Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Proceedings of a Canadian Working Group Consensus Conference

doi:10.1016/j.cjca.2011.05.007

Canadian Journal of Cardiology

Volume 27, Issue 5, September–October 2011, Pages 635-662

https://doi.org/10.1016/j.cjca.2011.05.007 Get rights and content

Abstract

While the proportion of patients with significant statin-associated adverse effects or intolerance is very low, the increasing use and broadening indications have led to a significant absolute number of such patients commonly referred to tertiary care facilities and specialists. This report provides a comprehensive overview of the evidence pertaining to a broad variety of statin-associated adverse effects followed by a consensus approach for the prevention, assessment, diagnosis, and management. The overview is intended both to provide clarification of the untoward effects of statins and to impart confidence in managing the most common issues in a fashion that avoids excessive ancillary testing and/or subspecialty referral except when truly necessary. The ultimate goal is to ensure that patients who warrant cardiovascular risk reduction can be treated optimally, safely, and confidently with statin medications or alternatives when warranted.

Résumé

Bien que la proportion de patients ayant des effets indésirables importants ou une intolérance associés aux statines soit très faible, leur utilisation croissante et leurs indications diversifiées ont mené à un nombre important de patients couramment dirigés vers des établissements et des spécialistes en soins tertiaires. Ce rapport fournit un survol complet de la preuve concernant une grande variété d'effets indésirables associés aux statines suivi par une approche consensuelle de la prévention, de l'évaluation, du diagnostic et de la gestion. Ce survol est destiné à fournir à la fois une clarification des effets déplorables des statines et à donner confiance en la gestion des enjeux les plus fréquents de manière à éviter les tests auxiliaires excessifs ou les références en sous-spécialités, ou les deux, excepté lorsque cela est vraiment nécessaire. Le but ultime est de s'assurer que les patients qui bénéficieraient d'une réduction du risque cardiovasculaire peuvent être traités de manière optimale, en sûreté et en toute confiance par des statines ou d'autres solutions lorsqu'elles sont justifiées.

Section snippets

Methods

The preliminary stage was an informal review of recent (up to December, 2010) literature on statin side effects and therapy for statin intolerance (G.B.J.M.). From that review, a list of subtopics was identified for specific side effects and their management and a subsequent literature search was undertaken using online databases, including PubMed and Embase, to compile studies of relevance. Through the literature search, Canadian physicians who had either published in the area of statin

General Background

In addition to common, nonspecific, mild symptoms or transient side effects encountered with almost any medication, such as gastrointestinal discomfort, fatigue, and skin involvement, statins have more specific effects.⁵ The main concerns with statins usually pertain to elevated liver enzymes and adverse muscle effects. While these effects will dominate this review, there are many other purported effects that can lead to medical assessment, diagnostic testing, and inappropriate discontinuation

Adverse muscle effects

Muscle complaints constitute the major symptom limiting the use of statins. The clinical features of statin myopathy include symptoms such as muscle aches or myalgia, weakness, stiffness, and cramps. These muscle-related side effects (MRSEs) may or may not be associated with elevations in serum creatine kinase (CK) levels.

Clinical Assessment of Predisposition and Risk Factors for Adverse Effects From Statins

In practice, it is important to have an appreciation of predisposing factors, including drug interactions, which may underlie adverse effects of statins.

Prevention of Statin Intolerance

There are several measures that healthcare providers and their patients can take to reduce the risk of statin intolerance. These include comprehensive pretreatment assessment, patient counselling, and ongoing monitoring.

Diagnosis of Statin Intolerance

A diagnosis of statin intolerance should be entertained only when a patient reports symptoms associated with use of a statin (with or without abnormal laboratory findings), symptoms resolve when the statin is stopped, and the symptoms recur with the same or a different statin. These obvious and axiomatic criteria, however, are seldom met in clinical practice. Consequently, many who need treatment go without it. A further consequence is that of a skewed perception of statin-associated side

Therapy for Statin Intolerance

For patients who demonstrate actual intolerance to statin therapy, there are several therapeutic options that may be considered, including the use of different or lower dose statins. Additionally, nonstatin alternatives or adjuncts for lowering LDL-C may be warranted. Interventions to alleviate the symptoms of myalgia while continuing to take statins have also been considered.

