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November 15, 2016

What to Believe and Do About Statin-Associated Adverse Effects

Author Affiliations
  • 1Hartford Healthcare Heart & Vascular Institute, Hartford Hospital, Hartford, Connecticut
JAMA. 2016;316(19):1969-1970. doi:10.1001/jama.2016.16557

Statins prevent cardiac death and reduce the incidence of acute coronary syndrome, stroke, and venous thromboembolic disease. Patients who take less than 80% of their statin dose have a 45% relative increase in total mortality compared with more adherent patients, an increase greater than that observed with poor adherence to other cardiac drugs including antihypertensive and β-adrenergic blocking agents.1 Yet thousands of patients avoid these life-saving medications because of the presence of or concern about possible statin-associated adverse effects.

Possible statin-associated adverse effects include diabetes mellitus, hemorrhagic stroke, decreased cognition, tendon rupture, interstitial lung disease, as well as muscle-related symptoms.1 Statins increase the risk of diabetes consistent with the observation that low cholesterol levels increase diabetes risk.1 Although statins reduce total stroke, they increase the risk of hemorrhagic stroke consistent with the observation that low cholesterol levels are associated with an increase in hemorrhagic stroke.1 Statins appear to reduce or have no effect on cognitive decline.1 Tendinopathies and interstitial lung disease have possible mechanistic links to statins, but their association with statins is based solely on a small case series.1 The frequency of these possible drug-related complications is unknown but is low and outweighed by the vascular benefits of statins therapy.

Statin-associated muscle symptoms are the most frequent statin-related symptoms. Experts agree that statins can cause muscle symptoms with marked increases in creatine kinase (CK) levels, usually defined as 10 times the upper limits of normal because this has been observed in randomized clinical trials (RCTs) with an estimated occurrence of 1 additional case per 10 000 individuals treated each year.2 In addition, statins can cause a necrotizing myopathy with antibodies against hydroxyl-methyl-glutaryl Co-A reductase.1 This condition must be recognized promptly because it can lead to persistent myopathy. These patients present with muscle pain and weakness plus marked increases in CK levels that do not resolve with drug cessation. Statin-associated necrotizing myopathy is newly recognized and rare but may be more frequently diagnosed now that a commercial test for the antibody is available.

In contrast, there is considerable debate as to whether statins can produce milder symptoms such as myalgia, muscle cramps, or weakness with little or no increase in CK levels. Collins et al2 reviewed the possible adverse effects found in RCTs of statin therapy and concluded that statin-associated muscle symptoms without marked CK elevations do not exist or are extremely rare because they are not reported in the statin RCTs. These authors suggested that these symptoms may be inappropriately attributed to statins due in part to patients being warned of such possible adverse effects by their clinicians.

Most clinicians, however, are convinced that these symptoms exist and are caused by statins. The incidence of statin myalgia has been estimated at 10% from observational studies.1 The Effect of Statins on Skeletal Muscle Performance (STOMP) study is the only randomized, controlled double-blind study designed specifically to examine the effects of statins on skeletal muscle.3 The STOMP trial had predefined criteria for statin myalgia, which included onset of symptoms during treatment, persistence for 2 weeks, symptom resolution within 2 weeks of treatment cessation, and symptom reappearance within 4 week of restarting treatment. Nineteen of 203 patients treated with statins and 10 of 217 patients treated with placebo met the study definition of myalgia (9.4% vs 4.6%, P = .054). This finding did not reach statistical significance, but it indicates a 94.6% probability that statins were responsible for the symptoms. This result occurred even though the study participants were young (mean age, 44.1 years), healthy, and treated with statins for only 6 months. Creatine kinase values were not different between the 2 groups. These results not only suggest that the true incidence of statin myalgia is approximately 5% but also support the observation that approximately 10% of patients will report symptoms of myalgia. Collins et al2 reanalyzed the STOMP trial data after including 29 patients treated with atorvastatin and 10 with placebo who discontinued participation because of personal reasons, yielding a P value of .08 and used this finding to support their assertion that statins do not cause muscle symptoms without markedly increased CK levels.

Diagnosing true statin-associated muscle symptoms is difficult. In the Goal Achievement After Utilizing an Anti PCSK9 Antibody in Statin Intolerant Subjects (GAUSS-3) study,4 the presence of statin myalgia was determined by randomly assigning patients with presumed statin muscle symptoms to receive either 20 mg of atorvastatin or placebo each day for 10 weeks followed by a 2-week hiatus before crossover to the alternative treatment. Only 209 patients (42.6%) developed muscle symptoms during atorvastatin treatment. An additional 130 (26.5%) developed muscle symptoms during placebo-only treatment, 48 (9.6%) developed muscle symptoms during both treatments, and 85 (17.3%) did not develop symptoms during either treatment.

