sex, and BE characteristics (length and dysplasia). When the reviewers analyzed only these studies, older age and smoking no longer predicted BE progression. Use of proton pump inhibitors remained protective, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) became protective, while statin use lost significance.

The reviewers disclosed no external funding sources or conflicts of interest.

SOURCE: Krishnamoorthi R, et al. Clinical Gastroenterol and Hepatol. 2017 Nov 30. doi: 10.1016/j.cgh.2017.11.044

Older age, male sex, smoking, longer segment length, and low-grade dysplasia were significant risk factors for progression of Barrett’s esophagus in a meta-analysis of 20 studies.

“Individuals with these features should undergo more intensive surveillance or endoscopic therapy,” Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., and his associates wrote in Clinical Gastroenterology and Hepatology. “Smoking is a modifiable risk factor for cancer prevention in patients with BE.”

“Currently, gastrointestinal societies’ guidelines on BE surveillance are solely based on dysplasia grade and do not take into account any of the other risk factors,” the reviewers concluded. Their findings could form the backbone of a risk score that identifies high-risk BE patients with baseline low-grade dysplasia or nondysplastic BE “who would benefit from intensive surveillance or endoscopic therapy.”

Esophageal adenocarcinoma is on the rise and fewer than one in five patients survive 5 years past diagnosis. Endoscopic surveillance for esophageal adenocarcinoma is recommended in Barrett’s esophagus, but only about one in 10 esophageal adenocarcinoma patients has a preceding BE diagnosis. “This ostensible discrepancy has raised concerns about the effectiveness of current screening and surveillance programs,” the reviewers noted. Studies also have yielded conflicting evidence about the value of endoscopic surveillance as currently performed. To help prioritize BE patients for surveillance, the reviewers searched EMBASE, MEDLINE, and Web of Science from inception through May 2016 for cohort studies of risk factors for progression of BE among patients with either no dysplasia or low-grade dysplasia.

The 20 studies covered 1,231 BE progression events among 74,943 patients. In separate pooled estimates, progression of BE correlated significantly with older age (odds ratio, 1.03; 95% CI, 1.01–1.05), male sex (OR, 2.2; 95% CI, 1.8-2.5), current or former smoking (OR, 1.5; 95% CI, 1.09-2.0), and greater BE segment length (OR, 1.3; 95% CI, 1.16-1.36). Results tended to be homogeneous among studies, said the reviewers. Low-grade dysplasia correlated strongly with progression (OR, 4.3; 95% CI, 2.6-7.0), while use of proton pump inhibitors (OR, 0.55; 95% CI, 0.32–0.96) and statins (OR, 0.48; 95% CI, 0.31-0.73) showed the opposite trend. “Alcohol use and obesity did not associate with risk of progression,” the reviewers added.

Thirteen studies in the meta-analysis were from Europe, six were from the United States, and one was from Australia. Ten were multicenter studies, 13 were deemed high-quality, three were deemed medium-quality, and four were deemed low-quality. The reviewers were unable to assess dose-response relationships for relevant factors, such as alcohol, tobacco, and medications, and not all studies accounted for potential confounding.

Only four studies included multivariate analyses to control for the confounding effects of age, sex, and BE characteristics (length and dysplasia). When the reviewers analyzed only these studies, older age and smoking no longer predicted BE progression. Use of proton pump inhibitors remained protective, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) became protective, while statin use lost significance.

The reviewers disclosed no external funding sources or conflicts of interest.

SOURCE: Krishnamoorthi R, et al. Clinical Gastroenterol and Hepatol. 2017 Nov 30. doi: 10.1016/j.cgh.2017.11.044

Older age, male sex, smoking, longer segment length, and low-grade dysplasia were significant risk factors for progression of Barrett’s esophagus in a meta-analysis of 20 studies.

“Individuals with these features should undergo more intensive surveillance or endoscopic therapy,” Rajesh Krishnamoorthi, MD, of Mayo Clinic in Rochester, Minn., and his associates wrote in Clinical Gastroenterology and Hepatology. “Smoking is a modifiable risk factor for cancer prevention in patients with BE.”

