Cleveland Clinic Journal of Medicine

“When I see a patient with arthritis coming in the front door, I leave by the back door.”
—Sir William Ostler

Fortunately for today’s physicians treating patients with osteoarthritis, we need not be as pessimistic as Osler was more than a century ago when he uttered his now-famous words. Still, there is no magic bullet for the contemporary clinician treating an elderly patient with osteoarthritis. Instead, there are many imperfect bullets, and choosing between them is always a balancing act between benefit and risk from various agents: nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics such as acetaminophen and tramadol, opioids, and supplements such as glucosamine and chondroitin sulfate.

So there was great interest when, in 2012,¹ the American College of Rheumatology (ACR) updated its previous guidelines (from 2000) on drug and nondrug therapies for osteoarthritis of the hip and the knee² and added new recommendations on osteoarthritis of the hand.

Revising the guidelines was appropriate, since new therapies have become available. But, as the guideline authors state, with osteoarthritis, as with other diseases, guidelines cannot be a “cookbook.”

The treatment approach differs depending on the patient’s clinical presentation and on the preferences of the patient and the physician. Often, more than one approach is possible, and more than one approach may be appropriate in a given patient at a given time. The guideline authors also point out that some physicians may disagree with some of the recommendations.

I wish to review here several of the key recommendations. But I also provide some of my personal perspective and experience after 4 decades of treating patients with osteoarthritis.

HOW THE GUIDELINES WERE MADE

The new ACR guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, a formal process to develop recommendations that are as evidence-based as possible.³

The authors are outstanding experts in the field of osteoarthritis from throughout the United States and Canada. Further, the recommendations were voted on by a “technical expert panel” representing the fields of rheumatology, orthopedics, physical medicine, and rehabilitation, from both academic medicine and private practice. This representation provides a balance of input from the types of clinicians frequently involved in managing osteoarthritis.

The initial literature searches for drug therapies were conducted during late 2008, and those for nonpharmacologic treatments were conducted during the second and third quarters of 2009. The goal of the literature searches was to identify the most current systematic reviews and meta-analyses that would provide reliable estimates of benefits of intervention for the prespecified clinically relevant outcomes of pain and function, as well as data on safety.

Recommendations: For or against, strong or weak—and the informed patient’s perspective

Therapies received the following possible recommendations:

• Strong recommendation to use
• Weak (or conditional) recommendation to use
• No recommendation
• Weak (or conditional) recommendation not to use
• Strong recommendation not to use.

A strong recommendation required high-quality evidence and evidence of a large difference between desirable and undesirable effects of the treatment. A conditional recommendation was based on the absence of high-quality evidence, evidence of only a small difference between desirable and undesirable effects of the treatment, or both.

One interesting feature of these recommendations is that they took into account how informed patients might themselves evaluate the data with their medical condition.

For instance, if a therapy received a strong favorable recommendation, we can assume that most informed patients would choose to receive it, and we can shape our interaction with the patient accordingly. A conditional recommendation means that most informed patients would choose the treatment—but many would not, and physicians should keep the patient’s values and preferences in mind.

I admit I had a problem with the meaning of the word “conditional” in the context of these guidelines. When evaluating a treatment, the term “weak” is readily understood and clearer. By using the word “weak,” one is making a positive statement in support of use but letting you know that the data and recommendation are weak. The word “conditional” is less readily defined and does not necessarily imply support for use.

Recommendations were drafted after discussion of the evidence at each meeting of the technical expert panel. Consensus was defined as 75% or more of the members of the panel voting to either strongly or conditionally recommend using a therapy, to either strongly or conditionally recommend not using it, or to choose not to make a recommendation on its use.

OSTEOARTHRITIS OF THE HAND: NO STRONG RECOMMENDATIONS

The technical expert panel gave no strong recommendations for any nondrug or drug treatment for osteoarthritis of the hand.

Conditional recommendations for nondrug treatments

The panel conditionally recommended the following:

• All patients with osteoarthritis of the hand should be evaluated either by their primary physician or by an occupational or physical therapist, particularly with respect to ability to perform activities of daily living.
• Assistive devices such as jar openers, key turners, and pull tabs for zippers should be recommended, as needed.
• Patients should be instructed in joint protection and in the use of thermal treatments (eg, heating pads, ultrasound devices, hot packs, and ice packs).

Comments. Appliances are often beneficial in patients who have involvement of the first carpometacarpal (trapeziometacarpal) joint. Although over-the-counter thumb splints are an option, referral to an occupational therapist for splint prescription is advantageous to achieve a comfortable fit and, importantly, for instructions to the patient on how to avoid joint trauma.

It would be unrealistic to expect primary care physicians and internists to have the expertise to make detailed recommendations about orthopedic appliances. Accordingly, referral to an occupational therapist or an orthopedist is advisable for these situations. It is important, however, that the physician be aware of what treatments are available and most effective, and of the indications for referral.

As for heat treatment, elastic stretch gloves may relieve symptoms through their warming and massaging effects.⁴

The expert panel gave conditional recommendations in favor of:

• Topical capsaicin
• Topical NSAIDs
• Oral NSAIDs (including both nonselective and selective agents)
• Tramadol (Ultram)
• Topical rather than oral NSAIDs for patients age 75 and older.

Other drug treatments got conditional recommendations against their use

The expert panel gave conditional recommendations against using:

• Intra-articular injections, and in particular, corticosteroid injections in the trapeziometacarpal (first carpometacarpal) joint
• Opioid analgesics
• Oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis.

No recommendation for or against

• Hydroxychloroquine.

Comments—Intra-articular injections, opioids, and oral NSAIDs

I differ with these recommendations on several points.

Although the guidelines committee conditionally recommended against using intra-articular therapies for hand osteoarthritis, I find that intra-articular corticosteroid injections are often effective, particularly in patients who have inflammatory forms of the disease, ie, “erosive inflammatory osteoarthritis.” Most nonspecialist physicians probably have limited experience in giving injections into small joints, and referral to a rheumatologist or orthopedist would be appropriate.

I disagree as well with the conditional recommendation that intra-articular corticosteroid injections not be used for involvement of the trapeziometacarpal (first carpometacarpal) joint. I find that many patients with osteoarthritis of this joint experience improvement with intra-articular corticosteroid injections.

I agree that there are limited data on the use of intra-articular hyaluronan injections in this situation and do not routinely use them in this joint.

Opioid analgesics also received a conditional recommendation against their use. The same caveats apply here as for these drugs elsewhere.⁵ If used, opioids should be used at the lowest dose possible and for as short a time as possible. If the physician is uncomfortable prescribing opioids for patients with osteoarthritis, referral to a pain specialist is recommended.

I disagree to some extent with the conditional recommendation that people age 75 and older should use topical rather than oral NSAIDs. I understand the recommendation, given that older people have a higher frequency of gastrointestinal, renal, and cardiac disease and are best served by avoiding NSAIDs. However, we all see patients over age 75 who are physiologically younger than their numerical age. Accordingly, I feel that the judgment of the physician plays a role in whether NSAIDs are reasonable for some older patients.

The committee recommended not using oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis. I have used oral hydroxychloroquine off-label in such patients and find that they respond in a very rewarding fashion.

Given that this is an off-label use of hydroxychloroquine, the drug should be used only with appropriate consideration and after discussion with the patient about toxicity, especially about the risk of ocular manifestations.

OSTEOARTHRITIS OF THE KNEE

Some nondrug therapies got strong recommendations

The expert panel strongly recommended:

• Exercise (aerobic, resistance, land-based, and aquatic)
• Weight loss (for patients who are overweight).

Other nondrug therapies got conditional recommendations

The panel conditionally recommended:

• Self-management programs
• Manual therapy in combination with supervised exercise
• Psychosocial interventions
• Medially directed patellar taping
• Medially wedged insoles (if the patient has lateral compartment osteoarthritis)
• Laterally wedged subtalar strapped insoles (if the patient has medial compartment osteoarthritis)
• Heat therapy
• Walking aids, as needed
• Tai chi
• Chinese acupuncture
• Transcutaneous electrical nerve stimulation.

Comments. The ACR panel appropriately noted that Chinese acupuncture or transcutaneous electrical stimulation should be recommended only if the patient has chronic moderate to severe pain and is a candidate for total knee arthroplasty but is unwilling to undergo the procedure or has comorbid medical conditions that rule out surgery.

Nondrug therapies for knee osteoarthritis that got no recommendation for or against

• Balance exercise
• Laterally wedged insoles
• Manual therapy alone
• Knee braces
• Laterally directed patellar taping.

Comments. It was somewhat surprising that there were no recommendations about laterally wedged insoles or knee braces. Laterally wedged insoles have been recommended for patients who have medial compartment knee osteoarthritis⁶; being thinner at the instep and thicker at the outer edge of the foot, they reduce load on the medial aspect of the knee. One has to be cautious in using knee wedging in patients who have concomitant ankle or hip angle deformities, lest these joints be compromised.

Some of these treatments would be out of the realm of the nonspecialist physician.

Conditional recommendations for initial drug therapy for knee osteoarthritis

The panel conditionally recommended that patients who have osteoarthritis of the knee use one of the following:

• Acetaminophen (contained in Tylenol and a host of other products)
• Oral NSAIDs
• Topical NSAIDs (with a strong recommendation for topical NSAIDs rather than oral NSAIDs in patients age 75 and older)
• Tramadol
• Intra-articular corticosteroid injections.

Comments. In the past, it was recommended that acetaminophen in full doses of up to 4,000 mg per day be considered.⁷ Current dogma, however, is that doses of acetaminophen should not exceed 3,000 mg per day to avoid damaging the liver. This concern led the US Food and Drug Administration (FDA) in 2011 to advise that the maximum daily dose be limited.⁸ The ACR panel recommended that patients be counseled to avoid all other products that contain acetaminophen, which is especially cogent, given the presence of this agent in many over-the-counter medications.⁹

The panel conditionally recommended that people age 75 and older use topical rather than oral NSAIDs. As mentioned earlier, a specific age limit does not take into account that many people age 75 and older may actually be physiologically younger than some in their 50s or 60s. Accordingly, it is recommended that the physician use judgment in this regard so that NSAIDs will not be denied to patients for whom they might be of significant value.

Strong recommendation for gastric protection in patients at risk on NSAIDs

If a patient with knee osteoarthritis has a history of a symptomatic or complicated upper gastrointestinal ulcer but has not had an upper gastrointestinal bleed in the past year and the physician chooses to prescribe an oral NSAID, the expert panel strongly recommended using either a cyclooxygenase (COX)-2-selective inhibitor or a nonselective NSAID in combination with a proton pump inhibitor.

Comment. The suggestion that patients who have had a complicated upper gastrointestinal ulcer in the past year could be considered for treatment with a COX-2-selective inhibitor or nonselective NSAID in combination with a proton pump inhibitor seemed a bit aggressive. My own inclination would be to avoid both nonselective and selective inhibitors in this situation. Alternative agents such as acetaminophen in full doses, tramadol, intra-articular hyaluronan injections, and intra-articular corticosteroid injections seem preferable with respect to safety in such patients.

The suggestion that a proton pump inhibitor be used whenever an NSAID is given for chronic management of knee or hip osteoarthritis is reasonable.^10,11 Although some studies have suggested that chronic use of proton pump inhibitors may predispose to osteopenia or osteoporosis, others have not, and gastric protection should be considered in patients at gastrointestinal risk.

Strong recommendation against ibuprofen in patients taking aspirin

The ACR panel strongly recommended that ibuprofen (Advil) not be prescribed to patients with knee osteoarthritis who are using aspirin in low doses for cardioprotection, and strongly recommended using another nonselective NSAID plus a proton pump inhibitor instead. The panel also strongly recommended against using a COX-2-selective inhibitor in this situation.^12,13

Comment. The rationale for these recommendations is that ibuprofen may render aspirin ineffective as a cardioprotective agent. Ibuprofen interferes with the aspirin-binding site on platelets, so that the protective effect of aspirin is lost.^14,15 Celecoxib (Celebrex)¹⁶ and diclofenac (Voltaren) have binding sites different from that of aspirin, although the ACR recommends against using COX-2-selective inhibitors such as celecoxib in the situation and gives no recommendation about other NSAIDs.

No recommendations for or against

The panel issued no recommendations for or against the following treatments for patients with knee osteoarthritis:

• Intra-articular hyaluronan injections
• Duloxetine (Cymbalta)
• Opioid analgesics.

Comments on knee injections

Intra-articular injections of corticosteroids or hyaluronan are commonly used for knee osteoarthritis. As noted, corticosteroid injections received a conditional recommendation, while hyaluronan injections received no recommendation for or against.

How often to inject corticosteroids? In general, too-frequent injection of corticosteroids is to be avoided, in view of the risk of promoting joint breakdown. There is no “magic” number of injections that is safe, although more than 4 per year in the same joint should generally be avoided. In some situations, however, repeat injections may be reasonable if alternative therapies are associated with higher risk.

Raynauld et al,¹⁷ in a randomized, double-blind, placebo-controlled trial, demonstrated that intra-articular corticosteroid injections at 3-month intervals for 2 years were not deleterious to knees.

My philosophy is generally not to inject on a regular basis, but to be selective and be guided by the patient’s clinical condition and response to prior injections.

Are hyaluronan injections effective? Although experts differ in their enthusiasm for intra-articular hyaluronan injections in the knee, I have found that many patients benefit from this treatment. Multiple studies have found it efficacious and safe overall.^18–21 However, some systematic reviews have called its efficacy into question.⁷

Although differences in efficacy have been noted, this therapy was approved as being useful in patients with knee osteoarthritis in the Osteoarthritis Research Society International (OARSI) recommendations.⁷ The effect sizes were smaller in later assessments.²²

Hyaluronan injections do not pose the risk of joint breakdown that corticosteroid injections do, but their clinical efficacy is not as dramatic. Adverse reactions to most intraarticular hyaluronans are limited, with slight increases in pain and stiffness after injection. Significant inflammatory reactions characterized as “postinjection flares” are more commonly seen with high-molecular-weight crosslinked preparations. These reactions can be severe and can mimic joint infection clinically. Joint aspiration with synovial fluid analysis and culture may be necessary to exclude infection. Response to aspiration and nonsteroidal inflammatory agents or intra-articular corticosteroids is usually excellent.

Ultrasonographic guidance. As with intraarticular injections in other areas, ultrasonographic guidance is becoming more common, as it allows for more accurate drug administration.

Pes anserine bursitis must be ruled out as a cause of the patient’s knee symptoms—misdiagnosis is not uncommon. The bursa is located on the medial aspect of the tibia, and inflammation of the bursa is a common cause of pain in this area. Local steroid injection is extremely effective in symptomatic therapy. Physical therapy and NSAIDs may be adequate to treat milder cases.

Conditional recommendation against glucosamine, chondroitin, capsaicin

The ACR panel conditionally recommended that patients with knee osteoarthritis not use:

• Chondroitin sulfate
• Glucosamine
• Topical capsaicin.

Comment. Evidence is mixed about the efficacy of glucosamine and chondroitin sulfate, which are so-called nutraceuticals. Some studies found them useful^23–25 but some did not,²⁶ and a meta-analysis concluded that they do not help.²⁷ The OARSI guidelines published in 2008 stated that these agents may relieve symptoms of osteoarthritis of the knee.⁷ The OARSI update published in 2010 found that glucosamine was effective, but less so than in previous studies.²² If glucosamine is effective, some studies suggest that glucosamine sulfate is more effective than glucosamine hydrochloride.²²

The same OARSI review revealed that chondroitin sulfate relieved pain but with heterogeneous, dissimilar effect sizes. Of interest was the finding that the 5-year incidence of total knee replacement was lower in patients treated with glucosamine sulfate 1,500 mg/day than with placebo. Also, the rate of decline of joint space narrowing was reported to be reduced in chondroitin sulfate-treated patients.²²

In practice, a conditional recommendation against a treatment means that most informed patients would not want the treatment, but some would. Accordingly, if patients still want to take chondroitin or glucosamine after being informed of the limited evidence of benefit, I feel a trial of their use is reasonable.