Other evidence supports the idea that statins can cause skeletal muscle symptoms without abnormal CK values. Muscle biopsies show differences in gene expression among patients with statin-associated muscle symptoms during statin treatment and compared them with asymptomatic controls.5 Statins also produce slight increases in average CK levels and augment the increase in CK observed after exercise.1 Rhabdomyolysis is more frequent in participants in RCTs who are receiving statins and have variants in the gene for solute carrier organic anion transporter family member 1B1 (SLCO1B1),2 which regulates hepatic statin uptake. The SLCO1B1 gene variants that reduce hepatic uptake allow more statin to escape the liver and enter the extra portal circulation and ultimately skeletal muscle. The SLCO1B1 variants are also associated with mild muscle adverse effects in study participants treated with statins.6

How could the statin RCTs miss detecting mild statin-related muscle adverse effects such as myalgia? By not asking. A review of 44 statin RCTs reveals that only 1 directly asked about muscle-related adverse effects.7 In the STOMP trial, investigators called patients twice monthly to ask specifically about muscle symptoms.

Whether statins cause muscle symptoms with no or only mild CK elevations is probably a moot point. If patients are convinced that the statins are responsible, it is difficult to convince them otherwise or to ignore their symptoms. So, how should these symptoms be managed?

Managing statin-associated muscle symptoms is not evidenced based but requires reassuring the patient, reassessing the need for statin therapy, determining if statins may be responsible for the symptoms, eliminating possible contributors to the process, and developing alternative treatment plans.1 Other medications (especially gemfibrozil) and conditions (hypothyroidism and vitamin D deficiency) can increase muscle symptoms. Vitamin D deficiency alone can produce myopathy, but evidence that vitamin D supplementation reduces statin-associated muscle symptoms is limited.1 Coenzyme Q10 supplementation has not been effective in reducing symptoms in a meta-analysis of 10 studies,1 although some patients and clinicians are convinced this agent works perhaps via a placebo effect. Coenzyme Q10 can be tried after informing the patients that it has not been effective in clinical trials but has been useful in some patients.

Creatine kinase measurements are required to ensure that there is no major muscle injury and also because even small increases in CK levels with treatment may help identify patients with true statin myalgia. In a double-blind, randomized, placebo-controlled, crossover study evaluating symptoms in 120 patients with possible statin myalgia, CK levels were slightly but significantly higher in patients who developed muscle pain only during statin treatment.8 Patients without major increases in CK and tolerable symptoms should be reassured that statins rarely cause severe muscle injury and that the muscle symptoms usually resolve with drug cessation. Symptoms in typical statin myalgia resolve in most patients within weeks of stopping the statin. Failure to resolve should prompt a search for other sources of the discomfort.

Once the patient is asymptomatic, treatment can be started with alternative regimens or low-dose statins. Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) by approximately 20%, providing treatment benefit for some patients. Low doses of long-acting statins such as 5 mg of rosuvastatin or 10 mg of atorvastatin twice weekly can then be added, and increased at 4-week intervals as necessary and as tolerated. Guidelines recommend only moderate- to high-dose statins because such regimens were studied in RCTs, but the greatest percent reduction in LDL-C occurs with low-statin doses.1 The combination of ezetimibe and very low doses of a statin can produce LDL-C reductions similar to those produced by moderate- and high-dose statin therapy.1 Other agents such as bile acid sequestrant resins and niacin can be tried if the clinician and patient are willing to deal with gastrointestinal adverse effects of resins and the cutaneous and other adverse effects niacin. Niacin is no longer recommended as an add-on to statins because it was ineffective in reducing cardiovascular events in 2 recent trials.1 Niacin alone was effective in reducing cardiac morbidity and mortality in the Coronary Drug Project,1 so niacin may be useful for patients who are total intolerant to statins. Perhaps the easiest but most expensive approach is to use proprotein convertase subtilism/kexin type 9 (PCSK9) inhibitors. These monoclonal antibodies produce remarkable reductions in LDL-C but are presently only indicated for patients with familial hypercholesterolemia or documented atherosclerotic cardiovascular disease who have not achieved a sufficiently low LDL-C level with the highest tolerated statin therapy.

The effectiveness and safety of statins have been documented by numerous RCTs, so every effort should be made for appropriate patients to continue taking these medications. Many patients can ultimately tolerate these drugs, but doing so requires acknowledging the possible relationship of statins with primarily muscle symptoms and developing with the patient a collaborative treatment plan.

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Article Information

Corresponding Author: Paul D. Thompson, MD, Hartford Healthcare Heart & Vascular Institute, Hartford Hospital, 80 Seymour St, Hartford, CT 06102 (paul.thompson@hhchealth.org).

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and Dr Thompson reports that he has spoken for Regeneron, Sanofi, Amgen, and Amarin; consulted for Amgen, Regeneron, Merck, Esperion, and Sanofi; received research support from Genomas, Roche, Sanofi, Regeneron, Esperion, Amarin, and Pfizer; and owns stock in Abbvie, Abbott Labs, CVS, General Electric, Johnson & Johnson, Medtronic, and Sarepta.

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