“Currently, gastrointestinal societies’ guidelines on BE surveillance are solely based on dysplasia grade and do not take into account any of the other risk factors,” the reviewers concluded. Their findings could form the backbone of a risk score that identifies high-risk BE patients with baseline low-grade dysplasia or nondysplastic BE “who would benefit from intensive surveillance or endoscopic therapy.”

Esophageal adenocarcinoma is on the rise and fewer than one in five patients survive 5 years past diagnosis. Endoscopic surveillance for esophageal adenocarcinoma is recommended in Barrett’s esophagus, but only about one in 10 esophageal adenocarcinoma patients has a preceding BE diagnosis. “This ostensible discrepancy has raised concerns about the effectiveness of current screening and surveillance programs,” the reviewers noted. Studies also have yielded conflicting evidence about the value of endoscopic surveillance as currently performed. To help prioritize BE patients for surveillance, the reviewers searched EMBASE, MEDLINE, and Web of Science from inception through May 2016 for cohort studies of risk factors for progression of BE among patients with either no dysplasia or low-grade dysplasia.

The 20 studies covered 1,231 BE progression events among 74,943 patients. In separate pooled estimates, progression of BE correlated significantly with older age (odds ratio, 1.03; 95% CI, 1.01–1.05), male sex (OR, 2.2; 95% CI, 1.8-2.5), current or former smoking (OR, 1.5; 95% CI, 1.09-2.0), and greater BE segment length (OR, 1.3; 95% CI, 1.16-1.36). Results tended to be homogeneous among studies, said the reviewers. Low-grade dysplasia correlated strongly with progression (OR, 4.3; 95% CI, 2.6-7.0), while use of proton pump inhibitors (OR, 0.55; 95% CI, 0.32–0.96) and statins (OR, 0.48; 95% CI, 0.31-0.73) showed the opposite trend. “Alcohol use and obesity did not associate with risk of progression,” the reviewers added.

Thirteen studies in the meta-analysis were from Europe, six were from the United States, and one was from Australia. Ten were multicenter studies, 13 were deemed high-quality, three were deemed medium-quality, and four were deemed low-quality. The reviewers were unable to assess dose-response relationships for relevant factors, such as alcohol, tobacco, and medications, and not all studies accounted for potential confounding.

Only four studies included multivariate analyses to control for the confounding effects of age, sex, and BE characteristics (length and dysplasia). When the reviewers analyzed only these studies, older age and smoking no longer predicted BE progression. Use of proton pump inhibitors remained protective, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) became protective, while statin use lost significance.

The reviewers disclosed no external funding sources or conflicts of interest.

SOURCE: Krishnamoorthi R, et al. Clinical Gastroenterol and Hepatol. 2017 Nov 30. doi: 10.1016/j.cgh.2017.11.044

Click here to access the July 2018 Digital Edition.

Table of Contents

• Vertebral Artery Dissection Due to Mixed Martial Arts Choke Hold
• Using Stroke Order Sets to Improve Compliance With Quality Measures for Stroke Admissions
• Screening and Treating HCV in the VA: Achieving Excellence Using Lean and System Redesign
• Transgender Care in the Primary Care Setting
• Pharmacist-Led ED Antimicrobial Surveillance
• Risks vs Benefits for SGLT2 Inhibitor Medications
• Caring Under a Microscope
• Tedizolid Use in Immunocompromised Patients

Click here to access the July 2018 Digital Edition.

Table of Contents

• Vertebral Artery Dissection Due to Mixed Martial Arts Choke Hold
• Using Stroke Order Sets to Improve Compliance With Quality Measures for Stroke Admissions
• Screening and Treating HCV in the VA: Achieving Excellence Using Lean and System Redesign
• Transgender Care in the Primary Care Setting
• Pharmacist-Led ED Antimicrobial Surveillance
• Risks vs Benefits for SGLT2 Inhibitor Medications
• Caring Under a Microscope
• Tedizolid Use in Immunocompromised Patients

Click here to access the July 2018 Digital Edition.

