Statin Intolerance: Pathophysiology, Risk Factors, Manifestations, and Management Strategies

Abstract

Introduction: Cardiovascular disease (CVD) is the primary cause of morbidity and mortality among people across the globe, and the high levels of low-density lipoprotein cholesterol (LDL-C) are one of the main risk factors that can contribute to the occurrence of atherosclerotic cardiovascular disease. The statins, which are 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the mainstay of lipid-lowering therapy and have proven to have a markedly reduced cardiovascular event and mortality. In addition to decreasing LDL-C, statins have pleiotropic actions, such as endothelial repair, vascular inflammation, and atherosclerotic plaque stabilization. Although statin therapy has been proven to be both effective and safe over time, adherence to statin treatment is often impaired over time because of statin intolerance, which manifests as statin-associated muscle symptoms (SAMS). Statin intolerance is a complex disorder, which depends on the pharmacokinetic features, individual peculiarities of patients, genetic factors, and interactions between drugs. Some of the proposed mechanisms are mitochondrial dysfunction, which is associated with decreased coenzyme Q10 production, impaired calcium homeostasis, immune- mediated muscular damage, and genetic differences related to drug transport and metabolism. The given review is a comprehensive summary of the pathophysiology, risk factors, clinical manifestations, and evidence-based management of statin intolerance. It also highlights the need to have a systematic diagnostic methodology, which incorporates the temporal association, laboratory analysis, and dechallenge/ rechallenge methods to differentiate between true intolerance and nocebo-based effects. To ensure a sufficient level of cardiovascular risk reduction, it is crucial to optimize therapy with the help of personal dosing, replacement of statins with non-statin agents, ezetimibe, PCSK9 inhibitors and bempedoic acid. The adherence to treatment and long-term cardioprotective effects can be improved by better awareness and systematic control of statin intolerance. Objective of the Review: The purpose of this review is to deliver an in-depth and critical review of statin intolerance, including its underlying pathophysiology, risk factors, clinical presentation, and the current evidence-based approaches to optimize cardiovascular outcomes.