OSTEOARTHRITIS OF THE HIP

Indications for therapy of osteoarthritis of the hip are similar to those for osteoarthritis of the knee.

As in the knee, nonpharmacologic therapies are important. Loss of weight for overweight patients is extremely important; supervised exercise is especially valuable. Use of canes or crutches as needed is conditionally recommended.

Pharmacologic management is similar to that of osteoarthritis of the knee, with particular use of acetaminophen, NSAIDs, tramadol, and intra-articular corticosteroid injections.

Comment. Intra-articular injection of corticosteroids into the hip would be out of the realm of most nonspecialist practices. Although some rheumatologists are expert in such injections, this treatment is generally best left to an orthopedist or invasive radiologist. The use of ultrasonographic guidance is becoming more frequent, with many rheumatologists having developed expertise in this approach to the knee and the hip. Since most studies were in patients with osteoarthritis of the knee, fewer data are available as to the efficacy of these agents in patients with hip osteoarthritis.

Fewer data are available also with respect to the benefit of chondroitin sulfate and glucosamine in patients with osteoarthritis of the hip. Total joint replacement is extremely effective if conservative therapy does not help.

FIRST, DO NO HARM

Guidelines from the ACR,^1,2 the European League Against Rheumatism (EULAR),^28,29 the American Academy of Orthopedic Surgeons (AAOS),³⁰ and the OARSI^7,22 all differ somewhat, owing to the different evidence available at the time each guideline was developed and to different geographic and cultural backgrounds.

The compositions of these various panels also differ sufficiently to affect their overall recommendations. For example, the EULAR panel consisted of only rheumatologists and an orthopedic surgeon; for the hand osteoarthritis recommendations they added a physiatrist and two allied health professionals.^28,29 The OARSI panel included two primary care physicians in addition to rheumatologists and an orthopedic surgeon.⁷ The ACR was the only professional society to include primary care physicians, physiatrists, and geriatricians along with rheumatologists, an orthopedic surgeon, and physical and occupational therapists.

Although it is to be expected that there will not be universal agreement on all points of management of osteoarthritis by diverse groups, it is essential that input from all these experts representing various subspecialties be recognized. Therapeutic approaches will vary depending on patient characteristics and the experience of the treating physician. As long as therapy is based on reasonable supportive data, beneficial effects can be anticipated. Therapies that received conditional recommendations are not to be discounted if a reasonable percent of patients respond in positive fashion. Obviously, strong recommendations are more likely to be universally accepted since the likelihood that they will be beneficial is stronger.

In any approach to therapy, the caveat primum non nocere—first, do no harm—must always be kept in mind.

“When I see a patient with arthritis coming in the front door, I leave by the back door.”
—Sir William Ostler

Fortunately for today’s physicians treating patients with osteoarthritis, we need not be as pessimistic as Osler was more than a century ago when he uttered his now-famous words. Still, there is no magic bullet for the contemporary clinician treating an elderly patient with osteoarthritis. Instead, there are many imperfect bullets, and choosing between them is always a balancing act between benefit and risk from various agents: nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics such as acetaminophen and tramadol, opioids, and supplements such as glucosamine and chondroitin sulfate.

So there was great interest when, in 2012,¹ the American College of Rheumatology (ACR) updated its previous guidelines (from 2000) on drug and nondrug therapies for osteoarthritis of the hip and the knee² and added new recommendations on osteoarthritis of the hand.

Revising the guidelines was appropriate, since new therapies have become available. But, as the guideline authors state, with osteoarthritis, as with other diseases, guidelines cannot be a “cookbook.”

The treatment approach differs depending on the patient’s clinical presentation and on the preferences of the patient and the physician. Often, more than one approach is possible, and more than one approach may be appropriate in a given patient at a given time. The guideline authors also point out that some physicians may disagree with some of the recommendations.

I wish to review here several of the key recommendations. But I also provide some of my personal perspective and experience after 4 decades of treating patients with osteoarthritis.

HOW THE GUIDELINES WERE MADE

The new ACR guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, a formal process to develop recommendations that are as evidence-based as possible.³

The authors are outstanding experts in the field of osteoarthritis from throughout the United States and Canada. Further, the recommendations were voted on by a “technical expert panel” representing the fields of rheumatology, orthopedics, physical medicine, and rehabilitation, from both academic medicine and private practice. This representation provides a balance of input from the types of clinicians frequently involved in managing osteoarthritis.

The initial literature searches for drug therapies were conducted during late 2008, and those for nonpharmacologic treatments were conducted during the second and third quarters of 2009. The goal of the literature searches was to identify the most current systematic reviews and meta-analyses that would provide reliable estimates of benefits of intervention for the prespecified clinically relevant outcomes of pain and function, as well as data on safety.

Recommendations: For or against, strong or weak—and the informed patient’s perspective

Therapies received the following possible recommendations:

• Strong recommendation to use
• Weak (or conditional) recommendation to use
• No recommendation
• Weak (or conditional) recommendation not to use
• Strong recommendation not to use.

A strong recommendation required high-quality evidence and evidence of a large difference between desirable and undesirable effects of the treatment. A conditional recommendation was based on the absence of high-quality evidence, evidence of only a small difference between desirable and undesirable effects of the treatment, or both.

One interesting feature of these recommendations is that they took into account how informed patients might themselves evaluate the data with their medical condition.

For instance, if a therapy received a strong favorable recommendation, we can assume that most informed patients would choose to receive it, and we can shape our interaction with the patient accordingly. A conditional recommendation means that most informed patients would choose the treatment—but many would not, and physicians should keep the patient’s values and preferences in mind.

I admit I had a problem with the meaning of the word “conditional” in the context of these guidelines. When evaluating a treatment, the term “weak” is readily understood and clearer. By using the word “weak,” one is making a positive statement in support of use but letting you know that the data and recommendation are weak. The word “conditional” is less readily defined and does not necessarily imply support for use.

Recommendations were drafted after discussion of the evidence at each meeting of the technical expert panel. Consensus was defined as 75% or more of the members of the panel voting to either strongly or conditionally recommend using a therapy, to either strongly or conditionally recommend not using it, or to choose not to make a recommendation on its use.

OSTEOARTHRITIS OF THE HAND: NO STRONG RECOMMENDATIONS

The technical expert panel gave no strong recommendations for any nondrug or drug treatment for osteoarthritis of the hand.

Conditional recommendations for nondrug treatments

The panel conditionally recommended the following:

• All patients with osteoarthritis of the hand should be evaluated either by their primary physician or by an occupational or physical therapist, particularly with respect to ability to perform activities of daily living.
• Assistive devices such as jar openers, key turners, and pull tabs for zippers should be recommended, as needed.
• Patients should be instructed in joint protection and in the use of thermal treatments (eg, heating pads, ultrasound devices, hot packs, and ice packs).

Comments. Appliances are often beneficial in patients who have involvement of the first carpometacarpal (trapeziometacarpal) joint. Although over-the-counter thumb splints are an option, referral to an occupational therapist for splint prescription is advantageous to achieve a comfortable fit and, importantly, for instructions to the patient on how to avoid joint trauma.

It would be unrealistic to expect primary care physicians and internists to have the expertise to make detailed recommendations about orthopedic appliances. Accordingly, referral to an occupational therapist or an orthopedist is advisable for these situations. It is important, however, that the physician be aware of what treatments are available and most effective, and of the indications for referral.

As for heat treatment, elastic stretch gloves may relieve symptoms through their warming and massaging effects.⁴

The expert panel gave conditional recommendations in favor of:

• Topical capsaicin
• Topical NSAIDs
• Oral NSAIDs (including both nonselective and selective agents)
• Tramadol (Ultram)
• Topical rather than oral NSAIDs for patients age 75 and older.

Other drug treatments got conditional recommendations against their use

The expert panel gave conditional recommendations against using:

• Intra-articular injections, and in particular, corticosteroid injections in the trapeziometacarpal (first carpometacarpal) joint
• Opioid analgesics
• Oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis.

No recommendation for or against

• Hydroxychloroquine.

Comments—Intra-articular injections, opioids, and oral NSAIDs

I differ with these recommendations on several points.

Although the guidelines committee conditionally recommended against using intra-articular therapies for hand osteoarthritis, I find that intra-articular corticosteroid injections are often effective, particularly in patients who have inflammatory forms of the disease, ie, “erosive inflammatory osteoarthritis.” Most nonspecialist physicians probably have limited experience in giving injections into small joints, and referral to a rheumatologist or orthopedist would be appropriate.

I disagree as well with the conditional recommendation that intra-articular corticosteroid injections not be used for involvement of the trapeziometacarpal (first carpometacarpal) joint. I find that many patients with osteoarthritis of this joint experience improvement with intra-articular corticosteroid injections.

I agree that there are limited data on the use of intra-articular hyaluronan injections in this situation and do not routinely use them in this joint.

Opioid analgesics also received a conditional recommendation against their use. The same caveats apply here as for these drugs elsewhere.⁵ If used, opioids should be used at the lowest dose possible and for as short a time as possible. If the physician is uncomfortable prescribing opioids for patients with osteoarthritis, referral to a pain specialist is recommended.

I disagree to some extent with the conditional recommendation that people age 75 and older should use topical rather than oral NSAIDs. I understand the recommendation, given that older people have a higher frequency of gastrointestinal, renal, and cardiac disease and are best served by avoiding NSAIDs. However, we all see patients over age 75 who are physiologically younger than their numerical age. Accordingly, I feel that the judgment of the physician plays a role in whether NSAIDs are reasonable for some older patients.

The committee recommended not using oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis. I have used oral hydroxychloroquine off-label in such patients and find that they respond in a very rewarding fashion.

Given that this is an off-label use of hydroxychloroquine, the drug should be used only with appropriate consideration and after discussion with the patient about toxicity, especially about the risk of ocular manifestations.

OSTEOARTHRITIS OF THE KNEE

Some nondrug therapies got strong recommendations

The expert panel strongly recommended:

• Exercise (aerobic, resistance, land-based, and aquatic)
• Weight loss (for patients who are overweight).

Other nondrug therapies got conditional recommendations

The panel conditionally recommended:

• Self-management programs
• Manual therapy in combination with supervised exercise
• Psychosocial interventions
• Medially directed patellar taping
• Medially wedged insoles (if the patient has lateral compartment osteoarthritis)
• Laterally wedged subtalar strapped insoles (if the patient has medial compartment osteoarthritis)
• Heat therapy
• Walking aids, as needed
• Tai chi
• Chinese acupuncture
• Transcutaneous electrical nerve stimulation.

Comments. The ACR panel appropriately noted that Chinese acupuncture or transcutaneous electrical stimulation should be recommended only if the patient has chronic moderate to severe pain and is a candidate for total knee arthroplasty but is unwilling to undergo the procedure or has comorbid medical conditions that rule out surgery.

Nondrug therapies for knee osteoarthritis that got no recommendation for or against

• Balance exercise
• Laterally wedged insoles
• Manual therapy alone
• Knee braces
• Laterally directed patellar taping.

Comments. It was somewhat surprising that there were no recommendations about laterally wedged insoles or knee braces. Laterally wedged insoles have been recommended for patients who have medial compartment knee osteoarthritis⁶; being thinner at the instep and thicker at the outer edge of the foot, they reduce load on the medial aspect of the knee. One has to be cautious in using knee wedging in patients who have concomitant ankle or hip angle deformities, lest these joints be compromised.

Some of these treatments would be out of the realm of the nonspecialist physician.

Conditional recommendations for initial drug therapy for knee osteoarthritis

The panel conditionally recommended that patients who have osteoarthritis of the knee use one of the following:

• Acetaminophen (contained in Tylenol and a host of other products)
• Oral NSAIDs
• Topical NSAIDs (with a strong recommendation for topical NSAIDs rather than oral NSAIDs in patients age 75 and older)
• Tramadol
• Intra-articular corticosteroid injections.

Comments. In the past, it was recommended that acetaminophen in full doses of up to 4,000 mg per day be considered.⁷ Current dogma, however, is that doses of acetaminophen should not exceed 3,000 mg per day to avoid damaging the liver. This concern led the US Food and Drug Administration (FDA) in 2011 to advise that the maximum daily dose be limited.⁸ The ACR panel recommended that patients be counseled to avoid all other products that contain acetaminophen, which is especially cogent, given the presence of this agent in many over-the-counter medications.⁹

The panel conditionally recommended that people age 75 and older use topical rather than oral NSAIDs. As mentioned earlier, a specific age limit does not take into account that many people age 75 and older may actually be physiologically younger than some in their 50s or 60s. Accordingly, it is recommended that the physician use judgment in this regard so that NSAIDs will not be denied to patients for whom they might be of significant value.

Strong recommendation for gastric protection in patients at risk on NSAIDs

If a patient with knee osteoarthritis has a history of a symptomatic or complicated upper gastrointestinal ulcer but has not had an upper gastrointestinal bleed in the past year and the physician chooses to prescribe an oral NSAID, the expert panel strongly recommended using either a cyclooxygenase (COX)-2-selective inhibitor or a nonselective NSAID in combination with a proton pump inhibitor.

Comment. The suggestion that patients who have had a complicated upper gastrointestinal ulcer in the past year could be considered for treatment with a COX-2-selective inhibitor or nonselective NSAID in combination with a proton pump inhibitor seemed a bit aggressive. My own inclination would be to avoid both nonselective and selective inhibitors in this situation. Alternative agents such as acetaminophen in full doses, tramadol, intra-articular hyaluronan injections, and intra-articular corticosteroid injections seem preferable with respect to safety in such patients.

The suggestion that a proton pump inhibitor be used whenever an NSAID is given for chronic management of knee or hip osteoarthritis is reasonable.^10,11 Although some studies have suggested that chronic use of proton pump inhibitors may predispose to osteopenia or osteoporosis, others have not, and gastric protection should be considered in patients at gastrointestinal risk.

Strong recommendation against ibuprofen in patients taking aspirin

The ACR panel strongly recommended that ibuprofen (Advil) not be prescribed to patients with knee osteoarthritis who are using aspirin in low doses for cardioprotection, and strongly recommended using another nonselective NSAID plus a proton pump inhibitor instead. The panel also strongly recommended against using a COX-2-selective inhibitor in this situation.^12,13

Comment. The rationale for these recommendations is that ibuprofen may render aspirin ineffective as a cardioprotective agent. Ibuprofen interferes with the aspirin-binding site on platelets, so that the protective effect of aspirin is lost.^14,15 Celecoxib (Celebrex)¹⁶ and diclofenac (Voltaren) have binding sites different from that of aspirin, although the ACR recommends against using COX-2-selective inhibitors such as celecoxib in the situation and gives no recommendation about other NSAIDs.

No recommendations for or against

The panel issued no recommendations for or against the following treatments for patients with knee osteoarthritis:

• Intra-articular hyaluronan injections
• Duloxetine (Cymbalta)
• Opioid analgesics.

Comments on knee injections

Intra-articular injections of corticosteroids or hyaluronan are commonly used for knee osteoarthritis. As noted, corticosteroid injections received a conditional recommendation, while hyaluronan injections received no recommendation for or against.

How often to inject corticosteroids? In general, too-frequent injection of corticosteroids is to be avoided, in view of the risk of promoting joint breakdown. There is no “magic” number of injections that is safe, although more than 4 per year in the same joint should generally be avoided. In some situations, however, repeat injections may be reasonable if alternative therapies are associated with higher risk.

Raynauld et al,¹⁷ in a randomized, double-blind, placebo-controlled trial, demonstrated that intra-articular corticosteroid injections at 3-month intervals for 2 years were not deleterious to knees.

My philosophy is generally not to inject on a regular basis, but to be selective and be guided by the patient’s clinical condition and response to prior injections.

