Statin Safety: An Overview and Assessment of the Data—2005

https://doi.org/10.1016/j.amjcard.2005.12.006Get rights and content

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statin drugs, have been studied in numerous controlled human research trials involving hundreds of thousands of study participants. Statins have been prescribed for millions of patients. Based on this vast research and clinical experience, statins have been shown to improve lipid blood levels and reduce atherosclerotic coronary artery disease (CAD) risk, resulting in reduced CAD morbidity and mortality, and in several studies, reduced overall (“all-cause”) mortality. From a safety perspective, both research trial evidence and clinical practice experience have demonstrated that statins are generally well tolerated. However, as with all pharmaceuticals, safety considerations exist with both monotherapy and combination statin therapy, mainly involving potential adverse effects on muscle, liver, kidney, and the nervous system. The evidence supporting statin-related potential adverse experiences on these organ systems is sometimes strong and based on clear clinical trial evidence (such as the increased risk of muscle enzyme elevation with higher statin doses). The evidence is at other times more speculative, being based on case reports and inconclusive clinical trial data (such as possible favorable or unfavorable effects of statins on cognition). Because the use of statins is so widespread, it is useful for the clinician to understand statin safety issues and the level of available evidence supporting the contention that various adverse effects are caused by statins. This review presents an assessment of statin safety based on an overview of the current statin safety data and their clinical implications.

Section snippets

Grading of the Scientific Evidence

The strength of the current scientific evidence supporting the association of statins with specific potential adverse experiences varies with the adverse experience being considered. In some cases, the clinical trial evidence is clear; in other cases, potential adverse experiences are unproved, having only been described in isolated case reports. It therefore is useful to assess the level of scientific evidence of potential safety issues associated with statins. Although no universally accepted

Definitions

Before a drug can be said to be associated with a potential toxicity, it is helpful to have a clear understanding of what defines the adverse experience. Unfortunately, the definitions ascribed to muscle adverse experiences have not always been consistent. In 2002, the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute (ACC/AHA/NHLBI) issued a clinical advisory statement on the use and safety of statins.18 In this advisory statement, myalgia was

Combination Lipid-Altering Drug Therapy

Combination lipid-altering drug treatment is a well-established therapeutic approach for (1) patients with severe hypercholesterolemia, (2) those with more complicated lipid abnormalities, or (3) patients who need aggressive lipid management.19, 67, 68, 69 Clinical trials have shown that the combination of bile acid sequestrants (such as colesevelam) with statins lowers cholesterol levels more than does the same dose of statin monotherapy, without an increased risk of muscle adverse experiences.

Currently Marketed Statin Monotherapy and Clinical Trial Assessment of Muscle Adverse Experiences

With regard to currently marketed statins used as monotherapy at recommended doses, and administered under recommended conditions, no conclusive comparative evidence exists that these statins differ with regard to potential muscle adverse experiences. The exception to this, theoretically, might be in cases where potential drug interactions may occur.6 For example, pravastatin78 and rosuvastatin79 are not significantly metabolized through the cytochrome P450 enzyme (CYP) system. Therefore,

Potential Liver Adverse Experiences

As with muscle, statins have a low risk for potential liver adverse experiences. The levels of evidence for determining whether such an adverse event is associated with statin use are presented in Table 4.27, 34, 77, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 Severe potential liver adverse experiences have been described in isolated case reports (such as rare reports of possible statin-related cholestatic hepatotoxicity, autoimmune hepatitis, fulminant

Potential Renal Adverse Experiences

Levels of evidence for determining whether potential renal adverse experiences are associated with use of statins are shown in Table 5.7, 18, 21, 22, 23, 131, 132, 133, 134

Proteinuria and hematuria has been described as rare, potential kidney effects associated with all statins (Table 6).21, 135 Although these renal findings had previously been recognized with statin therapy, this issue resurfaced during the vast rosuvastatin development program,131 most likely because (1) rosuvastatin was

Potential Neurologic Adverse Experiences

Levels of evidence supporting that potential neurologic adverse experiences may be related to statin use are listed in Table 7.144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 Although much is known about the effects of statins on muscle, liver, and even kidney, less is known about potential statin-related neurologic adverse experiences. Neurologic conditions that have been described in

References (212)

  • A.A. Alsheikh-Ali et al.

    Risk of adverse events with fibrates

    Am J Cardiol

    (2004)
  • 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 fenofibric acid in healthy male volunteers

    Clin Ther

    (2003)
  • R.L. Ellen et al.

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

    Am J Cardiol

    (1998)
  • P.H. Jones et al.

    Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin

    Am J Cardiol

    (2005)
  • H.E. Bays et al.

    A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia

    Clin Ther

    (2004)
  • C. Gagne et al.

    Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia

    Am J Cardiol

    (2002)
  • P. Chazerain et al.

