Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

Beatrice A. Golomb; Marcella A. Evans

Disclosures

Am J Cardiovasc Drugs. 2008;8(6):373-418. 

In This Article

Abstract and Introduction

Abstract

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

Introduction

HMG-CoA reductase inhibitors (statins), the best selling prescription drug class in the US, include atorvastatin, the best selling prescription drug in the world.[1,2,3] These drugs are perceived to have a favorable safety profile[4,5,6] and have well documented benefits to cardiovascular disease in many groups, including persons who are younger and older, male and female, at moderate and high cardiovascular risk. In addition, benefits have been objectively shown to exceed risks on average for both total mortality and total morbidity (indexed by serious adverse events), specifically in clinical-trial equivalent middle-aged men who are at high cardiovascular risk.[7,8,9] Although many people treated with statins do well, no drug is without a potential for adverse effects (AEs). There is a need for awareness of the risks as well as benefits of all drugs, particularly those that, like statins, are used on a wide scale where even uncommon effects can translate to significant public health impact.

Statins inhibit the enzyme HMG-CoA reductase, at a stage early in the mevalonate pathway.[10] This pathway generates a range of other products in addition to cholesterol, such as coenzyme Q10, heme-A, and isoprenylated proteins,[10] which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins.[11,12,13] Additionally, cholesterol itself is not merely a final product (with its own range of vital roles) but also an intermediate to a suite of additional products of fundamental relevance to health and well-being, such as sex steroids, corticosteroids, bile acids, and colecalciferol (vitamin D), several of which have been shown to be affected with statin administration.[14,15] The biochemical influences of statins extend well beyond the lipid profile and its constituents (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), and even beyond the direct products of the mevalonate pathway, to include a wide swath of products and functions modified through these as well as nonmevalonate effects of statins, ranging from nitric oxide and inflammatory markers[16] to polyunsaturated fatty acids,[17] among many others.

This report reviews evidence related to statin induction of AEs and evidence for a dose-response relationship, and describes reported drug interactions. Muscle is emphasized as it is the best recognized AE of statins (as well as liver), on which much of the information on mechanism, drug interactions, and dose-response is targeted – information that, as we show, has relevance to other statin AEs.[18,19] Statins lead to dose-dependent reductions in coenzyme Q10,[20,21,22] a key mitochondrial antioxidant and electron transport carrier that serves to help bypass existing mitochondrial respiratory chain defects.[23,24,25] We review convergent evidence supporting a role for mitochondrial predispositions and mechanisms for statin muscle AEs. We seek to place other statin AEs in the context this evidence provides, proposing that mitochondrial dysfunction may underlie additional AEs reported on statins.

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