Are hyaluronan injections effective? Although experts differ in their enthusiasm for intra-articular hyaluronan injections in the knee, I have found that many patients benefit from this treatment. Multiple studies have found it efficacious and safe overall.^18–21 However, some systematic reviews have called its efficacy into question.⁷

Although differences in efficacy have been noted, this therapy was approved as being useful in patients with knee osteoarthritis in the Osteoarthritis Research Society International (OARSI) recommendations.⁷ The effect sizes were smaller in later assessments.²²

Hyaluronan injections do not pose the risk of joint breakdown that corticosteroid injections do, but their clinical efficacy is not as dramatic. Adverse reactions to most intraarticular hyaluronans are limited, with slight increases in pain and stiffness after injection. Significant inflammatory reactions characterized as “postinjection flares” are more commonly seen with high-molecular-weight crosslinked preparations. These reactions can be severe and can mimic joint infection clinically. Joint aspiration with synovial fluid analysis and culture may be necessary to exclude infection. Response to aspiration and nonsteroidal inflammatory agents or intra-articular corticosteroids is usually excellent.

Ultrasonographic guidance. As with intraarticular injections in other areas, ultrasonographic guidance is becoming more common, as it allows for more accurate drug administration.

Pes anserine bursitis must be ruled out as a cause of the patient’s knee symptoms—misdiagnosis is not uncommon. The bursa is located on the medial aspect of the tibia, and inflammation of the bursa is a common cause of pain in this area. Local steroid injection is extremely effective in symptomatic therapy. Physical therapy and NSAIDs may be adequate to treat milder cases.

Conditional recommendation against glucosamine, chondroitin, capsaicin

The ACR panel conditionally recommended that patients with knee osteoarthritis not use:

• Chondroitin sulfate
• Glucosamine
• Topical capsaicin.

Comment. Evidence is mixed about the efficacy of glucosamine and chondroitin sulfate, which are so-called nutraceuticals. Some studies found them useful^23–25 but some did not,²⁶ and a meta-analysis concluded that they do not help.²⁷ The OARSI guidelines published in 2008 stated that these agents may relieve symptoms of osteoarthritis of the knee.⁷ The OARSI update published in 2010 found that glucosamine was effective, but less so than in previous studies.²² If glucosamine is effective, some studies suggest that glucosamine sulfate is more effective than glucosamine hydrochloride.²²

The same OARSI review revealed that chondroitin sulfate relieved pain but with heterogeneous, dissimilar effect sizes. Of interest was the finding that the 5-year incidence of total knee replacement was lower in patients treated with glucosamine sulfate 1,500 mg/day than with placebo. Also, the rate of decline of joint space narrowing was reported to be reduced in chondroitin sulfate-treated patients.²²

In practice, a conditional recommendation against a treatment means that most informed patients would not want the treatment, but some would. Accordingly, if patients still want to take chondroitin or glucosamine after being informed of the limited evidence of benefit, I feel a trial of their use is reasonable.

OSTEOARTHRITIS OF THE HIP

Indications for therapy of osteoarthritis of the hip are similar to those for osteoarthritis of the knee.

As in the knee, nonpharmacologic therapies are important. Loss of weight for overweight patients is extremely important; supervised exercise is especially valuable. Use of canes or crutches as needed is conditionally recommended.

Pharmacologic management is similar to that of osteoarthritis of the knee, with particular use of acetaminophen, NSAIDs, tramadol, and intra-articular corticosteroid injections.

Comment. Intra-articular injection of corticosteroids into the hip would be out of the realm of most nonspecialist practices. Although some rheumatologists are expert in such injections, this treatment is generally best left to an orthopedist or invasive radiologist. The use of ultrasonographic guidance is becoming more frequent, with many rheumatologists having developed expertise in this approach to the knee and the hip. Since most studies were in patients with osteoarthritis of the knee, fewer data are available as to the efficacy of these agents in patients with hip osteoarthritis.

Fewer data are available also with respect to the benefit of chondroitin sulfate and glucosamine in patients with osteoarthritis of the hip. Total joint replacement is extremely effective if conservative therapy does not help.

FIRST, DO NO HARM

Guidelines from the ACR,^1,2 the European League Against Rheumatism (EULAR),^28,29 the American Academy of Orthopedic Surgeons (AAOS),³⁰ and the OARSI^7,22 all differ somewhat, owing to the different evidence available at the time each guideline was developed and to different geographic and cultural backgrounds.

The compositions of these various panels also differ sufficiently to affect their overall recommendations. For example, the EULAR panel consisted of only rheumatologists and an orthopedic surgeon; for the hand osteoarthritis recommendations they added a physiatrist and two allied health professionals.^28,29 The OARSI panel included two primary care physicians in addition to rheumatologists and an orthopedic surgeon.⁷ The ACR was the only professional society to include primary care physicians, physiatrists, and geriatricians along with rheumatologists, an orthopedic surgeon, and physical and occupational therapists.

Although it is to be expected that there will not be universal agreement on all points of management of osteoarthritis by diverse groups, it is essential that input from all these experts representing various subspecialties be recognized. Therapeutic approaches will vary depending on patient characteristics and the experience of the treating physician. As long as therapy is based on reasonable supportive data, beneficial effects can be anticipated. Therapies that received conditional recommendations are not to be discounted if a reasonable percent of patients respond in positive fashion. Obviously, strong recommendations are more likely to be universally accepted since the likelihood that they will be beneficial is stronger.

In any approach to therapy, the caveat primum non nocere—first, do no harm—must always be kept in mind.

“When I see a patient with arthritis coming in the front door, I leave by the back door.”
—Sir William Ostler

Fortunately for today’s physicians treating patients with osteoarthritis, we need not be as pessimistic as Osler was more than a century ago when he uttered his now-famous words. Still, there is no magic bullet for the contemporary clinician treating an elderly patient with osteoarthritis. Instead, there are many imperfect bullets, and choosing between them is always a balancing act between benefit and risk from various agents: nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics such as acetaminophen and tramadol, opioids, and supplements such as glucosamine and chondroitin sulfate.

So there was great interest when, in 2012,¹ the American College of Rheumatology (ACR) updated its previous guidelines (from 2000) on drug and nondrug therapies for osteoarthritis of the hip and the knee² and added new recommendations on osteoarthritis of the hand.

Revising the guidelines was appropriate, since new therapies have become available. But, as the guideline authors state, with osteoarthritis, as with other diseases, guidelines cannot be a “cookbook.”

The treatment approach differs depending on the patient’s clinical presentation and on the preferences of the patient and the physician. Often, more than one approach is possible, and more than one approach may be appropriate in a given patient at a given time. The guideline authors also point out that some physicians may disagree with some of the recommendations.

I wish to review here several of the key recommendations. But I also provide some of my personal perspective and experience after 4 decades of treating patients with osteoarthritis.

HOW THE GUIDELINES WERE MADE

The new ACR guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, a formal process to develop recommendations that are as evidence-based as possible.³

The authors are outstanding experts in the field of osteoarthritis from throughout the United States and Canada. Further, the recommendations were voted on by a “technical expert panel” representing the fields of rheumatology, orthopedics, physical medicine, and rehabilitation, from both academic medicine and private practice. This representation provides a balance of input from the types of clinicians frequently involved in managing osteoarthritis.

The initial literature searches for drug therapies were conducted during late 2008, and those for nonpharmacologic treatments were conducted during the second and third quarters of 2009. The goal of the literature searches was to identify the most current systematic reviews and meta-analyses that would provide reliable estimates of benefits of intervention for the prespecified clinically relevant outcomes of pain and function, as well as data on safety.

Recommendations: For or against, strong or weak—and the informed patient’s perspective

Therapies received the following possible recommendations:

• Strong recommendation to use
• Weak (or conditional) recommendation to use
• No recommendation
• Weak (or conditional) recommendation not to use
• Strong recommendation not to use.

A strong recommendation required high-quality evidence and evidence of a large difference between desirable and undesirable effects of the treatment. A conditional recommendation was based on the absence of high-quality evidence, evidence of only a small difference between desirable and undesirable effects of the treatment, or both.

One interesting feature of these recommendations is that they took into account how informed patients might themselves evaluate the data with their medical condition.

For instance, if a therapy received a strong favorable recommendation, we can assume that most informed patients would choose to receive it, and we can shape our interaction with the patient accordingly. A conditional recommendation means that most informed patients would choose the treatment—but many would not, and physicians should keep the patient’s values and preferences in mind.

I admit I had a problem with the meaning of the word “conditional” in the context of these guidelines. When evaluating a treatment, the term “weak” is readily understood and clearer. By using the word “weak,” one is making a positive statement in support of use but letting you know that the data and recommendation are weak. The word “conditional” is less readily defined and does not necessarily imply support for use.

Recommendations were drafted after discussion of the evidence at each meeting of the technical expert panel. Consensus was defined as 75% or more of the members of the panel voting to either strongly or conditionally recommend using a therapy, to either strongly or conditionally recommend not using it, or to choose not to make a recommendation on its use.

OSTEOARTHRITIS OF THE HAND: NO STRONG RECOMMENDATIONS

The technical expert panel gave no strong recommendations for any nondrug or drug treatment for osteoarthritis of the hand.

Conditional recommendations for nondrug treatments

The panel conditionally recommended the following:

• All patients with osteoarthritis of the hand should be evaluated either by their primary physician or by an occupational or physical therapist, particularly with respect to ability to perform activities of daily living.
• Assistive devices such as jar openers, key turners, and pull tabs for zippers should be recommended, as needed.
• Patients should be instructed in joint protection and in the use of thermal treatments (eg, heating pads, ultrasound devices, hot packs, and ice packs).

Comments. Appliances are often beneficial in patients who have involvement of the first carpometacarpal (trapeziometacarpal) joint. Although over-the-counter thumb splints are an option, referral to an occupational therapist for splint prescription is advantageous to achieve a comfortable fit and, importantly, for instructions to the patient on how to avoid joint trauma.

It would be unrealistic to expect primary care physicians and internists to have the expertise to make detailed recommendations about orthopedic appliances. Accordingly, referral to an occupational therapist or an orthopedist is advisable for these situations. It is important, however, that the physician be aware of what treatments are available and most effective, and of the indications for referral.

As for heat treatment, elastic stretch gloves may relieve symptoms through their warming and massaging effects.⁴

The expert panel gave conditional recommendations in favor of:

• Topical capsaicin
• Topical NSAIDs
• Oral NSAIDs (including both nonselective and selective agents)
• Tramadol (Ultram)
• Topical rather than oral NSAIDs for patients age 75 and older.

Other drug treatments got conditional recommendations against their use

The expert panel gave conditional recommendations against using:

• Intra-articular injections, and in particular, corticosteroid injections in the trapeziometacarpal (first carpometacarpal) joint
• Opioid analgesics
• Oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis.

No recommendation for or against

• Hydroxychloroquine.

Comments—Intra-articular injections, opioids, and oral NSAIDs

I differ with these recommendations on several points.

Although the guidelines committee conditionally recommended against using intra-articular therapies for hand osteoarthritis, I find that intra-articular corticosteroid injections are often effective, particularly in patients who have inflammatory forms of the disease, ie, “erosive inflammatory osteoarthritis.” Most nonspecialist physicians probably have limited experience in giving injections into small joints, and referral to a rheumatologist or orthopedist would be appropriate.

I disagree as well with the conditional recommendation that intra-articular corticosteroid injections not be used for involvement of the trapeziometacarpal (first carpometacarpal) joint. I find that many patients with osteoarthritis of this joint experience improvement with intra-articular corticosteroid injections.

I agree that there are limited data on the use of intra-articular hyaluronan injections in this situation and do not routinely use them in this joint.

Opioid analgesics also received a conditional recommendation against their use. The same caveats apply here as for these drugs elsewhere.⁵ If used, opioids should be used at the lowest dose possible and for as short a time as possible. If the physician is uncomfortable prescribing opioids for patients with osteoarthritis, referral to a pain specialist is recommended.

I disagree to some extent with the conditional recommendation that people age 75 and older should use topical rather than oral NSAIDs. I understand the recommendation, given that older people have a higher frequency of gastrointestinal, renal, and cardiac disease and are best served by avoiding NSAIDs. However, we all see patients over age 75 who are physiologically younger than their numerical age. Accordingly, I feel that the judgment of the physician plays a role in whether NSAIDs are reasonable for some older patients.

The committee recommended not using oral methotrexate or sulfasalazine in patients with erosive inflammatory interphalangeal osteoarthritis. I have used oral hydroxychloroquine off-label in such patients and find that they respond in a very rewarding fashion.

Given that this is an off-label use of hydroxychloroquine, the drug should be used only with appropriate consideration and after discussion with the patient about toxicity, especially about the risk of ocular manifestations.

OSTEOARTHRITIS OF THE KNEE

Some nondrug therapies got strong recommendations

The expert panel strongly recommended:

• Exercise (aerobic, resistance, land-based, and aquatic)
• Weight loss (for patients who are overweight).

Other nondrug therapies got conditional recommendations

The panel conditionally recommended:

• Self-management programs
• Manual therapy in combination with supervised exercise
• Psychosocial interventions
• Medially directed patellar taping
• Medially wedged insoles (if the patient has lateral compartment osteoarthritis)
• Laterally wedged subtalar strapped insoles (if the patient has medial compartment osteoarthritis)
• Heat therapy
• Walking aids, as needed
• Tai chi
• Chinese acupuncture
• Transcutaneous electrical nerve stimulation.

Comments. The ACR panel appropriately noted that Chinese acupuncture or transcutaneous electrical stimulation should be recommended only if the patient has chronic moderate to severe pain and is a candidate for total knee arthroplasty but is unwilling to undergo the procedure or has comorbid medical conditions that rule out surgery.

Nondrug therapies for knee osteoarthritis that got no recommendation for or against

• Balance exercise
• Laterally wedged insoles
• Manual therapy alone
• Knee braces
• Laterally directed patellar taping.

Comments. It was somewhat surprising that there were no recommendations about laterally wedged insoles or knee braces. Laterally wedged insoles have been recommended for patients who have medial compartment knee osteoarthritis⁶; being thinner at the instep and thicker at the outer edge of the foot, they reduce load on the medial aspect of the knee. One has to be cautious in using knee wedging in patients who have concomitant ankle or hip angle deformities, lest these joints be compromised.

Some of these treatments would be out of the realm of the nonspecialist physician.

Conditional recommendations for initial drug therapy for knee osteoarthritis

The panel conditionally recommended that patients who have osteoarthritis of the knee use one of the following:

• Acetaminophen (contained in Tylenol and a host of other products)
• Oral NSAIDs
• Topical NSAIDs (with a strong recommendation for topical NSAIDs rather than oral NSAIDs in patients age 75 and older)
• Tramadol
• Intra-articular corticosteroid injections.

Comments. In the past, it was recommended that acetaminophen in full doses of up to 4,000 mg per day be considered.⁷ Current dogma, however, is that doses of acetaminophen should not exceed 3,000 mg per day to avoid damaging the liver. This concern led the US Food and Drug Administration (FDA) in 2011 to advise that the maximum daily dose be limited.⁸ The ACR panel recommended that patients be counseled to avoid all other products that contain acetaminophen, which is especially cogent, given the presence of this agent in many over-the-counter medications.⁹

The panel conditionally recommended that people age 75 and older use topical rather than oral NSAIDs. As mentioned earlier, a specific age limit does not take into account that many people age 75 and older may actually be physiologically younger than some in their 50s or 60s. Accordingly, it is recommended that the physician use judgment in this regard so that NSAIDs will not be denied to patients for whom they might be of significant value.

Strong recommendation for gastric protection in patients at risk on NSAIDs

If a patient with knee osteoarthritis has a history of a symptomatic or complicated upper gastrointestinal ulcer but has not had an upper gastrointestinal bleed in the past year and the physician chooses to prescribe an oral NSAID, the expert panel strongly recommended using either a cyclooxygenase (COX)-2-selective inhibitor or a nonselective NSAID in combination with a proton pump inhibitor.

Comment. The suggestion that patients who have had a complicated upper gastrointestinal ulcer in the past year could be considered for treatment with a COX-2-selective inhibitor or nonselective NSAID in combination with a proton pump inhibitor seemed a bit aggressive. My own inclination would be to avoid both nonselective and selective inhibitors in this situation. Alternative agents such as acetaminophen in full doses, tramadol, intra-articular hyaluronan injections, and intra-articular corticosteroid injections seem preferable with respect to safety in such patients.

