REVIEW CME EDUCATIONAL OBJECTIVE: Readers will assess possible statin-induced myopathy in their patients on statins CREDIT GENARO FERNANDEZ, MD ERICA S. SPATZ, MD CHARLES JABLECKI, MD PAUL S. PHILLIPS, MD Internal Medicine Residency Program, Robert Wood Johnson Clinical Scholars Department of Neurosciences, University Director, Interventional Cardiology, The University of Utah, Salt Lake City Program, Cardiovascular Disease Fellow, of California San Diego, La Jolla Department of Cardiology, Scripps Mercy Yale University School of Medicine, New Hospital, San Diego, CA Haven, CT Statin myopathy: A common dilemma not reflected in clinical trials ■■ ABSTRACT hen a patient taking a statin complains Wof muscle aches, is he or she experiencing Although statins are remarkably effective, they are still statin-induced myopathy or some other prob- underprescribed because of concerns about muscle toxic- lem? Should statin therapy be discontinued? Statins have proven efficacy in preventing ity. We review the aspects of statin myopathy that are 1 important to the primary care physician and provide a heart attacks and death, and they are the most guide for evaluating patients on statins who present with widely prescribed drugs worldwide. Neverthe- less, they remain underused, with only 50% of muscle complaints. We outline the differential diagnosis, those who would benefit from being on a statin the risks and benefits of statin therapy in patients with receiving one.2,3 In addition, at least 25% of possible toxicity, and the subsequent treatment options. adults who start taking statins stop taking them 4 ■■ by 6 months, and up to 60% stop by 2 years. KEY POINTS Patient and physician fears about myopathy There is little consensus on the definition of statin-in- remain a key reason for stopping. Myopathy, a duced myopathy, and it is underdiagnosed. The incidence known side effect of statins, is rare in random- of statin-induced muscle toxicity in randomized con- ized controlled trials, but less so in observational studies and clinical experience. This discrepancy trolled trials is lower than in clinical practice. between clinical trials and clinical experience reduces confidence in lipid-lowering therapy and Abnormal pharmacokinetic activity contributes to toxic- contributes to its underuse. ity, but some patients may be predisposed by underlying This review emphasizes clinical aspects metabolic muscle disorders. of statin myopathy that are important to the practicing physician. We will define myopathy, A focused history and neuromusculoskeletal examination review its purported mechanisms, and describe are important in the evaluation of muscle complaints that a clinical approach to patients with possible toxicity, including risk factors, physical find- may be induced by statins. ings, and consideration of alternate diagnoses. Since there is no single test to diagnose statin- In patients with possible statin-induced myopathy, assess- induced myopathy, we offer a framework to ing the risks and benefits of statin therapy is essential. aid clinicians in stratifying patients based on the likelihood that their symptoms are due to For patients who cannot tolerate statin therapy, alternatives statin toxicity weighed against the likelihood include a “statin holiday” followed by a rechallenge with a that they will benefit from statin therapy. different statin, intermittent rosuvastatin (Crestor), or resin therapy. Sometimes the best alternative is a compromise be- ■ DEFINITIONS DIFFER tween the goal level for low-density-lipoprotein cholesterol and the level achievable with alternative therapy. Little consensus exists on how to define the adverse muscle effects of statins,5 which may doi:10.3949/ccjm.78a.10073 contribute to the underdiagnosis of this com- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NUMBER 6 JUNE 2011 393 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. STATIN MYOPATHY plication. The magnitude of creatine kinase Another reason is that these trials were (CK) elevation required to define rhabdomy- designed to assess the efficacy of statins and olysis has increased from 500 IU/L in 1982,6 were not sensitive to adverse effects like mus- to 1,000 IU/L in 1988,7 to 50 times the upper cle pain. When they looked at myopathy, they limit of normal in one current definition.8 The focused on rhabdomyolysis—the most severe American Heart Association, the American form—rather than on myalgia, fatigue, or College of Cardiology, the National Heart other minor muscle complaints.15 Addition- Lung and Blood Institute,9 the National Lipid ally, most trials enrolled too few patients and Association,8 and the US Food and Drug Ad- did not have long enough follow-up to reveal ministration10 all differ in their definitions. infrequent toxicities. Despite the strict criteria, a significant Our definitions number of trial patients discontinued statin For the purpose of this article, we offer the fol- therapy during the study period. In the Treat lowing definitions: to New Targets (TNT) trial, 5% of patients Myalgia—muscle weakness, soreness, tender- in both the high- and low-dose atorvastatin ness, stiffness, cramping, or aching, either at rest (Lipitor) groups experienced muscle toxicity, or with exertion, without any elevation in CK. even though 35% of eligible patients had been Myositis—elevated CK with or without excluded during the open-label run-in phase.14 muscle symptoms. The “-itis” suffix is unfor- Also, physicians may overlook and pa- tunate since myositis does not correspond to tients may fail to report symptoms such as inflammation on biopsy. fatigue, malaise, or dyspnea that are not com- Rhabdomyolysis—muscle symptoms with monly accepted as signs of statin toxicity.16 a CK level 10 times the upper limit of normal or higher. Evidence of renal dysfunction is not Findings from observational studies required for the diagnosis, as preexisting renal Observational studies in nonselected outpa- disease and hydration status are more closely tients show a higher frequency of muscle com- related to kidney damage than the degree of plaints in the statin groups than in the control In observational muscle injury.11 groups. These studies suggest the frequency of studies, muscle statin myopathy is 9% to 20%.17–19 ■ STATIN MYOPATHY IS MORE COMMON The Prediction of Muscular Risk in Ob- symptoms IN THE REAL WORLD THAN IN TRIALS servational Conditions (PRIMO) study20 was occurred one of the largest and best-defined observa- in up to 20% The incidence of statin-induced myopathy is tional studies of muscular symptoms in an un- significantly lower in randomized controlled selected population. It included 7,924 French of patients trials of statin efficacy than in observational outpatients with hypercholesterolemia, ages on statins studies of real-world patients. In randomized 18 to 75 years, on high-dose statins for 3 or clinical trials, myalgia was reported in 1% to more months before the study. Daily statin 5% of patients in the statin groups and pla- regimens included atorvastatin 40 to 80 mg, cebo groups alike,9,12 whereas clinical practice fluvastatin (Lescol) 80 mg, pravastatin (Prava- would suggest it is more common. chol) 40 mg, and simvastatin (Zocor) 40 to 80 mg. In this study, 10.5% of patients reported Why is statin-induced myopathy muscle-related symptoms. so uncommon in clinical trials? Buettner et al,21 in another cross-sectional A reason may be that patients in clinical trials study, interviewed and examined 3,580 adults are carefully screened. To minimize toxicity, over age 40. Of those taking statins, 22% re- the clinical trials of statins excluded patients ported having had musculoskeletal pain in at with renal insufficiency, hepatic insufficiency, least one anatomic region in the last 30 days, a history of muscular complaints, and poorly compared with 16.7% of those not taking a controlled diabetes, as well as patients taking statin. drugs with possible interactions. Large efficacy In the United States, where an estimated trials have excluded up to 30% of the partici- 33 million adults use statins, musculoskeletal pants in active prerandomization phases.13,14 pain can be expected to occur in 7 million 394 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 78 • NUMBER 6 JUNE 2011 Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. FERNANDEZ AND COLLEAGUES people, likely induced by statin therapy in 22 LDL-C reduction and creatine kinase (CK) elevation 25% of cases. 2.5 Cerivastatin (Baycol) ■ WHAT CAUSES STATIN MYOPATHY? 0.8 mg 2.0 The causes of statin-induced myopathy are 1.5 0.4 mg Simvastatin poorly understood. (Zocor) Atorvastatin Pravastatin 80 mg Historically, statin-induced toxicity was (Lipitor) 1.0 (Pravachol) 40 80 mg thought to be caused by inhibition of the syn- mg 20 thesis of mevalonate, leading to depletion of mg 40 mg Rosuvastatin (Crestor) 0.5 10 mg 0.2 mg 40 mg its metabolites, such as cholesterol, isopren- 10 mg 20 mg 0.3 20 mg oids, and ubiquinone (coenzyme Q10). De- Occurrence of CK >10 x ULN (%) mg 40 mg 0.0 pletion of intracellular cholesterol may lead 20 25 30 35 40 5045 6055 7065 to abnormal membrane behaviors; depletion % Reduction in low-density lipoprotein cholesterol (LDL–C) of isoprenoids may affect intracellular signal- ing; depletion of coenzyme Q10 may in turn FIGURE 1 reduce mitochondrial respiratory function. REPRINTED FROM BREwER HB JR. BENEFIT-RIsk AssEssMENT OF ROsuvastatin 10 TO 40 MILLIgRAMs. AM J CARDIOL 2003; 92(sUPPL):23k–29k, Genetic factors may also play a role, contrib- COPyRIgHT 2003, wITH PERMIssION FROM ELsEVIER; uting to pharmacokinetics and predisposing www.sCIENCEDIRECT.COM/sCIENCE/JOURNAL/ 00029149. metabolic muscle disorders.23,24 Statin-induced myopathy seems to be that lessens the lipid substrate available to different in randomized efficacy trials than muscle rather than from the reduction of in the clinical setting. In randomized trials, products downstream from mevalonate by the mechanism appears to involve abnormal statins.