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Overcoming toxicity and side-effects of lipid-lowering therapies

https://doi.org/10.1016/j.beem.2014.01.006Get rights and content

Lowering serum lipid levels is part of the foundation of treating and preventing clinically significant cardiovascular disease. Recently, the American Heart Association/American College of Cardiology released cholesterol guidelines which advocate for high efficacy statins rather than LDL-c goals for five patient subgroups at high risk for cardiovascular disease. Therefore, it is critical that clinicians have an approach for managing side-effects of statin therapy. Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. Statin-related adverse effects might be minimized by careful assessment of patient risk factors. Strategies to continue statin therapy despite adverse effects include switching to another statin at a lower dose and titrating up, giving intermittent doses of statins, and adding non-statin agents. Non-statin lipid-lowering drugs have their own unique limitations. Management strategies and algorithms for statin-associated toxicities are available to help guide clinicians. Clinical practice should emphasize tailoring therapy to address each individual's cholesterol goals and risk of developing adverse effects on lipid-lowering drugs.

Introduction

Lipid altering drugs, especially statins, are among the most widely prescribed drugs in the world. Clinical trials over the past 25 years demonstrate that statins are well tolerated and prevent cardiovascular (CV) deaths, major CV events (stroke, myocardial infarction), and total mortality in high risk patients [1]. Although a significant decline in cardiovascular mortality began prior to the regulatory approval of statins in 1987, cholesterol lowering to prevent coronary heart disease (CHD) has been credited with much of the marked reduction of CHD incidence worldwide [2]. Little controversy remains regarding the clinical benefits of statins in high risk patients, and increasingly data and guidelines support more widespread statin use and more intensive statin therapy [1]. However, a significant number of patients (perhaps 10% or more) [3] develop intolerant symptoms to statins, and another 1–2% develop serious side-effects such as myositis or liver enzyme elevations [4]. The growing number of patients receiving these drugs, and the recent recommendations for higher intensity therapy [1], creates a significant absolute number of people intolerant of statin therapy or who suffer side-effects. Many primary care physicians face the challenge of identifying a therapeutic regimen that achieves desired lipid goals, but also is well tolerated by the patient. Consequently, a leading reason for a referral to a lipid clinic is statin intolerance. The purpose of this review is to identify risk factors for statin-induced side-effects, strategies to overcome true or perceived intolerance, and alternative approaches to treat elevated low-density lipoprotein cholesterol (LDL-c) and non-high-density lipoprotein cholesterol (non-HDL-c) if statins cannot be utilized. In addition, safety issues related to non-statin lipid altering therapy will also be addressed. An enhanced understanding regarding the risk factors for statin-induced toxicity and deploying successful approaches to overcome statin intolerance will hopefully avoid unnecessary ancillary tests or referrals which ultimately could reduce health costs with improved patient outcomes.

Section snippets

Myopathy

Among the symptoms associated with statins, muscle-related complaints are common and frequently limit the use of statins ∗[5], ∗[6]. The term myopathy has been used to describe muscle-related symptoms that occur with evidence of muscle injury (serum creatine kinase (CK) >10 times the upper limit of normal (ULN)) [5]. This definition of myopathy is used by the National Lipid Association. However, the term myopathy may also be used more broadly; for example, the American College of Cardiology

Risk factors associated with adverse effects from statins

Recent guidelines from the ACC/AHA suggest that patients who would otherwise begin treatment with high dose statin therapy, but who have risk factors for statin intolerance, should be started on moderate doses of statins to avoid side-effects. These risk factors include significant comorbidities (including renal and hepatic dysfunction), history of prior statin intolerance or muscle disorder, unexplained alanine aminotransferase (ALT) elevation >3 times the ULN, presence of factors which might

Diagnosing statin intolerance

Statin intolerance generally involves: development of symptoms while on a statin, resolution of symptoms when the statin is discontinued, and recurrence of symptoms when the same or a different statin is restarted. When symptoms such as myopathy occur, risk factors should be re-evaluated; for example, patients should be asked about changes in physical activity and thyroid function should be re-assessed. Further testing, such as with electromyography and muscle biopsy, may be warranted in cases