    Four cases of tendinopathy in patients on statin therapy

    Joint Bone Spine

    (2001)
  • D.B. Hunninghake

    Clinical efficacy of cerivastatinphase IIa dose-ranging and dose-scheduling studies

    Am J Cardiol

    (1998)
  • R.S. Rosenson et al.

    Results of two clinical trials on the safety and efficacy of pravastatin 80 and 160 mg per day

    Am J Cardiol

    (2003)
  • G.L. Vega

    Management of atherogenic dyslipidemia of the metabolic syndromeevolving rationale for combined drug therapy

    Endocrinol Metab Clin North Am

    (2004)
  • P.H. Jones

    Statins as the cornerstone of drug therapy for dyslipidemiamonotherapy and combination therapy options

    Am Heart J

    (2004)
  • T.H. Taher et al.

    Tolerability of statin-fibrate and statin-niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events

    Am J Cardiol

    (2002)
  • H.E. Bays et al.

    Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE])

    Am J Cardiol

    (2003)
  • X.Q. Zhao et al.

    Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study)

    Am J Cardiol

    (2004)
  • T.A. Jacobson

    Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors

    Am J Cardiol

    (2004)
  • R.H. Bradford et al.

    Expanded Clinical Evaluation of Lovastatin (EXCEL) study resultstwo-year efficacy and safety follow-up

    Am J Cardiol

    (1994)
  • C.B. Newman et al.

    Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients

    Am J Cardiol

    (2003)
  • E.C. Charles et al.

    Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization

    Am J Med

    (2005)
  • J.L. Parra et al.

    Hepatotoxicity of hypolipidemic drugs

    Clin Liver Dis

    (2003)
  • D.M. Black

    A general assessment of the safety of HMG CoA reductase inhibitors (statins)

    Curr Atheroscler Rep

    (2002)
  • H. Bays et al.

    Pharmacotherapy for dyslipidaemia—current therapies and future agents

    Expert Opin Pharmacother

    (2003)
  • C.M. Ballantyne et al.

    Risk for myopathy with statin therapy in high-risk patients

    Arch Intern Med

    (2003)
  • P.D. Thompson et al.

    Statin-associated myopathy

    JAMA

    (2003)
  • M. Ucar et al.

    HMG-CoA reductase inhibitors and myotoxicity

    Drug Saf

    (2000)
  • J.A. Staffa et al.

    Cerivastatin and reports of fatal rhabdomyolysis

    N Engl J Med

    (2002)
  • B.M. Psaty et al.

    Potential for conflict of interest in the evaluation of suspected adverse drug reactionsuse of cerivastatin and risk of rhabdomyolysis

    JAMA

    (2004)
  • M.H. Davidson

    Controversy surrounding the safety of cerivastatin

    Expert Opin Drug Saf

    (2002)
  • M. Evans et al.

    The myotoxicity of statins

    Curr Opin Lipidol

    (2002)
  • M.B. Bottorff

    Safety and statinspharmacologic and clinical perspectives

    Am J Manag Care

    (2004)
  • S.M. Grundy

    Can statins cause chronic low-grade myopathy [editorial]?

    Ann Intern Med

    (2002)
  • S.M. Grundy

    The issue of statin safetywhere do we stand [editorial]?

    Circulation

    (2005)
  • B.L. Strom

    Potential for conflict of interest in the evaluation of suspected adverse drug reactionsa counterpoint

    JAMA

    (2004)
  • J.D. Piorkowski

    Bayer’s response to “potential for conflict of interest in the evaluation of suspected adverse drug reactionsuse of cerivastatin and risk of rhabdomyolysis.”

    JAMA

    (2004)
  • Position StatementStandards of Medical Care in Diabetes [American Diabetes Association Clinical Practice Recommendation]

    Diabetes Care

    (2005)
  • Bays HE. Combination lipid-altering drug therapy with statins: an update [slide talk]. [Lipids Online Website.]...
  • P.A. Gabow et al.

    The spectrum of rhabdomyolysis

    Medicine (Baltimore)

    (1982)
  • CRESTOR (ZD4522, rosuvastatin calcium) TABLETS

    Briefing Document NDA 21-366 for the Use of CRESTOR

    (2003)
  • Alert for Healthcare ProfessionalCrestor (Rosuvastatin Calcium)

    (2005)
  • S.S. Tomlinson et al.

    Potential adverse effects of statins on muscle

    Phys Ther

    (2005)
  • S.E. Nissen

    High-dose statins in acute coronary syndromesnot just lipid levels

    JAMA

    (2004)
  • Cited by (234)

    • Is there a role for earlier use of combination therapy?

      2024, American Journal of Preventive Cardiology
    • Statin associated muscle symptoms: An update and review

      2022, Progress in Cardiovascular Diseases
    • That Myalgia of Yours Is Not From Statin Intolerance

      2021, Journal of the American College of Cardiology
    View all citing articles on Scopus
    View full text