Table of Contents

• Vertebral Artery Dissection Due to Mixed Martial Arts Choke Hold
• Using Stroke Order Sets to Improve Compliance With Quality Measures for Stroke Admissions
• Screening and Treating HCV in the VA: Achieving Excellence Using Lean and System Redesign
• Transgender Care in the Primary Care Setting
• Pharmacist-Led ED Antimicrobial Surveillance
• Risks vs Benefits for SGLT2 Inhibitor Medications
• Caring Under a Microscope
• Tedizolid Use in Immunocompromised Patients

I am a nurse practitioner living in the South; I am also a concealed carry permit holder and an NRA pistol instructor who competes. I own an AR15; it is not an assault rifle—it’s just a rifle. 

I often see articles about the “ease” of purchasing a gun, but this is just not true. Even with the laxer gun control of the South, obtaining a concealed carry license entails going through both the FBI and local police, a review of mental health rec­ords, a long questionnaire, and an eight-hour class that involves shooting. So, yes, I can purchase a gun in 30 minutes—but only because I’ve already been through this process.

If I wanted to purchase a gun without a permit, I would have to go to the courthouse and be fingerprinted and run through the system before I could get a one-time purchase permit. I could not get a permit if I had a mental illness, had ever been arrested or accused of domestic violence, etc.

My heart breaks every time a mass shooting, like the one at Marjory Stoneman Douglas High School, happens. Guns have been around in our area for many, many years. High school kids used to mount a shotgun in a rack on the top of their truck to hunt before school; they didn’t think of using it to hurt a person. I believe the problems we face today are multifaceted: a lack of parenting, absent fathers, people not getting the mental health services they need, and HIPAA! Mental health professionals are afraid to call authorities for fear of being sued.

I truly believe we need to stop politicizing this issue. Let’s quit blaming the guns themselves and work on real solutions. For example, parents have an obligation to lock up all firearms! Kids should never have access to guns from their own home. In my house, when we have visitors—even if they are adults—we lock our guns in our safe. Security at our schools should mimic that at courthouses, with metal detectors, armed security personnel, and limited entrance/exit areas.

Deborah Johnson, FNP-C
Kinston, NC

I am a nurse practitioner living in the South; I am also a concealed carry permit holder and an NRA pistol instructor who competes. I own an AR15; it is not an assault rifle—it’s just a rifle. 

I often see articles about the “ease” of purchasing a gun, but this is just not true. Even with the laxer gun control of the South, obtaining a concealed carry license entails going through both the FBI and local police, a review of mental health rec­ords, a long questionnaire, and an eight-hour class that involves shooting. So, yes, I can purchase a gun in 30 minutes—but only because I’ve already been through this process.

If I wanted to purchase a gun without a permit, I would have to go to the courthouse and be fingerprinted and run through the system before I could get a one-time purchase permit. I could not get a permit if I had a mental illness, had ever been arrested or accused of domestic violence, etc.

My heart breaks every time a mass shooting, like the one at Marjory Stoneman Douglas High School, happens. Guns have been around in our area for many, many years. High school kids used to mount a shotgun in a rack on the top of their truck to hunt before school; they didn’t think of using it to hurt a person. I believe the problems we face today are multifaceted: a lack of parenting, absent fathers, people not getting the mental health services they need, and HIPAA! Mental health professionals are afraid to call authorities for fear of being sued.

I truly believe we need to stop politicizing this issue. Let’s quit blaming the guns themselves and work on real solutions. For example, parents have an obligation to lock up all firearms! Kids should never have access to guns from their own home. In my house, when we have visitors—even if they are adults—we lock our guns in our safe. Security at our schools should mimic that at courthouses, with metal detectors, armed security personnel, and limited entrance/exit areas.

Deborah Johnson, FNP-C
Kinston, NC

I am a nurse practitioner living in the South; I am also a concealed carry permit holder and an NRA pistol instructor who competes. I own an AR15; it is not an assault rifle—it’s just a rifle. 

I often see articles about the “ease” of purchasing a gun, but this is just not true. Even with the laxer gun control of the South, obtaining a concealed carry license entails going through both the FBI and local police, a review of mental health rec­ords, a long questionnaire, and an eight-hour class that involves shooting. So, yes, I can purchase a gun in 30 minutes—but only because I’ve already been through this process.