The suggestion that a proton pump inhibitor be used whenever an NSAID is given for chronic management of knee or hip osteoarthritis is reasonable.^10,11 Although some studies have suggested that chronic use of proton pump inhibitors may predispose to osteopenia or osteoporosis, others have not, and gastric protection should be considered in patients at gastrointestinal risk.

Strong recommendation against ibuprofen in patients taking aspirin

The ACR panel strongly recommended that ibuprofen (Advil) not be prescribed to patients with knee osteoarthritis who are using aspirin in low doses for cardioprotection, and strongly recommended using another nonselective NSAID plus a proton pump inhibitor instead. The panel also strongly recommended against using a COX-2-selective inhibitor in this situation.^12,13

Comment. The rationale for these recommendations is that ibuprofen may render aspirin ineffective as a cardioprotective agent. Ibuprofen interferes with the aspirin-binding site on platelets, so that the protective effect of aspirin is lost.^14,15 Celecoxib (Celebrex)¹⁶ and diclofenac (Voltaren) have binding sites different from that of aspirin, although the ACR recommends against using COX-2-selective inhibitors such as celecoxib in the situation and gives no recommendation about other NSAIDs.

No recommendations for or against

The panel issued no recommendations for or against the following treatments for patients with knee osteoarthritis:

• Intra-articular hyaluronan injections
• Duloxetine (Cymbalta)
• Opioid analgesics.

Comments on knee injections

Intra-articular injections of corticosteroids or hyaluronan are commonly used for knee osteoarthritis. As noted, corticosteroid injections received a conditional recommendation, while hyaluronan injections received no recommendation for or against.

How often to inject corticosteroids? In general, too-frequent injection of corticosteroids is to be avoided, in view of the risk of promoting joint breakdown. There is no “magic” number of injections that is safe, although more than 4 per year in the same joint should generally be avoided. In some situations, however, repeat injections may be reasonable if alternative therapies are associated with higher risk.

Raynauld et al,¹⁷ in a randomized, double-blind, placebo-controlled trial, demonstrated that intra-articular corticosteroid injections at 3-month intervals for 2 years were not deleterious to knees.

My philosophy is generally not to inject on a regular basis, but to be selective and be guided by the patient’s clinical condition and response to prior injections.

Are hyaluronan injections effective? Although experts differ in their enthusiasm for intra-articular hyaluronan injections in the knee, I have found that many patients benefit from this treatment. Multiple studies have found it efficacious and safe overall.^18–21 However, some systematic reviews have called its efficacy into question.⁷

Although differences in efficacy have been noted, this therapy was approved as being useful in patients with knee osteoarthritis in the Osteoarthritis Research Society International (OARSI) recommendations.⁷ The effect sizes were smaller in later assessments.²²

Hyaluronan injections do not pose the risk of joint breakdown that corticosteroid injections do, but their clinical efficacy is not as dramatic. Adverse reactions to most intraarticular hyaluronans are limited, with slight increases in pain and stiffness after injection. Significant inflammatory reactions characterized as “postinjection flares” are more commonly seen with high-molecular-weight crosslinked preparations. These reactions can be severe and can mimic joint infection clinically. Joint aspiration with synovial fluid analysis and culture may be necessary to exclude infection. Response to aspiration and nonsteroidal inflammatory agents or intra-articular corticosteroids is usually excellent.

Ultrasonographic guidance. As with intraarticular injections in other areas, ultrasonographic guidance is becoming more common, as it allows for more accurate drug administration.

Pes anserine bursitis must be ruled out as a cause of the patient’s knee symptoms—misdiagnosis is not uncommon. The bursa is located on the medial aspect of the tibia, and inflammation of the bursa is a common cause of pain in this area. Local steroid injection is extremely effective in symptomatic therapy. Physical therapy and NSAIDs may be adequate to treat milder cases.

Conditional recommendation against glucosamine, chondroitin, capsaicin

The ACR panel conditionally recommended that patients with knee osteoarthritis not use:

• Chondroitin sulfate
• Glucosamine
• Topical capsaicin.

Comment. Evidence is mixed about the efficacy of glucosamine and chondroitin sulfate, which are so-called nutraceuticals. Some studies found them useful^23–25 but some did not,²⁶ and a meta-analysis concluded that they do not help.²⁷ The OARSI guidelines published in 2008 stated that these agents may relieve symptoms of osteoarthritis of the knee.⁷ The OARSI update published in 2010 found that glucosamine was effective, but less so than in previous studies.²² If glucosamine is effective, some studies suggest that glucosamine sulfate is more effective than glucosamine hydrochloride.²²

The same OARSI review revealed that chondroitin sulfate relieved pain but with heterogeneous, dissimilar effect sizes. Of interest was the finding that the 5-year incidence of total knee replacement was lower in patients treated with glucosamine sulfate 1,500 mg/day than with placebo. Also, the rate of decline of joint space narrowing was reported to be reduced in chondroitin sulfate-treated patients.²²

In practice, a conditional recommendation against a treatment means that most informed patients would not want the treatment, but some would. Accordingly, if patients still want to take chondroitin or glucosamine after being informed of the limited evidence of benefit, I feel a trial of their use is reasonable.

OSTEOARTHRITIS OF THE HIP

Indications for therapy of osteoarthritis of the hip are similar to those for osteoarthritis of the knee.

As in the knee, nonpharmacologic therapies are important. Loss of weight for overweight patients is extremely important; supervised exercise is especially valuable. Use of canes or crutches as needed is conditionally recommended.

Pharmacologic management is similar to that of osteoarthritis of the knee, with particular use of acetaminophen, NSAIDs, tramadol, and intra-articular corticosteroid injections.

Comment. Intra-articular injection of corticosteroids into the hip would be out of the realm of most nonspecialist practices. Although some rheumatologists are expert in such injections, this treatment is generally best left to an orthopedist or invasive radiologist. The use of ultrasonographic guidance is becoming more frequent, with many rheumatologists having developed expertise in this approach to the knee and the hip. Since most studies were in patients with osteoarthritis of the knee, fewer data are available as to the efficacy of these agents in patients with hip osteoarthritis.

Fewer data are available also with respect to the benefit of chondroitin sulfate and glucosamine in patients with osteoarthritis of the hip. Total joint replacement is extremely effective if conservative therapy does not help.

FIRST, DO NO HARM

Guidelines from the ACR,^1,2 the European League Against Rheumatism (EULAR),^28,29 the American Academy of Orthopedic Surgeons (AAOS),³⁰ and the OARSI^7,22 all differ somewhat, owing to the different evidence available at the time each guideline was developed and to different geographic and cultural backgrounds.

The compositions of these various panels also differ sufficiently to affect their overall recommendations. For example, the EULAR panel consisted of only rheumatologists and an orthopedic surgeon; for the hand osteoarthritis recommendations they added a physiatrist and two allied health professionals.^28,29 The OARSI panel included two primary care physicians in addition to rheumatologists and an orthopedic surgeon.⁷ The ACR was the only professional society to include primary care physicians, physiatrists, and geriatricians along with rheumatologists, an orthopedic surgeon, and physical and occupational therapists.

Although it is to be expected that there will not be universal agreement on all points of management of osteoarthritis by diverse groups, it is essential that input from all these experts representing various subspecialties be recognized. Therapeutic approaches will vary depending on patient characteristics and the experience of the treating physician. As long as therapy is based on reasonable supportive data, beneficial effects can be anticipated. Therapies that received conditional recommendations are not to be discounted if a reasonable percent of patients respond in positive fashion. Obviously, strong recommendations are more likely to be universally accepted since the likelihood that they will be beneficial is stronger.

In any approach to therapy, the caveat primum non nocere—first, do no harm—must always be kept in mind.

In an article in the November 2012 issue (McGill JJ, Shoskes DA, Sabanegh ES Jr. Androgen deficiency in older men: Indications, advantages, and pitfalls of testosterone replacement therapy. Cleve Clin J Med 2012; 79:797–806), the final sentence of the abstract was omitted. The missing sentence should read as follows: “This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications, diagnosis, treatments, and the risks and benefits of treatment.” The online version of the article has been corrected.

In an article in the November 2012 issue (McGill JJ, Shoskes DA, Sabanegh ES Jr. Androgen deficiency in older men: Indications, advantages, and pitfalls of testosterone replacement therapy. Cleve Clin J Med 2012; 79:797–806), the final sentence of the abstract was omitted. The missing sentence should read as follows: “This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications, diagnosis, treatments, and the risks and benefits of treatment.” The online version of the article has been corrected.

In an article in the November 2012 issue (McGill JJ, Shoskes DA, Sabanegh ES Jr. Androgen deficiency in older men: Indications, advantages, and pitfalls of testosterone replacement therapy. Cleve Clin J Med 2012; 79:797–806), the final sentence of the abstract was omitted. The missing sentence should read as follows: “This article reviews androgen decline in men, focusing on those over age 40, and covers symptoms, indications, contraindications, diagnosis, treatments, and the risks and benefits of treatment.” The online version of the article has been corrected.

On february 28, 2012, the US Food and Drug Administration (FDA) updated its labeling requirements for statins. In addition to revising its recommendations for monitoring liver function and its alerts about reports of memory loss, the FDA also warned of the possibility of new-onset diabetes mellitus and worse glycemic control in patients taking statin drugs.¹

This change stoked an ongoing debate about the risk of diabetes with statin use and the implications of such an effect. To understand the clinical consequences of this alert and its effect on treatment decisions, we need to consider the degree to which statins lower the risk of cardiovascular disease in patients at high risk (including diabetic patients), the magnitude of the risk of developing new diabetes while on statin therapy, and the ratio of risk to benefit in treated populations.

This review will discuss the evidence for this possible adverse effect and the implications for clinical practice.

DO STATINS CAUSE DIABETES?

Individual controlled trials dating back more than a decade have had conflicting results about new diabetes and poorer diabetic control in patients taking statins.

The West of Scotland Coronary Prevention Study (WOSCOPS)² suggested that the incidence of diabetes was 30% lower in patients taking pravastatin (Pravachol) 40 mg/day than with placebo. However, this was not observed with atorvastatin (Lipitor) 10 mg/day in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)³ in hypertensive patients or in the Collaborative Atorvastatin Diabetes Study (CARDS)⁴ in diabetic patients,⁴ nor was it noted with simvastatin (Zocor) 40 mg/day in the Heart Protection Study (HPS).⁵

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),⁶ using the more potent agent rosuvastatin (Crestor) 20 mg/day in patients with elevated levels of C-reactive protein (CRP), was stopped early when an interim analysis found a 44% lower incidence of the primary end point. However, the trial also reported a 26% higher incidence of diabetes in follow-up of less than 2 years.

In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),⁷ with a mean age at entry of 75, there was a 32% higher incidence of diabetes with pravastatin therapy.⁷

Results of meta-analyses

Several meta-analyses have addressed these differences.

Rajpathak et al⁸ performed a meta-analysis, published in 2009, of six trials—WOSCOPS,² ASCOT-LLA,³ JUPITER,⁶ HPS,⁵ the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) study,⁹ and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA),¹⁰ with a total of 57,593 patients. They calculated that the incidence of diabetes was 13% higher (an absolute difference of 0.5%) in statin recipients, which was statistically significant. In their initial analysis, the authors excluded WOSCOPS, describing it as hypothesis-generating. The relative increase in risk was less—6%—and was not statistically significant when WOSCOPS was included.

Sattar et al,¹¹ in a larger meta-analysis published in 2010, included 91,140 participants in 13 major statin trials conducted between 1994 and 2009; each trial had more than 1,000 patients and more than 1 year of follow-up.^{2,3,5–7,9,10,12–17} New diabetes was defined as physician reporting of new diabetes, new diabetic medication use, or a fasting glucose greater than 7 mmol/L (126 mg/dL).

New diabetes occurred in 2,226 (4.89%) of the statin recipients and in 2,052 (4.5%) of the placebo recipients, an absolute difference of 0.39%, or 9% more (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02–1.17) (Figure 1).

The incidence of diabetes varied substantially among the 13 trials, with only JUPITER⁶ and PROSPER⁷ finding statistically significant increases in rates (26% and 32%, respectively). Of the other 11 trials, 4 had nonsignificant trends toward lower incidence,^2,9,13,17 while the 7 others had nonsignificant trends toward higher incidence.

Does the specific statin make a difference?

Questions have been raised as to whether the type of statin used, the intensity of therapy, or the population studied contributed to these differences. Various studies suggest that factors such as using hydrophilic vs lipophilic statins (hydrophilic statins include pravastatin and rosuvastatin; lipophilic statins include atorvastatin, lovastatin, and simvastatin), the dose, the extent of lowering of low-density lipoprotein cholesterol (LDL-C), and the age or clinical characteristics of the population studied may influence this relationship.^18–20

Yamakawa et al¹⁸ examined the effect of atorvastatin 10 mg/day, pravastatin 10 mg/day, and pitavastatin (Livalo) 2 mg/day on glycemic control over 3 months in a retrospective analysis. Random blood glucose and hemoglobin A_1c levels were increased in the atorvastatin group but not in the other two.¹⁸

A prospective comparison of atorvastatin 20 mg vs pitavastatin 4 mg in patients with type 2 diabetes, presented at the American College of Cardiology’s 2011 annual meeting, reported a significant increase in fasting glucose levels with atorvastatin, particularly in women, but not with pitavastatin.¹⁹

In the Compare the Effect of Rosuvastatin With Atorvastatin on Apo B/Apo A-1 Ratio in Patients With Type 2 Diabetes Mellitus and Dyslipidaemia (CORALL) study,²⁰ both high-dose rosuvastatin (40 mg) and high-dose atorvastatin (80 mg) were associated with significant increases in hemoglobin A_1c, although the mean fasting glucose levels were not significantly different at 18 weeks of therapy.

A meta-analysis by Sattar et al¹¹ did not find a clear difference between lipophilic statins (OR 1.10 vs placebo) and hydrophilic statins (OR 1.08). In analysis by statin type, the combined rosuvastatin trials were statistically significant in favor of a higher diabetes risk (OR 1.18, 95% CI 1.04–1.44). Nonsignificant trends were noted for atorvastatin trials (OR 1.14) and simvastatin trials (OR 1.11) and less so for pravastatin (OR 1.03); the OR for lovastatin was 0.98. This may suggest that there is a stronger effect with more potent statins or with greater lowering of LDL-C.

Meta-regression analysis in this study demonstrated that diabetes risk with statins was higher in older patients but was not influenced by body mass index or by the extent that LDL-C was lowered.

Intensive-dose statin therapy has been shown to reduce cardiovascular risk more than low-dose or moderate-dose therapy, thus supporting more aggressive treatment of LDL-C in higher-risk patients. However, some controlled studies comparing more-potent with less-potent statin regimens suggest that there may also be a higher risk of incident diabetes at higher doses.^21–24

In a post hoc analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial,²¹ patients who had experienced an acute coronary syndrome had a greater increase in hemoglobin A_1c if treated with atorvastatin 80 mg/day than with pravastatin 40 mg/day.

Waters et al²³ reported a higher risk of new diabetes with atorvastatin 80 mg than with placebo and a trend toward a higher risk with atorvastatin 80 mg than with atorvastatin 10 mg or simvastatin 20 mg.

In contrast, a review by Yousef et al²⁴ of the data from the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study did not find a higher diabetes risk with more intensive statin therapy based on the magnitude of LDL-C reduction. A propensity-matched examination of deaths, recurrent acute ischemic events, or new diabetes in patients previously hospitalized with myocardial infarction found no differences in these end points each year out to 5 years. The risk of diabetes was in fact lower (but the difference was not statistically significant) in the high-dose groups out to 5 years. The risk of myocardial infarction or death was numerically different in the high-dose groups, but the difference was not statistically significant.

Preiss et al²⁵ in 2011 performed a meta-analysis of the impact of intensity of statin therapy on diabetes risk. They examined data from 32,752 participants without diabetes at baseline in five randomized controlled trials with more than 1,000 participants and more than 1 year of follow-up, comparing high-dose therapy against moderate-dose statin therapy.^{21,22,26–28} New diabetes was considered present if there was an adverse event report of diabetes, if glucose-lowering drugs were started, or if two fasting plasma glucose measurements were higher than 7 mmol/L (126 mg/dL).

