Best Practice & Research Clinical Endocrinology & Metabolism
11Overcoming toxicity and side-effects of lipid-lowering therapies
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.
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