Management Approach for Muscle Symptoms or HyperCKemia

This management scenario can be broadly divided into those patients who have muscle symptoms and those who have asymptomatic elevation of CK (Fig. 5). The ultimate goal is to achieve lipid-lowering with minimal or no symptoms of myalgia and with either normal or mild hyperCKemia (CK ≤ 10 times ULN). The following recommendations use terminology pertaining to subjects with a normal, baseline CK. High CK prior to initiation of therapy may be seen in patients with idiopathic hyperCKemia, patients

Management Approach for Liver Disease and Transaminitis

Patients being considered for statin therapy should be evaluated for possible chronic liver disease. By definition, jaundice is a sign of decompensated liver disease and such individuals should be treated with caution, ideally in conjunction with their hepatologist or gastroenterologist, if statins are deemed important. But in the absence of liver decompensation, even patients with cirrhosis or chronic hepatitis B or C may safely receive statin therapy. Patients with NAFLD or nonalcoholic

Summary and Conclusions

Statins remain 1 of the most important advances in the therapy of dyslipidemia and for the reduction of CVD event risk. The extensive experience with this class of drugs has substantiated its efficacy and safety. Moreover, this experience has helped to clarify the nature of specific side effects, of which those related to muscle represent the most tangible clinical issue. In contrast, possible long-term risks of diabetes or hemorrhagic stroke are far outweighed by the CVD event risk reduction

Funding Sources

The consensus conference and subsequent writing of this paper were supported by a grant to Dr G.B. John Mancini through the University of British Columbia from Merck Canada. A portion of this grant was used to provide to all authors an honourarium to support creation of talks, to draft components of the proceedings, and to aid in editing of the entire manuscript. All authors were provided travel and hotel costs to attend the consensus conference.

Disclosures

See Appendix I for disclosure information.

Acknowledgements

The authors acknowledge the expert critiques and advice provided during the final stages of writing this paper by Dr Lawrence A. Leiter (Director, Lipid Clinic, Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario), Dr Adeera Levin (Head, Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, British Columbia), and Dr Urs P. Steinbrecher (Division of Gastroenterology/Hepatology, Department of Medicine,

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ReviewDiagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Proceedings of a Canadian Working Group Consensus Conference

Abstract

Résumé

Section snippets

Methods

General Background

Adverse muscle effects

Clinical Assessment of Predisposition and Risk Factors for Adverse Effects From Statins

Prevention of Statin Intolerance

Diagnosis of Statin Intolerance

Therapy for Statin Intolerance

Management Approach for Muscle Symptoms or HyperCKemia

Management Approach for Liver Disease and Transaminitis

Summary and Conclusions

Funding Sources

Disclosures

Acknowledgements

Lancet

Chest

J Biol Chem

Am J Med

J Lipid Res

Am J Cardiol

Atheroscler Suppl

Toxicol Appl Pharmacol

Atherosclerosis

Atherosclerosis

Lancet

Lipids Health Dis

Atherosclerosis

Biochem Biophys Res Commun

Am J Med

Neuromuscul Disord

Clin Ther

Lancet

Am J Med Sci

Mayo Clin Proc

Clin Liver Dis

Ann Hepatol

Metab Clin Exp

Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins

Lancet

Circulation

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein

N Engl J Med

Explaining the decrease in U.S. deaths from coronary disease, 1980-2000

N Engl J Med

Statin safety: a systematic review

Am J Cardiol

Narrative review: statin-related myopathy

Ann Intern Med

An assessment of statin safety by muscle experts

Am J Cardiol

Statin-associated myopathy with normal creatine kinase levels

Ann Intern Med

Outcomes in 45 patients with statin-associated myopathy

Arch Intern Med

Case of the month: February 1999--54 year old man with severe muscle weakness

Brain Pathol

Detrimental effect of statin therapy in women with fibromyalgia

Arch Intern Med

Cerivastatin-induced polymyalgia rheumatica-like illness

Clin Rheumatol

Rhabdomyolysis

Am Fam Physician

Molecular clues into the pathogenesis of statin-mediated muscle toxicity

Muscle Nerve

SLCO1B1 variants and statin-induced myopathy--a genomewide study

N Engl J Med

Genetic risk factors associated with lipid-lowering drug-induced myopathies

Muscle Nerve

Myopathy with statin-fibrate combination therapy: clinical considerations

Nat Rev Endocrinol

Human skeletal muscle drug transporters determine local exposure and toxicity of statins

Circ Res

Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma : a randomised trial

Drug Saf

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

Eur J Clin Invest

Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio

Review
Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Proceedings of a Canadian Working Group Consensus Conference