Review
Current overview of statin-induced myopathy

https://doi.org/10.1016/j.amjmed.2003.10.033Get rights and content

Abstract

Statins are an efficacious and well-tolerated class of lipid-altering agents that have been shown to reduce the risk of initial and recurrent cardiovascular events. However, cerivastatin was withdrawn from the world market because of its potential for severe myotoxic effects. Since the benefits of statin treatment outweigh the small risk of adverse events, statins remain the first-line therapy for lipid lowering and preventing atherosclerotic cardiovascular diseases. The risk of myopathy may be minimized with the appropriate choice of agent and by identifying patients at risk of myotoxic effects. Elderly or female patients, or those with concomitant medications or impaired metabolic processes, may be at increased risk and should be monitored closely. The risk of myopathy may also be inferred from the pharmacologic and pharmacokinetic properties of the statin used. Since myotoxic events are more frequent at higher doses, statins that are effective in reducing cholesterol levels and helping patients to reach target levels at start doses may be useful. The lipophilicity of a statin and its potential for drug-drug interactions may also help to determine the likelihood of muscular effects. Drug-drug interactions may be avoided by selecting a statin that does not share the same metabolic pathway.

Section snippets

Statin-induced muscular adverse events

The terminology to describe muscle toxicity is not consistent. For example, myopathy has been defined as muscle pain, tenderness, or weakness associated with abnormal elevations in creatine kinase levels (>10 times the upper limit of normal) (14), whereas the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute (ACC/AHA/NHLBI) task force considers myopathy to be a general term for disease of the muscles (11). The incidence of dose-dependent

Factors influencing the myotoxic potential of statins

The low risk of myotoxicity with statin therapy may be increased by factors that predispose the patient to myopathy, such as age, sex, and body size, or increase in the concentration of statin in muscle tissue (Table 2) 11, 36. Many of these risk factors are increasing in prevalence. For example, the likelihood of living longer, and the effect of aging on muscles, coupled with the increased possibility of comorbid conditions or use of concomitant medications, can increase the risk of myotoxic

Combined lipid-lowering therapy: a special case of polypharmacy

Despite the efficacy of statin therapy, patients with severe hypercholesterolemia may require additional lipid-lowering therapy to reduce LDL cholesterol levels further and to achieve the goals recommended by the National Cholesterol Education Program (64). If necessary, a bile acid sequestrant or cholesterol absorption inhibitor (ezetimibe) may be used in combination with a statin to reduce LDL cholesterol levels further, whereas addition of a fibrate or niacin may be considered in patients

Benefit-risk ratio and the choice of statin

The small risk of myopathy does not outweigh the benefits of statins for reducing cardiovascular morbidity and mortality. Moreover, the benefit-risk ratio of statin therapy is favorable compared with other well-established therapies. For example, fibrates are less efficacious in reducing LDL cholesterol levels (77) and have been associated with a greater risk of myopathy (6.6 events/10,000 person-years vs. 1.2 events/10,000 person-years for statins) (31).

Despite differences in statin

Conclusion

The efficacy of statins for lipid lowering and reducing the risk of coronary heart disease is well established. Although statins are generally well tolerated, a small proportion of patients may develop myopathy. The incidence of severe statin-induced myopathy is low and does not outweigh the benefits of risk reduction of coronary events. Due to the increasing prevalence of metabolic syndrome and type 2 diabetes, the use of combination lipid-modifying therapies, such as statin-fibrate or

References (94)

  • K. Nakahara et al.

    Myopathy induced by HMG-CoA reductase inhibitors in rabbitsa pathological, electrophysiological, and biochemical study

    Toxicol Appl Pharmacol

    (1998)
  • U. Christians et al.

    Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patientsare statins mechanically similar?

    Pharmacol Ther

    (1998)
  • P.D. Martin et al.

    An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibrate acid in healthy male volunteers

    Clin Ther

    (2003)
  • P.B. Duell et al.

    Rhabdomyolysis after taking atorvastatin with gemfibrozil

    Am J Cardiol

    (1998)
  • R.L.B. Ellen et al.

    Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia

    Am J Cardiol

    (1998)
  • J. Davignon et al.

    Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia

    Am J Cardiol

    (1994)
  • H.L. Kennedy et al.

    Physicians' interpretation of “class effects:”a need for thoughtful re-evaluation

    J Am Coll Cardiol

    (2002)
  • P.H. Jones et al.

    Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial)

    Am J Cardiol

    (2003)
  • A.S. Brown et al.

    Treating patients with documented atherosclerosis to National Cholesterol Education Program–recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin

    J Am Coll Cardiol

    (1998)
  • T.C. Andrews et al.

    Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins

    Am J Med

    (2001)
  • O. Wiklund et al.

    Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia

    Am J Med

    (1993)
  • V.G. Athyros et al.

    Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia

    Am J Cardiol

    (1997)
  • Randomised trial of cholesterol lowering in 4444 patients with coronary heart diseasethe Scandinavian Simvastatin Survival Study (4S)

    Lancet

    (1994)
  • J. Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group

    N Engl J Med

    (1995)
  • F.M. Sacks et al.

    The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators

    N Engl J Med

    (1996)
  • J.R. Downs et al.

    Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levelsresults of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study

    JAMA

    (1998)
  • Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

    N Engl J Med

    (1998)
  • MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individualsa randomised placebo-controlled trial

    Lancet

    (2002)
  • The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual carethe Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)

    JAMA

    (2002)
  • D.J. Maron et al.

    Current perspectives on statins

    Circulation

    (2000)
  • R.C. Pasternak et al.

    ACC/AHA/NHLBI clinical advisory on the use and safety of statins

    Circulation

    (2002)
  • J.A. Staffa et al.

    Cerivastatin and reports of fatal rhabdomyolysis

    N Engl J Med

    (2002)
  • H.D. Scott et al.

    Rhode Island physicians' recognition and reporting of adverse drug reactions

    R I Med J

    (1987)
  • M. Evans et al.

    Effects of HMG-CoA reductase inhibitors on skeletal muscleare all statins the same?

    Drug Saf

    (2002)
  • M. Ucar et al.

    HMG-CoA reductase inhibitors and myotoxicity

    Drug Saf

    (2000)
  • M.A. Omar et al.

    FDA adverse event reports on statin-associated rhabdomyolysis

    Ann Pharmacother

    (2002)
  • S.M. Grundy

    Can statins cause low-grade myopathy?

    Ann Intern Med

    (2002)
  • Y. Levy et al.

    Reduction of plasma cholesterol by lovastatin normalizes erythrocyte membrane fluidity in patients with severe hypercholesterolaemia

    Br J Clin Pharmacol

    (1992)
  • I. Morita et al.

    Enhancement of membrane fluidity in cholesterol-poor endothelial cells pre-treated with simvastatin

    Endothelium

    (1997)
  • P. Lijnen et al.

    Influence of cholesterol lowering on plasma membrane lipids and cationic transport systems

    J Hypertens

    (1994)
  • Y. Sonoda et al.

    Electrical myotonia of rabbit skeletal muscles by HMG-CoA reductase inhibitors

    Muscle Nerve

    (1994)
  • F.L. Mastaglia

    Adverse effects of drugs on muscle

    Drugs

    (1982)
  • P.S. Philips et al.

    Statin-associated myopathy and normal creatine kinase levels

    Ann Intern Med

    (2002)
  • P.H. Chu et al.

    Rhabdomyolysis, acute renal failure and hepatopathy induced by lovastatin monotherapy

    Jpn Heart J

    (1997)
  • E.G. Bliznakov et al.

    Biochemical and clinical consequences of inhibiting coenzyme Q biosynthesis by lipid-lowering HMG-Co A reductase inhibitors (statins)a critical overview

    Adv Ther

    (1998)
  • G.F. Watts et al.

    Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin

    J Clin Pathol

    (1993)
  • A.M. Bargossi et al.

    Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

    Int J Clin Lab Res

    (1994)
  • Cited by (0)

    View full text