Diabetes developed in 1,449 (8.8%) of the intensive-therapy group and 1,300 (8.0%) of the moderate-therapy group (OR 1.12, 95% CI 1.04–1.22). In contrast, incident cardiovascular disease occurred in 3,134 (19.1%) of the intensive-therapy group and 3,550 (21.7%) of the moderate-therapy group (OR 0.84, 95% CI 0.75–0.94). Therefore, there was an 0.8% absolute increase in diabetes cases on high-dose statins and a 2.6% absolute reduction in adverse cardiovascular events.

CAUTION IN INTERPRETING THESE DATA

There are many reasons for caution in interpreting these studies.

The trials were not designed to look for diabetes

The data supporting the relationship between statin therapy and higher risk of diabetes are primarily from observational studies. These studies were not prospectively designed to address this question, and we therefore need to view this as association and not as causation.

The definition of diabetes varied between trials, and new-onset diabetes was often not rigorously screened for. In many trials the outcome of diabetes was at least partially based on nonstandardized, nonadjudicated physician reporting.

Consequently, if statins reduce the risk of diabetes, the results from WOSCOPS may overstate the reduction, since this study used a non-standard definition of incident diabetes (fasting plasma glucose > 126 mg/dL plus a > 36 mg/dL increase from baseline). When Sattar et al¹¹ reanalyzed WOSCOPS data using a more standard definition, they found a smaller effect.

On the other hand, nonstandardized physician reporting may overstate an adverse effect. Sattar et al¹¹ also found that when fasting plasma glucose levels alone were used as the definition for diabetes, the overall risk was attenuated and was no longer statistically significant (OR 1.07, 95% CI 0.97–1.17).

Perhaps statin therapy uncovers diabetes only in people at risk of diabetes

Perhaps statin therapy uncovers diabetes only in people at higher baseline risk of developing diabetes. Therefore, this adverse effect may be restricted to certain groups and not applicable to the general population.

In JUPITER, one of the two trials in which, on independent analysis, statin use was associated with new diabetes, 77% of patients in the rosuvastatin group who developed diabetes had impaired fasting glucose at entry and therefore were at higher risk of developing diabetes.⁶

Possibly, the relationship is driven by preexisting metabolic syndrome or other risk factors for diabetes. In the two studies that reported a statistically significantly higher incidence of new diabetes, more than 40% of patients in JUPITER met the criteria for metabolic syndrome, and metabolic syndrome, which increases in prevalence with age, was likely more prominent in the elderly population in PROSPER.

Waters et al²³ grouped patients according to whether they had risk factors for diabetes (impaired fasting glucose, obesity, elevated triglycerides, and hypertension) and found that those who had none or one of these risk factors had no difference in the rate of new-onset diabetes with either moderate or intensive statin therapy, but the risk was pronounced in those who had three or four risk factors.

Ridker et al²⁹ reanalyzed the JUPITER data from patients who did not have cardiovascular disease at baseline. Overall, for every 54 new cases of diabetes in follow-up, 134 cardiovascular events or deaths were prevented. In subgroup analysis, those who had one or more risk factors for diabetes at baseline (metabolic syndrome, impaired fasting glucose, obesity, or hemoglobin A_1c > 6%) had a 39% reduction in the primary end point and a 28% increase in new diabetes. Those who had none of these risk factors had a 52% lower rate of cardiovascular events but no increase in diabetes.

Other confounding factors

Bias and confounding factors are difficult to control for in studies without prospectively defined, recognized, and analyzed outcomes.

Although it may be a bit of a stretch, residual confounding factors such as myalgia side effects while on statins may reduce exercise in the statin-treatment groups. Perhaps a change to a healthier lifestyle after cardiovascular events may be more common in placebo groups. Improved survival with statins may allow more people at risk of diabetes to live longer and present with the diagnosis.³⁰

POSSIBLE EXPLANATIONS, BUT NO UNIFYING MECHANISM

If mechanisms could be identified to explain the association between statins and diabetes, this would strengthen the argument that it is a cause-and-effect relationship. Many explanations have been proposed as to how statins may influence glucose metabolism and insulin sensitivity.^31–34 These are possible explanations based on other observations.

In theory, statins may improve insulin sensitivity via their anti-inflammatory effect, since inflammatory markers and proinflammatory cytokines have been linked with insulin resistance. However, other effects of statins may adversely affect glycemic control.

In vivo analysis has shown that some but not all statins increase insulin levels and decrease insulin sensitivity in a dose-dependent fashion. Some statins decrease adiponectin and may worsen glycemic control through loss of adiponectin’s proposed protective anti-proliferative and antiangiogenic properties. In vitro studies and animal studies have demonstrated a decrease in expression of insulin-responsive glucose transporter 4 (GLUT4) with atorvastatin, and an increase in GLUT1. It has been hypothesized that reduction in isoprenoid biosynthesis or decreased insulin signaling may explain these effects and that changes in glucose transport in adipocytes may cause insulin resistance. Other studies suggest that dysregulation of cellular cholesterol may attenuate beta-cell function. Impaired biosynthesis of ubiquinones may result in delayed production of adenosine triphosphate and consequently diminish insulin release.

But different effects have been reported for atorvastatin, simvastatin, and pravastatin, arguing against a unifying explanation or, alternatively, suggesting that differences in lipophilicity and potency among statins are important. Hydrophilic statins may be less likely to be taken up by extrahepatic cells such as pancreatic cells and adipocytes, possibly lessening these effects. However, the strong association between rosuvastatin (which is hydrophilic) and new diabetes would not support this hypothesis.

Despite these speculations, lack of conformity in response to different statins and discrepancies in the clinical outcomes noted in trials fail to clearly identify a common causative mechanism.

OTHER COMMON THERAPIES MAY INFLUENCE GLYCEMIC CONTROL

Statins are not the first drugs for reducing cardiovascular risk that have been shown to affect glucose levels during treatment.

Niacin

Niacin has been known to increase glucose levels but has long been used as a treatment for dyslipidemia despite this caution. Reduced glycemic control during niacin treatment in diabetic patients does not seem to alter the beneficial effects of treatment.^35–37

In a post hoc analysis of the Coronary Drug Project (CDP), in patient subgroups defined by baseline fasting plasma glucose and compared with placebo, niacin reduced the 6-year risk of recurrent myocardial infarction and the combined end point of coronary heart disease death or nonfatal myocardial infarction similarly (interactive P value nonsignificant) across all levels of baseline fasting plasma glucose, including levels of 126 mg/dL or higher at study entry.³⁶

In another post hoc analysis of CDP patient subgroups defined by the change in glycemic status from baseline to 1 year, niacin reduced the 6-year risk of the same end points similarly (interactive P value nonsignificant) across all levels of change in fasting plasma glucose from baseline to year 1, whether baseline fasting plasma glucose levels decreased, stayed the same, or increased to 10 mg/dL or higher on niacin therapy.³⁶

Therefore, the beneficial effect of niacin of reducing the rate of recurrent nonfatal myocardial infarction and coronary heart disease events was not significantly diminished when impaired fasting glucose or diabetes was present when therapy was started or by on-therapy increases from baseline fasting plasma glucose.

In addition, on-therapy changes in glycemic control may be dose-related and minimized by surveillance and therapy adjustments. The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT)³⁸ found that changes in glycemic control were minimal as measured by fasting glucose and hemoglobin A_1c; were associated with a higher niacin dose (1.5 g/day vs 1 g/day); and, when present, were successfully managed by adjusting the diabetes treatment regimen.

Antihypertensive drugs

Diuretics as well as beta-blockers have been reported to increase the incidence of diabetes in patients with hypertension.^15,38–40

A retrospective longitudinal cohort study⁴⁰ in 2009 examined the development of new-onset diabetes (defined as a new ICD-9 code for diabetes or initiation of diabetes treatment) in 24,688 treated hypertensive patients without diabetes at baseline; 4,385 (17.8%) of the patients developed diabetes. After adjusting for sex and age, the risk of new diabetes was significant in users of diuretics (OR 1.10), beta-blockers (OR 1.12), and calcium channel blockers (OR 1.10) compared with users of angiotensin-converting enzyme inhibitors, (OR 0.92), angiotensin receptor blockers (OR 0.90), or alpha-blockers (OR 0.88).

However, the increase in blood glucose does not seem to attenuate the beneficial effects of reducing cardiovascular events. In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT),¹⁵ a long-term follow-up of those developing new-onset diabetes while taking chlorthalidone (Hygroton) found no difference in the risk of death from cardiovascular disease or from any cause (hazard ratio = 1.04).¹⁵

CLINICAL IMPLICATIONS

Balancing the benefits and risks of statins

It is important to examine how the 0.4% increase in absolute risk of new-onset diabetes as calculated in meta-analyses compares with the benefits of statin treatment in terms of cardiovascular risk reduction.

Using data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 participants, Sattar et al¹¹ estimated that statin treatment is associated with 5.4 fewer deaths from coronary heart disease and cases of nonfatal myocardial infarction per 255 patients treated over 4 years for each 1-mmol/L (39 mg/dL) reduction in LDL-C compared with controls. The benefit would be even greater if stroke, revascularization, and hospitalization are included as end points. This benefit is contrasted with the risk of developing 1 additional case of diabetes for every 255 patients treated with statins over the same period.

Preiss et al²⁵ calculated that there were 2 more cases of diabetes per 1,000 patient-years in patients receiving intensive doses than in those receiving moderate doses (18.9 vs 16.9), corresponding to 1 additional case of diabetes for every 498 patients treated per year. However, there were 6.5 fewer first major cardiovascular events per 1,000 patient-years (44.5 vs 51.0), corresponding to a number needed to treat per year to prevent 1 cardiovascular event of 155. Most of the benefit was due to fewer revascularizations, followed by nonfatal myocardial infarctions. The 12% increase in new diabetes with high-dose therapy contrasted with a 16% reduction in new cardiovascular disease combined events (OR 0.84, 95% CI 0.75–0.94).

As previously noted, in the JUPITER trial, the benefits of preventing cardiovascular events with statin therapy outweighed the risk of new diabetes in people both with and without baseline risk factors for diabetes.²⁹ Similar to the observations with niacin and some antihypertensive drugs, the increase in blood glucose with statins does not appear to reduce the benefits of cardiovascular risk reduction in these patients at moderate to high risk, even when used at high doses.

Diabetes is a coronary heart disease risk equivalent and is associated with high risk of cardiovascular events.^41–46 Overall, the risk for these adverse events is two to four times greater in people with diabetes than without. Atherosclerosis-related events account for approximately 65% to 75% of all deaths in people with diabetes, and 75% of these events are coronary. Lipid abnormalities are strongly correlated with the risk of cardiovascular disease in people with diabetes, and aggressive treatment of risk factors, particularly lipid abnormalities, has been shown to reduce this risk.^47–49 And data from multiple clinical trials support the use of statins to lower LDL-C as the first-line therapy for dyslipidemia in people with diabetes, just as it is in the general population.^{3–7,9,13,23,50–61}

Analyses of diabetic subgroups encompassing 18,000 to 20,000 patients in the large statin trials have clearly demonstrated the benefits of statin therapy. A recent metaanalysis of 10 placebo-controlled trials that included approximately 16,000 patients with diabetes and 54,000 without diabetes demonstrated a 30% reduction in coronary heart disease, a 19% reduction in strokes, and a 12% reduction in mortality.⁵⁴ Furthermore, in another meta-analysis of 14 trials, a similar 22% reduction in coronary heart disease was noted in people with diabetes whether or not they had a history of cardiovascular disease.⁵⁵

Therefore, aggressive treatment of lipid abnormalities with statins as primary treatment has generally been adopted as a standard of care in diabetic patients, particularly those with clinical cardiovascular disease or one or more risk factors. The Adult Treatment Panel III guidelines recommend a minimum LDL-C goal of less than 100 mg/dL and a goal of less than 70 mg/dL as an option for patients with diabetes (Table 1).^41,62 Similar recommendations have been issued by the American Diabetes Association together with the American College of Cardiology (Table 2),³⁰ the American Diabetes Association by itself,⁶³ and the American Academy of Pediatrics.⁶

Is new-onset diabetes as dangerous as established diabetes?

In studies to date, there did not appear to be more events in those who developed new-onset diabetes.

Waters et al,²⁴ evaluating three trials of high-dose atorvastatin therapy, found that major cardiovascular events occurred in 11.3% of those with new-onset diabetes, 10.8% of those without new-onset diabetes (HR 1.02, 95% CI 0.77–1.35), and 17.5% of those who had diabetes at baseline.

Therefore, it may not be appropriate to extrapolate the glucose changes seen on statin therapy to an equivalent increase in adverse cardiovascular events as seen in other diabetic patients. The beneficial reduction in cardiovascular events does not appear to be diminished in those developing diabetes. It is not clear that the increase in glucose on statins has the same implications of a new diagnosis of diabetes. Does this elevation in glucose represent true diabetes or some downstream effect? For example, thiazide diuretics have been known to increase blood glucose levels, but the levels drop when these drugs are discontinued, even after many years of treatment.

On the other hand, it is possible that follow-up of 5 years or less in clinical trials has not allowed sufficient time to examine the influence of the increase in new-onset diabetes on future cardiovascular events. In addition, because of the widespread use of statins across a broad range of cardiovascular risk, even if the effect is small in absolute terms, the potential adverse effects are magnified, particularly in a low-risk population in which the cardiovascular benefits are smaller.

The association is real, but questions remain

In view of the evidence, it is difficult to refute that an association exits between statin use and new-onset diabetes, at least in some subgroups. The dose response noted in some studies further reinforces the conclusion that the association is real. However, many questions remain unanswered regarding mechanism of effect, whether there are differences depending on the particular statin or dose used, or differential effects in the populations treated (such as patients with metabolic syndrome or the elderly).

Until the contradictory observations can be resolved and plausible mechanisms of action elucidated, causality cannot be established. From a clinical standpoint there is no current evidence suggesting that the elevations in blood glucose seen while on lipid-lowering or blood-pressure-lowering therapy are associated with an increased risk of cardiovascular events or that they attenuate the beneficial effects of the therapy.

Statins should continue to be used in patients at high risk

Until further studies are done, statins should continue to be used, after assessing the risks and the benefits.

Primary prevention patients at moderate to high risk and secondary prevention patients stand to gain from statin therapy, and it should not be denied or doses reduced on the basis of concerns about the development of new-onset diabetes. The recognized modest risk of developing diabetes does not appear to blunt the cardioprotective effects of statin therapy in these moderate-to high-risk groups.

Rather than stop statins in patients at risk of diabetes such as the elderly or those with prediabetes, insulin resistance, or metabolic syndrome who are on therapy for appropriate reasons, it is reasonable to continue these drugs, monitoring glucose more closely and emphasizing the importance of weight reduction, diet, and aerobic exercise for preventing diabetes. The Diabetes Prevention Program Research Group, for example, reduced the incidence of diabetes by 58% over 2.8 years of follow-up with intensive lifestyle interventions (a low-calorie, low-fat diet plus moderate physical activity 150 minutes per week) vs usual care in at-risk populations.⁶⁵

Should statins be used more cautiously in patients at lower risk?

The most recent Cholesterol Treatment Trialists meta-analysis of 27 randomized clinical trials (22 placebo-controlled, 134,537 people; 5 high-dose vs low-dose, 39,612 people) reported that reducing LDL-C with statins lowered cardiovascular risk even in low-risk patients.⁶⁶ Overall, there were 21% fewer major cardiovascular events (coronary heart disease, stroke, or coronary revascularization) for every 1-mmol/L reduction in LDL-C.

The proportional reduction in events was at least as large in the two lowest-risk groups (estimated 5-year risk of < 5% and 5% to < 10%, 53,152 people) as in the higher-risk groups. This was reflected mainly in fewer nonfatal myocardial infarctions and coronary revascularizations. In these groups, the absolute reduction in risk for each 1-mmol/L reduction in LDL-C was 11 per 1,000 patients over 5 years. Even in this low-risk population, the reduction in cardiovascular risk seems to compare favorably with the small estimated increase risk of diabetes.