Strategies to reduce statin toxicity

Prior to starting statin therapy, the risk of adverse effects can be minimized by assessing pre-existing risk factors for toxicity. Baseline values of CK, liver enzymes, creatinine, and thyroid-stimulating hormone should be obtained. Some groups suggest that additional CK and liver enzyme levels do not need to be checked in asymptomatic patients on statins. However, others feel it is reasonable to check these lab values 6–12 weeks after initiation of therapy to establish a new baseline for the

Management strategies for clinical practice

Cholesterol management in clinical practice requires integration of many strategies to help patients both meet their cholesterol goals and avoid side-effects. Certain groups have published guidelines and algorithms to help clinicians manage the possible adverse effects related to statins. We describe aspects of recently published algorithms from two groups intended to help guide management of statin-related myopathy and hepatotoxicity. We conclude this section with an algorithm for

Summary

Lipid-lowering therapy is proven to reduce the risk of cardiovascular disease and associated events. Statins represent the back-bone of lipid-lowering therapy for patients who have, or are at risk for, clinically significant cardiovascular disease. In patients for whom statin therapy is indicated, the benefits of statins almost always outweigh the risk of adverse effects. Muscle-related side-effects from statins may be reported commonly in clinical practice [5]. However, the incidence of

Conflict of interest

None declared.

References (64)

  • U. Julius et al.

    Nicotinic acid as a lipid-modifying drug – a review

    Atheroscler Suppl

    (2013)
  • C. Baigent et al.

    The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial

    Lancet

    (2011)
  • C.P. Cannon et al.

    Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes

    Am Heart J

    (2008)
  • S.C. Halbert et al.

    Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance

    Am J Cardiol

    (2010)
  • L. Childress et al.

    Review of red yeast rice content and current Food and Drug Administration oversight

    J Clin Lipidol

    (2013)
  • S. Larsen et al.

    Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance

    J Am Coll Cardiol

    (2013)
  • W. Ahmed et al.

    Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients

    Transl Res – J Lab Clin Med

    (2009)
  • L. Marcoff et al.

    The role of coenzyme Q10 in statin-associated myopathy: a systematic review

    J Am Coll Cardiol

    (2007)
  • G. Caso et al.

    Effect of coenzyme q10 on myopathic symptoms in patients treated with statins

    Am J Cardiol

    (2007)
  • D.A. Bookstaver et al.

    Effect of coenzyme Q10 supplementation on statin-induced myalgias

    Am J Cardiol

    (2012)
  • J.M. Young et al.

    Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia

    Am J Cardiol

    (2007)
  • B.A. Parker et al.

    A randomized trial of coenzyme Q10 in patients with statin myopathy: rationale and study design

    J Clin Lipidol

    (2013)
  • J.N. Hathcock et al.

    Risk assessment for coenzyme Q10 (Ubiquinone)

    Regul Toxicol Pharmacol

    (2006)
  • G.A. Plotnikoff et al.

    Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain

    Mayo Clin Proc

    (2003)
  • A. Gupta et al.

    The relationship of vitamin D deficiency to statin myopathy

    Atherosclerosis

    (2011)
  • N.J. Stone et al.

    2013 ACC/AHA Guideline on the treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

    Circulation

    (2013)
  • C. Baigent et al.

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

    Lancet

    (2005)
  • T.R. Joy et al.

    Narrative review: statin-related myopathy

    Ann Intern Med

    (2009)
  • S.M. Grundy

    Can statins cause chronic low-grade myopathy?

    Ann Intern Med

    (2002)
  • J.M. McKenney et al.

    Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force

    Am J Cardiol

    (2006)
  • J.A. Staffa et al.

    Cerivastatin and reports of fatal rhabdomyolysis

    N Engl J Med

    (2002)
  • E. Bruckert et al.

    Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study

    Cardiovasc Drugs Ther

    (2005)
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