If I wanted to purchase a gun without a permit, I would have to go to the courthouse and be fingerprinted and run through the system before I could get a one-time purchase permit. I could not get a permit if I had a mental illness, had ever been arrested or accused of domestic violence, etc.

My heart breaks every time a mass shooting, like the one at Marjory Stoneman Douglas High School, happens. Guns have been around in our area for many, many years. High school kids used to mount a shotgun in a rack on the top of their truck to hunt before school; they didn’t think of using it to hurt a person. I believe the problems we face today are multifaceted: a lack of parenting, absent fathers, people not getting the mental health services they need, and HIPAA! Mental health professionals are afraid to call authorities for fear of being sued.

I truly believe we need to stop politicizing this issue. Let’s quit blaming the guns themselves and work on real solutions. For example, parents have an obligation to lock up all firearms! Kids should never have access to guns from their own home. In my house, when we have visitors—even if they are adults—we lock our guns in our safe. Security at our schools should mimic that at courthouses, with metal detectors, armed security personnel, and limited entrance/exit areas.

Deborah Johnson, FNP-C
Kinston, NC

For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.

For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.

For children with Crohn’s disease, fecal calprotectin levels below 300 mcg indicated mucosal healing, while values below 100 mcg signified deep healing in a multicenter, 151-patient study.

Sensitivity was 80% for mucosal healing and 71% for deep healing, while specificities were 81% and 92%, respectively, said Inbar Nakar of the Hebrew University of Jerusalem, with her associates. In line with prior studies, adding C-reactive protein (CRP) to fecal calprotectin improved neither sensitivity or specificity, the researchers wrote in Clinical Gastroenterology and Hepatology.

Bowel healing is a crucial goal in Crohn’s disease (CD). Because pediatric transmural healing had not been studied, the researchers analyzed data from the ImageKids study, a multicenter effort to develop magnetic resonance enterography (MRE) measures for CD patients aged 6-18 years. Participants averaged 14 years old with a standard deviation of 2 years. Assessments included MRE, complete ileocolonoscopic evaluation, CRP, and fecal calprotectin. The researchers defined mucosal healing as a Simple Endoscopic Severity Index in Crohn’s Disease score below 3, transmural healing as an MRE visual analog score below 20 mm, and deep healing as transmural plus mucosal healing.

Nearly one-third of patients had healing only in the mucosa or the bowel wall, but not both; 6% had mucosal healing but transmural inflammation, and 25% of children had transmural healing but mucosal inflammation. In addition, 14% of children had deep healing, and 55% of children had both mucosal and transmural inflammation. Those findings highlight “the discrepancy between mucosal and transmural inflammation and the importance of evaluating the disease by both ileocolonoscopy and imaging,” the researchers wrote.

Median calprotectin levels varied significantly by healing status (P less than .001). They were lowest (10 mcg/g) for deep healing, followed by either transmural or mucosal inflammation, and were highest (median, 810 mcg/g) when children had both mucosal and transmural inflammation. Calprotectin in children with deep healing had an area under the receiver operating characteristic curve value of 0.93 (95% confidence interval, 0.89- 0.98). In contrast, CRP level identified children with deep healing with an AUROC value of only 0.81 (95% CI, 0.71-0.90).

Although “calprotectin level is driven primarily by mucosal healing, [it] is still superior to CRP,” the investigators concluded. “Although a calprotectin cutoff [less than] 300 mcg/g predicted mucosal healing, a lower cutoff of [less than] 100 mcg/g may be more suitable to predict deep healing.” However, they emphasized that fecal calprotectin level is only moderately accurate in predicting mucosal or transmural healing in children with CD. They advised physicians to “be familiar with the predictive values of each cutoff before incorporating them in clinical decision making.”

An educational grant from AbbVie funded the ImageKids study. AbbVie was not otherwise involved in the study. Two coinvestigators disclosed ties to AbbVie and other pharmaceutical companies. There were no other disclosures.

SOURCE: Nakar I et al. Clin Gastroenterol Hepatol. 2018 Mar 2. doi: 10.1016/j.cgh.2018.01.024.