However, even in the lowest-risk group studied, the average baseline LDL-C level was greater than 130 mg/dL.

Therefore, in groups in which the benefits of statins on cardiovascular risk reduction are less robust (eg, low-risk primary prevention groups without significant elevations in LDLC, particularly the elderly), it would not be difficult to justify the case for more cautious use of statin therapy. If statins are used in these low-risk groups, restricting their use to those with at least moderate LDL-C elevation, using less aggressive LDL-C-lowering targets, and regular monitoring of fasting glucose seem reasonable until further information is available.

On february 28, 2012, the US Food and Drug Administration (FDA) updated its labeling requirements for statins. In addition to revising its recommendations for monitoring liver function and its alerts about reports of memory loss, the FDA also warned of the possibility of new-onset diabetes mellitus and worse glycemic control in patients taking statin drugs.¹

This change stoked an ongoing debate about the risk of diabetes with statin use and the implications of such an effect. To understand the clinical consequences of this alert and its effect on treatment decisions, we need to consider the degree to which statins lower the risk of cardiovascular disease in patients at high risk (including diabetic patients), the magnitude of the risk of developing new diabetes while on statin therapy, and the ratio of risk to benefit in treated populations.

This review will discuss the evidence for this possible adverse effect and the implications for clinical practice.

DO STATINS CAUSE DIABETES?

Individual controlled trials dating back more than a decade have had conflicting results about new diabetes and poorer diabetic control in patients taking statins.

The West of Scotland Coronary Prevention Study (WOSCOPS)² suggested that the incidence of diabetes was 30% lower in patients taking pravastatin (Pravachol) 40 mg/day than with placebo. However, this was not observed with atorvastatin (Lipitor) 10 mg/day in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)³ in hypertensive patients or in the Collaborative Atorvastatin Diabetes Study (CARDS)⁴ in diabetic patients,⁴ nor was it noted with simvastatin (Zocor) 40 mg/day in the Heart Protection Study (HPS).⁵

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),⁶ using the more potent agent rosuvastatin (Crestor) 20 mg/day in patients with elevated levels of C-reactive protein (CRP), was stopped early when an interim analysis found a 44% lower incidence of the primary end point. However, the trial also reported a 26% higher incidence of diabetes in follow-up of less than 2 years.

In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),⁷ with a mean age at entry of 75, there was a 32% higher incidence of diabetes with pravastatin therapy.⁷

Results of meta-analyses

Several meta-analyses have addressed these differences.

Rajpathak et al⁸ performed a meta-analysis, published in 2009, of six trials—WOSCOPS,² ASCOT-LLA,³ JUPITER,⁶ HPS,⁵ the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) study,⁹ and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA),¹⁰ with a total of 57,593 patients. They calculated that the incidence of diabetes was 13% higher (an absolute difference of 0.5%) in statin recipients, which was statistically significant. In their initial analysis, the authors excluded WOSCOPS, describing it as hypothesis-generating. The relative increase in risk was less—6%—and was not statistically significant when WOSCOPS was included.

Sattar et al,¹¹ in a larger meta-analysis published in 2010, included 91,140 participants in 13 major statin trials conducted between 1994 and 2009; each trial had more than 1,000 patients and more than 1 year of follow-up.^{2,3,5–7,9,10,12–17} New diabetes was defined as physician reporting of new diabetes, new diabetic medication use, or a fasting glucose greater than 7 mmol/L (126 mg/dL).

New diabetes occurred in 2,226 (4.89%) of the statin recipients and in 2,052 (4.5%) of the placebo recipients, an absolute difference of 0.39%, or 9% more (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02–1.17) (Figure 1).

The incidence of diabetes varied substantially among the 13 trials, with only JUPITER⁶ and PROSPER⁷ finding statistically significant increases in rates (26% and 32%, respectively). Of the other 11 trials, 4 had nonsignificant trends toward lower incidence,^2,9,13,17 while the 7 others had nonsignificant trends toward higher incidence.

Does the specific statin make a difference?

Questions have been raised as to whether the type of statin used, the intensity of therapy, or the population studied contributed to these differences. Various studies suggest that factors such as using hydrophilic vs lipophilic statins (hydrophilic statins include pravastatin and rosuvastatin; lipophilic statins include atorvastatin, lovastatin, and simvastatin), the dose, the extent of lowering of low-density lipoprotein cholesterol (LDL-C), and the age or clinical characteristics of the population studied may influence this relationship.^18–20

Yamakawa et al¹⁸ examined the effect of atorvastatin 10 mg/day, pravastatin 10 mg/day, and pitavastatin (Livalo) 2 mg/day on glycemic control over 3 months in a retrospective analysis. Random blood glucose and hemoglobin A_1c levels were increased in the atorvastatin group but not in the other two.¹⁸

A prospective comparison of atorvastatin 20 mg vs pitavastatin 4 mg in patients with type 2 diabetes, presented at the American College of Cardiology’s 2011 annual meeting, reported a significant increase in fasting glucose levels with atorvastatin, particularly in women, but not with pitavastatin.¹⁹

In the Compare the Effect of Rosuvastatin With Atorvastatin on Apo B/Apo A-1 Ratio in Patients With Type 2 Diabetes Mellitus and Dyslipidaemia (CORALL) study,²⁰ both high-dose rosuvastatin (40 mg) and high-dose atorvastatin (80 mg) were associated with significant increases in hemoglobin A_1c, although the mean fasting glucose levels were not significantly different at 18 weeks of therapy.

A meta-analysis by Sattar et al¹¹ did not find a clear difference between lipophilic statins (OR 1.10 vs placebo) and hydrophilic statins (OR 1.08). In analysis by statin type, the combined rosuvastatin trials were statistically significant in favor of a higher diabetes risk (OR 1.18, 95% CI 1.04–1.44). Nonsignificant trends were noted for atorvastatin trials (OR 1.14) and simvastatin trials (OR 1.11) and less so for pravastatin (OR 1.03); the OR for lovastatin was 0.98. This may suggest that there is a stronger effect with more potent statins or with greater lowering of LDL-C.

Meta-regression analysis in this study demonstrated that diabetes risk with statins was higher in older patients but was not influenced by body mass index or by the extent that LDL-C was lowered.

Intensive-dose statin therapy has been shown to reduce cardiovascular risk more than low-dose or moderate-dose therapy, thus supporting more aggressive treatment of LDL-C in higher-risk patients. However, some controlled studies comparing more-potent with less-potent statin regimens suggest that there may also be a higher risk of incident diabetes at higher doses.^21–24

In a post hoc analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial,²¹ patients who had experienced an acute coronary syndrome had a greater increase in hemoglobin A_1c if treated with atorvastatin 80 mg/day than with pravastatin 40 mg/day.

Waters et al²³ reported a higher risk of new diabetes with atorvastatin 80 mg than with placebo and a trend toward a higher risk with atorvastatin 80 mg than with atorvastatin 10 mg or simvastatin 20 mg.

In contrast, a review by Yousef et al²⁴ of the data from the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study did not find a higher diabetes risk with more intensive statin therapy based on the magnitude of LDL-C reduction. A propensity-matched examination of deaths, recurrent acute ischemic events, or new diabetes in patients previously hospitalized with myocardial infarction found no differences in these end points each year out to 5 years. The risk of diabetes was in fact lower (but the difference was not statistically significant) in the high-dose groups out to 5 years. The risk of myocardial infarction or death was numerically different in the high-dose groups, but the difference was not statistically significant.

Preiss et al²⁵ in 2011 performed a meta-analysis of the impact of intensity of statin therapy on diabetes risk. They examined data from 32,752 participants without diabetes at baseline in five randomized controlled trials with more than 1,000 participants and more than 1 year of follow-up, comparing high-dose therapy against moderate-dose statin therapy.^{21,22,26–28} New diabetes was considered present if there was an adverse event report of diabetes, if glucose-lowering drugs were started, or if two fasting plasma glucose measurements were higher than 7 mmol/L (126 mg/dL).

Diabetes developed in 1,449 (8.8%) of the intensive-therapy group and 1,300 (8.0%) of the moderate-therapy group (OR 1.12, 95% CI 1.04–1.22). In contrast, incident cardiovascular disease occurred in 3,134 (19.1%) of the intensive-therapy group and 3,550 (21.7%) of the moderate-therapy group (OR 0.84, 95% CI 0.75–0.94). Therefore, there was an 0.8% absolute increase in diabetes cases on high-dose statins and a 2.6% absolute reduction in adverse cardiovascular events.

CAUTION IN INTERPRETING THESE DATA

There are many reasons for caution in interpreting these studies.

The trials were not designed to look for diabetes

The data supporting the relationship between statin therapy and higher risk of diabetes are primarily from observational studies. These studies were not prospectively designed to address this question, and we therefore need to view this as association and not as causation.

The definition of diabetes varied between trials, and new-onset diabetes was often not rigorously screened for. In many trials the outcome of diabetes was at least partially based on nonstandardized, nonadjudicated physician reporting.

Consequently, if statins reduce the risk of diabetes, the results from WOSCOPS may overstate the reduction, since this study used a non-standard definition of incident diabetes (fasting plasma glucose > 126 mg/dL plus a > 36 mg/dL increase from baseline). When Sattar et al¹¹ reanalyzed WOSCOPS data using a more standard definition, they found a smaller effect.

On the other hand, nonstandardized physician reporting may overstate an adverse effect. Sattar et al¹¹ also found that when fasting plasma glucose levels alone were used as the definition for diabetes, the overall risk was attenuated and was no longer statistically significant (OR 1.07, 95% CI 0.97–1.17).

Perhaps statin therapy uncovers diabetes only in people at risk of diabetes

Perhaps statin therapy uncovers diabetes only in people at higher baseline risk of developing diabetes. Therefore, this adverse effect may be restricted to certain groups and not applicable to the general population.

In JUPITER, one of the two trials in which, on independent analysis, statin use was associated with new diabetes, 77% of patients in the rosuvastatin group who developed diabetes had impaired fasting glucose at entry and therefore were at higher risk of developing diabetes.⁶

Possibly, the relationship is driven by preexisting metabolic syndrome or other risk factors for diabetes. In the two studies that reported a statistically significantly higher incidence of new diabetes, more than 40% of patients in JUPITER met the criteria for metabolic syndrome, and metabolic syndrome, which increases in prevalence with age, was likely more prominent in the elderly population in PROSPER.

Waters et al²³ grouped patients according to whether they had risk factors for diabetes (impaired fasting glucose, obesity, elevated triglycerides, and hypertension) and found that those who had none or one of these risk factors had no difference in the rate of new-onset diabetes with either moderate or intensive statin therapy, but the risk was pronounced in those who had three or four risk factors.

Ridker et al²⁹ reanalyzed the JUPITER data from patients who did not have cardiovascular disease at baseline. Overall, for every 54 new cases of diabetes in follow-up, 134 cardiovascular events or deaths were prevented. In subgroup analysis, those who had one or more risk factors for diabetes at baseline (metabolic syndrome, impaired fasting glucose, obesity, or hemoglobin A_1c > 6%) had a 39% reduction in the primary end point and a 28% increase in new diabetes. Those who had none of these risk factors had a 52% lower rate of cardiovascular events but no increase in diabetes.

Other confounding factors

Bias and confounding factors are difficult to control for in studies without prospectively defined, recognized, and analyzed outcomes.

Although it may be a bit of a stretch, residual confounding factors such as myalgia side effects while on statins may reduce exercise in the statin-treatment groups. Perhaps a change to a healthier lifestyle after cardiovascular events may be more common in placebo groups. Improved survival with statins may allow more people at risk of diabetes to live longer and present with the diagnosis.³⁰

POSSIBLE EXPLANATIONS, BUT NO UNIFYING MECHANISM

If mechanisms could be identified to explain the association between statins and diabetes, this would strengthen the argument that it is a cause-and-effect relationship. Many explanations have been proposed as to how statins may influence glucose metabolism and insulin sensitivity.^31–34 These are possible explanations based on other observations.

In theory, statins may improve insulin sensitivity via their anti-inflammatory effect, since inflammatory markers and proinflammatory cytokines have been linked with insulin resistance. However, other effects of statins may adversely affect glycemic control.

In vivo analysis has shown that some but not all statins increase insulin levels and decrease insulin sensitivity in a dose-dependent fashion. Some statins decrease adiponectin and may worsen glycemic control through loss of adiponectin’s proposed protective anti-proliferative and antiangiogenic properties. In vitro studies and animal studies have demonstrated a decrease in expression of insulin-responsive glucose transporter 4 (GLUT4) with atorvastatin, and an increase in GLUT1. It has been hypothesized that reduction in isoprenoid biosynthesis or decreased insulin signaling may explain these effects and that changes in glucose transport in adipocytes may cause insulin resistance. Other studies suggest that dysregulation of cellular cholesterol may attenuate beta-cell function. Impaired biosynthesis of ubiquinones may result in delayed production of adenosine triphosphate and consequently diminish insulin release.

But different effects have been reported for atorvastatin, simvastatin, and pravastatin, arguing against a unifying explanation or, alternatively, suggesting that differences in lipophilicity and potency among statins are important. Hydrophilic statins may be less likely to be taken up by extrahepatic cells such as pancreatic cells and adipocytes, possibly lessening these effects. However, the strong association between rosuvastatin (which is hydrophilic) and new diabetes would not support this hypothesis.

Despite these speculations, lack of conformity in response to different statins and discrepancies in the clinical outcomes noted in trials fail to clearly identify a common causative mechanism.

OTHER COMMON THERAPIES MAY INFLUENCE GLYCEMIC CONTROL

Statins are not the first drugs for reducing cardiovascular risk that have been shown to affect glucose levels during treatment.

Niacin

Niacin has been known to increase glucose levels but has long been used as a treatment for dyslipidemia despite this caution. Reduced glycemic control during niacin treatment in diabetic patients does not seem to alter the beneficial effects of treatment.^35–37

In a post hoc analysis of the Coronary Drug Project (CDP), in patient subgroups defined by baseline fasting plasma glucose and compared with placebo, niacin reduced the 6-year risk of recurrent myocardial infarction and the combined end point of coronary heart disease death or nonfatal myocardial infarction similarly (interactive P value nonsignificant) across all levels of baseline fasting plasma glucose, including levels of 126 mg/dL or higher at study entry.³⁶

In another post hoc analysis of CDP patient subgroups defined by the change in glycemic status from baseline to 1 year, niacin reduced the 6-year risk of the same end points similarly (interactive P value nonsignificant) across all levels of change in fasting plasma glucose from baseline to year 1, whether baseline fasting plasma glucose levels decreased, stayed the same, or increased to 10 mg/dL or higher on niacin therapy.³⁶

Therefore, the beneficial effect of niacin of reducing the rate of recurrent nonfatal myocardial infarction and coronary heart disease events was not significantly diminished when impaired fasting glucose or diabetes was present when therapy was started or by on-therapy increases from baseline fasting plasma glucose.

In addition, on-therapy changes in glycemic control may be dose-related and minimized by surveillance and therapy adjustments. The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT)³⁸ found that changes in glycemic control were minimal as measured by fasting glucose and hemoglobin A_1c; were associated with a higher niacin dose (1.5 g/day vs 1 g/day); and, when present, were successfully managed by adjusting the diabetes treatment regimen.

Antihypertensive drugs

Diuretics as well as beta-blockers have been reported to increase the incidence of diabetes in patients with hypertension.^15,38–40

A retrospective longitudinal cohort study⁴⁰ in 2009 examined the development of new-onset diabetes (defined as a new ICD-9 code for diabetes or initiation of diabetes treatment) in 24,688 treated hypertensive patients without diabetes at baseline; 4,385 (17.8%) of the patients developed diabetes. After adjusting for sex and age, the risk of new diabetes was significant in users of diuretics (OR 1.10), beta-blockers (OR 1.12), and calcium channel blockers (OR 1.10) compared with users of angiotensin-converting enzyme inhibitors, (OR 0.92), angiotensin receptor blockers (OR 0.90), or alpha-blockers (OR 0.88).

However, the increase in blood glucose does not seem to attenuate the beneficial effects of reducing cardiovascular events. In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT),¹⁵ a long-term follow-up of those developing new-onset diabetes while taking chlorthalidone (Hygroton) found no difference in the risk of death from cardiovascular disease or from any cause (hazard ratio = 1.04).¹⁵

CLINICAL IMPLICATIONS

Balancing the benefits and risks of statins

It is important to examine how the 0.4% increase in absolute risk of new-onset diabetes as calculated in meta-analyses compares with the benefits of statin treatment in terms of cardiovascular risk reduction.

Using data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 participants, Sattar et al¹¹ estimated that statin treatment is associated with 5.4 fewer deaths from coronary heart disease and cases of nonfatal myocardial infarction per 255 patients treated over 4 years for each 1-mmol/L (39 mg/dL) reduction in LDL-C compared with controls. The benefit would be even greater if stroke, revascularization, and hospitalization are included as end points. This benefit is contrasted with the risk of developing 1 additional case of diabetes for every 255 patients treated with statins over the same period.

Preiss et al²⁵ calculated that there were 2 more cases of diabetes per 1,000 patient-years in patients receiving intensive doses than in those receiving moderate doses (18.9 vs 16.9), corresponding to 1 additional case of diabetes for every 498 patients treated per year. However, there were 6.5 fewer first major cardiovascular events per 1,000 patient-years (44.5 vs 51.0), corresponding to a number needed to treat per year to prevent 1 cardiovascular event of 155. Most of the benefit was due to fewer revascularizations, followed by nonfatal myocardial infarctions. The 12% increase in new diabetes with high-dose therapy contrasted with a 16% reduction in new cardiovascular disease combined events (OR 0.84, 95% CI 0.75–0.94).

As previously noted, in the JUPITER trial, the benefits of preventing cardiovascular events with statin therapy outweighed the risk of new diabetes in people both with and without baseline risk factors for diabetes.²⁹ Similar to the observations with niacin and some antihypertensive drugs, the increase in blood glucose with statins does not appear to reduce the benefits of cardiovascular risk reduction in these patients at moderate to high risk, even when used at high doses.

Diabetes is a coronary heart disease risk equivalent and is associated with high risk of cardiovascular events.^41–46 Overall, the risk for these adverse events is two to four times greater in people with diabetes than without. Atherosclerosis-related events account for approximately 65% to 75% of all deaths in people with diabetes, and 75% of these events are coronary. Lipid abnormalities are strongly correlated with the risk of cardiovascular disease in people with diabetes, and aggressive treatment of risk factors, particularly lipid abnormalities, has been shown to reduce this risk.^47–49 And data from multiple clinical trials support the use of statins to lower LDL-C as the first-line therapy for dyslipidemia in people with diabetes, just as it is in the general population.^{3–7,9,13,23,50–61}

Analyses of diabetic subgroups encompassing 18,000 to 20,000 patients in the large statin trials have clearly demonstrated the benefits of statin therapy. A recent metaanalysis of 10 placebo-controlled trials that included approximately 16,000 patients with diabetes and 54,000 without diabetes demonstrated a 30% reduction in coronary heart disease, a 19% reduction in strokes, and a 12% reduction in mortality.⁵⁴ Furthermore, in another meta-analysis of 14 trials, a similar 22% reduction in coronary heart disease was noted in people with diabetes whether or not they had a history of cardiovascular disease.⁵⁵

Therefore, aggressive treatment of lipid abnormalities with statins as primary treatment has generally been adopted as a standard of care in diabetic patients, particularly those with clinical cardiovascular disease or one or more risk factors. The Adult Treatment Panel III guidelines recommend a minimum LDL-C goal of less than 100 mg/dL and a goal of less than 70 mg/dL as an option for patients with diabetes (Table 1).^41,62 Similar recommendations have been issued by the American Diabetes Association together with the American College of Cardiology (Table 2),³⁰ the American Diabetes Association by itself,⁶³ and the American Academy of Pediatrics.⁶

Is new-onset diabetes as dangerous as established diabetes?

In studies to date, there did not appear to be more events in those who developed new-onset diabetes.

Waters et al,²⁴ evaluating three trials of high-dose atorvastatin therapy, found that major cardiovascular events occurred in 11.3% of those with new-onset diabetes, 10.8% of those without new-onset diabetes (HR 1.02, 95% CI 0.77–1.35), and 17.5% of those who had diabetes at baseline.

Therefore, it may not be appropriate to extrapolate the glucose changes seen on statin therapy to an equivalent increase in adverse cardiovascular events as seen in other diabetic patients. The beneficial reduction in cardiovascular events does not appear to be diminished in those developing diabetes. It is not clear that the increase in glucose on statins has the same implications of a new diagnosis of diabetes. Does this elevation in glucose represent true diabetes or some downstream effect? For example, thiazide diuretics have been known to increase blood glucose levels, but the levels drop when these drugs are discontinued, even after many years of treatment.

On the other hand, it is possible that follow-up of 5 years or less in clinical trials has not allowed sufficient time to examine the influence of the increase in new-onset diabetes on future cardiovascular events. In addition, because of the widespread use of statins across a broad range of cardiovascular risk, even if the effect is small in absolute terms, the potential adverse effects are magnified, particularly in a low-risk population in which the cardiovascular benefits are smaller.

The association is real, but questions remain

In view of the evidence, it is difficult to refute that an association exits between statin use and new-onset diabetes, at least in some subgroups. The dose response noted in some studies further reinforces the conclusion that the association is real. However, many questions remain unanswered regarding mechanism of effect, whether there are differences depending on the particular statin or dose used, or differential effects in the populations treated (such as patients with metabolic syndrome or the elderly).

Until the contradictory observations can be resolved and plausible mechanisms of action elucidated, causality cannot be established. From a clinical standpoint there is no current evidence suggesting that the elevations in blood glucose seen while on lipid-lowering or blood-pressure-lowering therapy are associated with an increased risk of cardiovascular events or that they attenuate the beneficial effects of the therapy.

Statins should continue to be used in patients at high risk

Until further studies are done, statins should continue to be used, after assessing the risks and the benefits.

Primary prevention patients at moderate to high risk and secondary prevention patients stand to gain from statin therapy, and it should not be denied or doses reduced on the basis of concerns about the development of new-onset diabetes. The recognized modest risk of developing diabetes does not appear to blunt the cardioprotective effects of statin therapy in these moderate-to high-risk groups.

Rather than stop statins in patients at risk of diabetes such as the elderly or those with prediabetes, insulin resistance, or metabolic syndrome who are on therapy for appropriate reasons, it is reasonable to continue these drugs, monitoring glucose more closely and emphasizing the importance of weight reduction, diet, and aerobic exercise for preventing diabetes. The Diabetes Prevention Program Research Group, for example, reduced the incidence of diabetes by 58% over 2.8 years of follow-up with intensive lifestyle interventions (a low-calorie, low-fat diet plus moderate physical activity 150 minutes per week) vs usual care in at-risk populations.⁶⁵

Should statins be used more cautiously in patients at lower risk?

The most recent Cholesterol Treatment Trialists meta-analysis of 27 randomized clinical trials (22 placebo-controlled, 134,537 people; 5 high-dose vs low-dose, 39,612 people) reported that reducing LDL-C with statins lowered cardiovascular risk even in low-risk patients.⁶⁶ Overall, there were 21% fewer major cardiovascular events (coronary heart disease, stroke, or coronary revascularization) for every 1-mmol/L reduction in LDL-C.

The proportional reduction in events was at least as large in the two lowest-risk groups (estimated 5-year risk of < 5% and 5% to < 10%, 53,152 people) as in the higher-risk groups. This was reflected mainly in fewer nonfatal myocardial infarctions and coronary revascularizations. In these groups, the absolute reduction in risk for each 1-mmol/L reduction in LDL-C was 11 per 1,000 patients over 5 years. Even in this low-risk population, the reduction in cardiovascular risk seems to compare favorably with the small estimated increase risk of diabetes.

However, even in the lowest-risk group studied, the average baseline LDL-C level was greater than 130 mg/dL.

Therefore, in groups in which the benefits of statins on cardiovascular risk reduction are less robust (eg, low-risk primary prevention groups without significant elevations in LDLC, particularly the elderly), it would not be difficult to justify the case for more cautious use of statin therapy. If statins are used in these low-risk groups, restricting their use to those with at least moderate LDL-C elevation, using less aggressive LDL-C-lowering targets, and regular monitoring of fasting glucose seem reasonable until further information is available.

On february 28, 2012, the US Food and Drug Administration (FDA) updated its labeling requirements for statins. In addition to revising its recommendations for monitoring liver function and its alerts about reports of memory loss, the FDA also warned of the possibility of new-onset diabetes mellitus and worse glycemic control in patients taking statin drugs.¹

This change stoked an ongoing debate about the risk of diabetes with statin use and the implications of such an effect. To understand the clinical consequences of this alert and its effect on treatment decisions, we need to consider the degree to which statins lower the risk of cardiovascular disease in patients at high risk (including diabetic patients), the magnitude of the risk of developing new diabetes while on statin therapy, and the ratio of risk to benefit in treated populations.

This review will discuss the evidence for this possible adverse effect and the implications for clinical practice.

DO STATINS CAUSE DIABETES?

Individual controlled trials dating back more than a decade have had conflicting results about new diabetes and poorer diabetic control in patients taking statins.

The West of Scotland Coronary Prevention Study (WOSCOPS)² suggested that the incidence of diabetes was 30% lower in patients taking pravastatin (Pravachol) 40 mg/day than with placebo. However, this was not observed with atorvastatin (Lipitor) 10 mg/day in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)³ in hypertensive patients or in the Collaborative Atorvastatin Diabetes Study (CARDS)⁴ in diabetic patients,⁴ nor was it noted with simvastatin (Zocor) 40 mg/day in the Heart Protection Study (HPS).⁵

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),⁶ using the more potent agent rosuvastatin (Crestor) 20 mg/day in patients with elevated levels of C-reactive protein (CRP), was stopped early when an interim analysis found a 44% lower incidence of the primary end point. However, the trial also reported a 26% higher incidence of diabetes in follow-up of less than 2 years.

In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),⁷ with a mean age at entry of 75, there was a 32% higher incidence of diabetes with pravastatin therapy.⁷

Results of meta-analyses

Several meta-analyses have addressed these differences.

Rajpathak et al⁸ performed a meta-analysis, published in 2009, of six trials—WOSCOPS,² ASCOT-LLA,³ JUPITER,⁶ HPS,⁵ the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) study,⁹ and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA),¹⁰ with a total of 57,593 patients. They calculated that the incidence of diabetes was 13% higher (an absolute difference of 0.5%) in statin recipients, which was statistically significant. In their initial analysis, the authors excluded WOSCOPS, describing it as hypothesis-generating. The relative increase in risk was less—6%—and was not statistically significant when WOSCOPS was included.

Sattar et al,¹¹ in a larger meta-analysis published in 2010, included 91,140 participants in 13 major statin trials conducted between 1994 and 2009; each trial had more than 1,000 patients and more than 1 year of follow-up.^{2,3,5–7,9,10,12–17} New diabetes was defined as physician reporting of new diabetes, new diabetic medication use, or a fasting glucose greater than 7 mmol/L (126 mg/dL).

New diabetes occurred in 2,226 (4.89%) of the statin recipients and in 2,052 (4.5%) of the placebo recipients, an absolute difference of 0.39%, or 9% more (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02–1.17) (Figure 1).

The incidence of diabetes varied substantially among the 13 trials, with only JUPITER⁶ and PROSPER⁷ finding statistically significant increases in rates (26% and 32%, respectively). Of the other 11 trials, 4 had nonsignificant trends toward lower incidence,^2,9,13,17 while the 7 others had nonsignificant trends toward higher incidence.

Does the specific statin make a difference?

Questions have been raised as to whether the type of statin used, the intensity of therapy, or the population studied contributed to these differences. Various studies suggest that factors such as using hydrophilic vs lipophilic statins (hydrophilic statins include pravastatin and rosuvastatin; lipophilic statins include atorvastatin, lovastatin, and simvastatin), the dose, the extent of lowering of low-density lipoprotein cholesterol (LDL-C), and the age or clinical characteristics of the population studied may influence this relationship.^18–20

Yamakawa et al¹⁸ examined the effect of atorvastatin 10 mg/day, pravastatin 10 mg/day, and pitavastatin (Livalo) 2 mg/day on glycemic control over 3 months in a retrospective analysis. Random blood glucose and hemoglobin A_1c levels were increased in the atorvastatin group but not in the other two.¹⁸

A prospective comparison of atorvastatin 20 mg vs pitavastatin 4 mg in patients with type 2 diabetes, presented at the American College of Cardiology’s 2011 annual meeting, reported a significant increase in fasting glucose levels with atorvastatin, particularly in women, but not with pitavastatin.¹⁹

In the Compare the Effect of Rosuvastatin With Atorvastatin on Apo B/Apo A-1 Ratio in Patients With Type 2 Diabetes Mellitus and Dyslipidaemia (CORALL) study,²⁰ both high-dose rosuvastatin (40 mg) and high-dose atorvastatin (80 mg) were associated with significant increases in hemoglobin A_1c, although the mean fasting glucose levels were not significantly different at 18 weeks of therapy.

A meta-analysis by Sattar et al¹¹ did not find a clear difference between lipophilic statins (OR 1.10 vs placebo) and hydrophilic statins (OR 1.08). In analysis by statin type, the combined rosuvastatin trials were statistically significant in favor of a higher diabetes risk (OR 1.18, 95% CI 1.04–1.44). Nonsignificant trends were noted for atorvastatin trials (OR 1.14) and simvastatin trials (OR 1.11) and less so for pravastatin (OR 1.03); the OR for lovastatin was 0.98. This may suggest that there is a stronger effect with more potent statins or with greater lowering of LDL-C.

Meta-regression analysis in this study demonstrated that diabetes risk with statins was higher in older patients but was not influenced by body mass index or by the extent that LDL-C was lowered.

Intensive-dose statin therapy has been shown to reduce cardiovascular risk more than low-dose or moderate-dose therapy, thus supporting more aggressive treatment of LDL-C in higher-risk patients. However, some controlled studies comparing more-potent with less-potent statin regimens suggest that there may also be a higher risk of incident diabetes at higher doses.^21–24

In a post hoc analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial,²¹ patients who had experienced an acute coronary syndrome had a greater increase in hemoglobin A_1c if treated with atorvastatin 80 mg/day than with pravastatin 40 mg/day.

Waters et al²³ reported a higher risk of new diabetes with atorvastatin 80 mg than with placebo and a trend toward a higher risk with atorvastatin 80 mg than with atorvastatin 10 mg or simvastatin 20 mg.

In contrast, a review by Yousef et al²⁴ of the data from the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study did not find a higher diabetes risk with more intensive statin therapy based on the magnitude of LDL-C reduction. A propensity-matched examination of deaths, recurrent acute ischemic events, or new diabetes in patients previously hospitalized with myocardial infarction found no differences in these end points each year out to 5 years. The risk of diabetes was in fact lower (but the difference was not statistically significant) in the high-dose groups out to 5 years. The risk of myocardial infarction or death was numerically different in the high-dose groups, but the difference was not statistically significant.

Preiss et al²⁵ in 2011 performed a meta-analysis of the impact of intensity of statin therapy on diabetes risk. They examined data from 32,752 participants without diabetes at baseline in five randomized controlled trials with more than 1,000 participants and more than 1 year of follow-up, comparing high-dose therapy against moderate-dose statin therapy.^{21,22,26–28} New diabetes was considered present if there was an adverse event report of diabetes, if glucose-lowering drugs were started, or if two fasting plasma glucose measurements were higher than 7 mmol/L (126 mg/dL).

Diabetes developed in 1,449 (8.8%) of the intensive-therapy group and 1,300 (8.0%) of the moderate-therapy group (OR 1.12, 95% CI 1.04–1.22). In contrast, incident cardiovascular disease occurred in 3,134 (19.1%) of the intensive-therapy group and 3,550 (21.7%) of the moderate-therapy group (OR 0.84, 95% CI 0.75–0.94). Therefore, there was an 0.8% absolute increase in diabetes cases on high-dose statins and a 2.6% absolute reduction in adverse cardiovascular events.

CAUTION IN INTERPRETING THESE DATA

There are many reasons for caution in interpreting these studies.

The trials were not designed to look for diabetes

The data supporting the relationship between statin therapy and higher risk of diabetes are primarily from observational studies. These studies were not prospectively designed to address this question, and we therefore need to view this as association and not as causation.

The definition of diabetes varied between trials, and new-onset diabetes was often not rigorously screened for. In many trials the outcome of diabetes was at least partially based on nonstandardized, nonadjudicated physician reporting.

Consequently, if statins reduce the risk of diabetes, the results from WOSCOPS may overstate the reduction, since this study used a non-standard definition of incident diabetes (fasting plasma glucose > 126 mg/dL plus a > 36 mg/dL increase from baseline). When Sattar et al¹¹ reanalyzed WOSCOPS data using a more standard definition, they found a smaller effect.

On the other hand, nonstandardized physician reporting may overstate an adverse effect. Sattar et al¹¹ also found that when fasting plasma glucose levels alone were used as the definition for diabetes, the overall risk was attenuated and was no longer statistically significant (OR 1.07, 95% CI 0.97–1.17).

Perhaps statin therapy uncovers diabetes only in people at risk of diabetes

Perhaps statin therapy uncovers diabetes only in people at higher baseline risk of developing diabetes. Therefore, this adverse effect may be restricted to certain groups and not applicable to the general population.

In JUPITER, one of the two trials in which, on independent analysis, statin use was associated with new diabetes, 77% of patients in the rosuvastatin group who developed diabetes had impaired fasting glucose at entry and therefore were at higher risk of developing diabetes.⁶

Possibly, the relationship is driven by preexisting metabolic syndrome or other risk factors for diabetes. In the two studies that reported a statistically significantly higher incidence of new diabetes, more than 40% of patients in JUPITER met the criteria for metabolic syndrome, and metabolic syndrome, which increases in prevalence with age, was likely more prominent in the elderly population in PROSPER.

Waters et al²³ grouped patients according to whether they had risk factors for diabetes (impaired fasting glucose, obesity, elevated triglycerides, and hypertension) and found that those who had none or one of these risk factors had no difference in the rate of new-onset diabetes with either moderate or intensive statin therapy, but the risk was pronounced in those who had three or four risk factors.

Ridker et al²⁹ reanalyzed the JUPITER data from patients who did not have cardiovascular disease at baseline. Overall, for every 54 new cases of diabetes in follow-up, 134 cardiovascular events or deaths were prevented. In subgroup analysis, those who had one or more risk factors for diabetes at baseline (metabolic syndrome, impaired fasting glucose, obesity, or hemoglobin A_1c > 6%) had a 39% reduction in the primary end point and a 28% increase in new diabetes. Those who had none of these risk factors had a 52% lower rate of cardiovascular events but no increase in diabetes.

Other confounding factors

Bias and confounding factors are difficult to control for in studies without prospectively defined, recognized, and analyzed outcomes.

Although it may be a bit of a stretch, residual confounding factors such as myalgia side effects while on statins may reduce exercise in the statin-treatment groups. Perhaps a change to a healthier lifestyle after cardiovascular events may be more common in placebo groups. Improved survival with statins may allow more people at risk of diabetes to live longer and present with the diagnosis.³⁰

POSSIBLE EXPLANATIONS, BUT NO UNIFYING MECHANISM

If mechanisms could be identified to explain the association between statins and diabetes, this would strengthen the argument that it is a cause-and-effect relationship. Many explanations have been proposed as to how statins may influence glucose metabolism and insulin sensitivity.^31–34 These are possible explanations based on other observations.

In theory, statins may improve insulin sensitivity via their anti-inflammatory effect, since inflammatory markers and proinflammatory cytokines have been linked with insulin resistance. However, other effects of statins may adversely affect glycemic control.

In vivo analysis has shown that some but not all statins increase insulin levels and decrease insulin sensitivity in a dose-dependent fashion. Some statins decrease adiponectin and may worsen glycemic control through loss of adiponectin’s proposed protective anti-proliferative and antiangiogenic properties. In vitro studies and animal studies have demonstrated a decrease in expression of insulin-responsive glucose transporter 4 (GLUT4) with atorvastatin, and an increase in GLUT1. It has been hypothesized that reduction in isoprenoid biosynthesis or decreased insulin signaling may explain these effects and that changes in glucose transport in adipocytes may cause insulin resistance. Other studies suggest that dysregulation of cellular cholesterol may attenuate beta-cell function. Impaired biosynthesis of ubiquinones may result in delayed production of adenosine triphosphate and consequently diminish insulin release.

But different effects have been reported for atorvastatin, simvastatin, and pravastatin, arguing against a unifying explanation or, alternatively, suggesting that differences in lipophilicity and potency among statins are important. Hydrophilic statins may be less likely to be taken up by extrahepatic cells such as pancreatic cells and adipocytes, possibly lessening these effects. However, the strong association between rosuvastatin (which is hydrophilic) and new diabetes would not support this hypothesis.

Despite these speculations, lack of conformity in response to different statins and discrepancies in the clinical outcomes noted in trials fail to clearly identify a common causative mechanism.

OTHER COMMON THERAPIES MAY INFLUENCE GLYCEMIC CONTROL

Statins are not the first drugs for reducing cardiovascular risk that have been shown to affect glucose levels during treatment.

Niacin

Niacin has been known to increase glucose levels but has long been used as a treatment for dyslipidemia despite this caution. Reduced glycemic control during niacin treatment in diabetic patients does not seem to alter the beneficial effects of treatment.^35–37

In a post hoc analysis of the Coronary Drug Project (CDP), in patient subgroups defined by baseline fasting plasma glucose and compared with placebo, niacin reduced the 6-year risk of recurrent myocardial infarction and the combined end point of coronary heart disease death or nonfatal myocardial infarction similarly (interactive P value nonsignificant) across all levels of baseline fasting plasma glucose, including levels of 126 mg/dL or higher at study entry.³⁶

In another post hoc analysis of CDP patient subgroups defined by the change in glycemic status from baseline to 1 year, niacin reduced the 6-year risk of the same end points similarly (interactive P value nonsignificant) across all levels of change in fasting plasma glucose from baseline to year 1, whether baseline fasting plasma glucose levels decreased, stayed the same, or increased to 10 mg/dL or higher on niacin therapy.³⁶

Therefore, the beneficial effect of niacin of reducing the rate of recurrent nonfatal myocardial infarction and coronary heart disease events was not significantly diminished when impaired fasting glucose or diabetes was present when therapy was started or by on-therapy increases from baseline fasting plasma glucose.

In addition, on-therapy changes in glycemic control may be dose-related and minimized by surveillance and therapy adjustments. The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT)³⁸ found that changes in glycemic control were minimal as measured by fasting glucose and hemoglobin A_1c; were associated with a higher niacin dose (1.5 g/day vs 1 g/day); and, when present, were successfully managed by adjusting the diabetes treatment regimen.

Antihypertensive drugs

Diuretics as well as beta-blockers have been reported to increase the incidence of diabetes in patients with hypertension.^15,38–40

A retrospective longitudinal cohort study⁴⁰ in 2009 examined the development of new-onset diabetes (defined as a new ICD-9 code for diabetes or initiation of diabetes treatment) in 24,688 treated hypertensive patients without diabetes at baseline; 4,385 (17.8%) of the patients developed diabetes. After adjusting for sex and age, the risk of new diabetes was significant in users of diuretics (OR 1.10), beta-blockers (OR 1.12), and calcium channel blockers (OR 1.10) compared with users of angiotensin-converting enzyme inhibitors, (OR 0.92), angiotensin receptor blockers (OR 0.90), or alpha-blockers (OR 0.88).

However, the increase in blood glucose does not seem to attenuate the beneficial effects of reducing cardiovascular events. In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT),¹⁵ a long-term follow-up of those developing new-onset diabetes while taking chlorthalidone (Hygroton) found no difference in the risk of death from cardiovascular disease or from any cause (hazard ratio = 1.04).¹⁵

CLINICAL IMPLICATIONS

Balancing the benefits and risks of statins

It is important to examine how the 0.4% increase in absolute risk of new-onset diabetes as calculated in meta-analyses compares with the benefits of statin treatment in terms of cardiovascular risk reduction.

Using data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 participants, Sattar et al¹¹ estimated that statin treatment is associated with 5.4 fewer deaths from coronary heart disease and cases of nonfatal myocardial infarction per 255 patients treated over 4 years for each 1-mmol/L (39 mg/dL) reduction in LDL-C compared with controls. The benefit would be even greater if stroke, revascularization, and hospitalization are included as end points. This benefit is contrasted with the risk of developing 1 additional case of diabetes for every 255 patients treated with statins over the same period.

Preiss et al²⁵ calculated that there were 2 more cases of diabetes per 1,000 patient-years in patients receiving intensive doses than in those receiving moderate doses (18.9 vs 16.9), corresponding to 1 additional case of diabetes for every 498 patients treated per year. However, there were 6.5 fewer first major cardiovascular events per 1,000 patient-years (44.5 vs 51.0), corresponding to a number needed to treat per year to prevent 1 cardiovascular event of 155. Most of the benefit was due to fewer revascularizations, followed by nonfatal myocardial infarctions. The 12% increase in new diabetes with high-dose therapy contrasted with a 16% reduction in new cardiovascular disease combined events (OR 0.84, 95% CI 0.75–0.94).

As previously noted, in the JUPITER trial, the benefits of preventing cardiovascular events with statin therapy outweighed the risk of new diabetes in people both with and without baseline risk factors for diabetes.²⁹ Similar to the observations with niacin and some antihypertensive drugs, the increase in blood glucose with statins does not appear to reduce the benefits of cardiovascular risk reduction in these patients at moderate to high risk, even when used at high doses.

Diabetes is a coronary heart disease risk equivalent and is associated with high risk of cardiovascular events.^41–46 Overall, the risk for these adverse events is two to four times greater in people with diabetes than without. Atherosclerosis-related events account for approximately 65% to 75% of all deaths in people with diabetes, and 75% of these events are coronary. Lipid abnormalities are strongly correlated with the risk of cardiovascular disease in people with diabetes, and aggressive treatment of risk factors, particularly lipid abnormalities, has been shown to reduce this risk.^47–49 And data from multiple clinical trials support the use of statins to lower LDL-C as the first-line therapy for dyslipidemia in people with diabetes, just as it is in the general population.^{3–7,9,13,23,50–61}

Analyses of diabetic subgroups encompassing 18,000 to 20,000 patients in the large statin trials have clearly demonstrated the benefits of statin therapy. A recent metaanalysis of 10 placebo-controlled trials that included approximately 16,000 patients with diabetes and 54,000 without diabetes demonstrated a 30% reduction in coronary heart disease, a 19% reduction in strokes, and a 12% reduction in mortality.⁵⁴ Furthermore, in another meta-analysis of 14 trials, a similar 22% reduction in coronary heart disease was noted in people with diabetes whether or not they had a history of cardiovascular disease.⁵⁵

Therefore, aggressive treatment of lipid abnormalities with statins as primary treatment has generally been adopted as a standard of care in diabetic patients, particularly those with clinical cardiovascular disease or one or more risk factors. The Adult Treatment Panel III guidelines recommend a minimum LDL-C goal of less than 100 mg/dL and a goal of less than 70 mg/dL as an option for patients with diabetes (Table 1).^41,62 Similar recommendations have been issued by the American Diabetes Association together with the American College of Cardiology (Table 2),³⁰ the American Diabetes Association by itself,⁶³ and the American Academy of Pediatrics.⁶

Is new-onset diabetes as dangerous as established diabetes?

In studies to date, there did not appear to be more events in those who developed new-onset diabetes.

Waters et al,²⁴ evaluating three trials of high-dose atorvastatin therapy, found that major cardiovascular events occurred in 11.3% of those with new-onset diabetes, 10.8% of those without new-onset diabetes (HR 1.02, 95% CI 0.77–1.35), and 17.5% of those who had diabetes at baseline.

Therefore, it may not be appropriate to extrapolate the glucose changes seen on statin therapy to an equivalent increase in adverse cardiovascular events as seen in other diabetic patients. The beneficial reduction in cardiovascular events does not appear to be diminished in those developing diabetes. It is not clear that the increase in glucose on statins has the same implications of a new diagnosis of diabetes. Does this elevation in glucose represent true diabetes or some downstream effect? For example, thiazide diuretics have been known to increase blood glucose levels, but the levels drop when these drugs are discontinued, even after many years of treatment.

On the other hand, it is possible that follow-up of 5 years or less in clinical trials has not allowed sufficient time to examine the influence of the increase in new-onset diabetes on future cardiovascular events. In addition, because of the widespread use of statins across a broad range of cardiovascular risk, even if the effect is small in absolute terms, the potential adverse effects are magnified, particularly in a low-risk population in which the cardiovascular benefits are smaller.

The association is real, but questions remain

In view of the evidence, it is difficult to refute that an association exits between statin use and new-onset diabetes, at least in some subgroups. The dose response noted in some studies further reinforces the conclusion that the association is real. However, many questions remain unanswered regarding mechanism of effect, whether there are differences depending on the particular statin or dose used, or differential effects in the populations treated (such as patients with metabolic syndrome or the elderly).

Until the contradictory observations can be resolved and plausible mechanisms of action elucidated, causality cannot be established. From a clinical standpoint there is no current evidence suggesting that the elevations in blood glucose seen while on lipid-lowering or blood-pressure-lowering therapy are associated with an increased risk of cardiovascular events or that they attenuate the beneficial effects of the therapy.

Statins should continue to be used in patients at high risk

Until further studies are done, statins should continue to be used, after assessing the risks and the benefits.

Primary prevention patients at moderate to high risk and secondary prevention patients stand to gain from statin therapy, and it should not be denied or doses reduced on the basis of concerns about the development of new-onset diabetes. The recognized modest risk of developing diabetes does not appear to blunt the cardioprotective effects of statin therapy in these moderate-to high-risk groups.

Rather than stop statins in patients at risk of diabetes such as the elderly or those with prediabetes, insulin resistance, or metabolic syndrome who are on therapy for appropriate reasons, it is reasonable to continue these drugs, monitoring glucose more closely and emphasizing the importance of weight reduction, diet, and aerobic exercise for preventing diabetes. The Diabetes Prevention Program Research Group, for example, reduced the incidence of diabetes by 58% over 2.8 years of follow-up with intensive lifestyle interventions (a low-calorie, low-fat diet plus moderate physical activity 150 minutes per week) vs usual care in at-risk populations.⁶⁵

Should statins be used more cautiously in patients at lower risk?

The most recent Cholesterol Treatment Trialists meta-analysis of 27 randomized clinical trials (22 placebo-controlled, 134,537 people; 5 high-dose vs low-dose, 39,612 people) reported that reducing LDL-C with statins lowered cardiovascular risk even in low-risk patients.⁶⁶ Overall, there were 21% fewer major cardiovascular events (coronary heart disease, stroke, or coronary revascularization) for every 1-mmol/L reduction in LDL-C.

The proportional reduction in events was at least as large in the two lowest-risk groups (estimated 5-year risk of < 5% and 5% to < 10%, 53,152 people) as in the higher-risk groups. This was reflected mainly in fewer nonfatal myocardial infarctions and coronary revascularizations. In these groups, the absolute reduction in risk for each 1-mmol/L reduction in LDL-C was 11 per 1,000 patients over 5 years. Even in this low-risk population, the reduction in cardiovascular risk seems to compare favorably with the small estimated increase risk of diabetes.

However, even in the lowest-risk group studied, the average baseline LDL-C level was greater than 130 mg/dL.

Therefore, in groups in which the benefits of statins on cardiovascular risk reduction are less robust (eg, low-risk primary prevention groups without significant elevations in LDLC, particularly the elderly), it would not be difficult to justify the case for more cautious use of statin therapy. If statins are used in these low-risk groups, restricting their use to those with at least moderate LDL-C elevation, using less aggressive LDL-C-lowering targets, and regular monitoring of fasting glucose seem reasonable until further information is available.