Cardiovascular diseases (CVD) are a leading cause of morbidity and mortality globally, with elevated low-density lipoprotein cholesterol (LDL-C) as a major risk factor.(1,2) Statins, the first-line lipid-lowering therapies, effectively reduce LDL-C and lower cardiovascular risk.(3) However, statin intolerance, typically presenting as muscle-related symptoms, affects a subset of patients and poses a clinical challenge requiring alternative strategies.(4,5) The prevalence of statin intolerance varies, with a meta-analysis indicating that approximately 13% of statin users report muscle-related complaints,though this figure may underestimate the true rate due to exclusions in certain clinical trials.(6) Observational data indicate a prevalence between 7% and 29%.(4,7) For instance, in the Effect of Statins on Skeletal Muscle Function and Performance trial, 9.4% of patients on atorvastatin 80 mg experienced muscle-related complaints, compared to 4.6% on placebo, highlighting a significant increase in event rate with high-dose statin therapy.(8)

Despite efforts to identify tolerable regimens, healthcare providers may rely on less potent therapies, such as ezetimibe or intermittent low-dose statin regimens, potentially resulting in suboptimal LDL-C reductions.(9) This issue is particularly concerning for patients with established atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia, for whom aggressive LDL-C reduction is essential to improving clinical outcomes.(10,11) For patients with statin intolerance, non-statin therapies, including monoclonal antibodies (evolocumab and alirocumab), bempedoic acid, and ezetimibe, provide alternative options for lowering LDL-C.

A network meta-analysis of 15 trials demonstrated that adding PCSK9 inhibitors to maximally tolerated moderate-to-high intensity statins effectively and safely reduced LDL-C levels.(12) However, this analysis did not focus on patients with statin intolerance. Another recent network meta-analysis, which included a broader population and conducted a subgroup analysis for statin-intolerant patients, found that evolocumab and alirocumab effectively reduced LDL-C compared to placebo.(13) Bempedoic acid and ezetimibe also showed LDL-C reductions, albeit to a lesser extent. However, subgroup analyses in broader randomized controlled trials (RCTs) often lack the focus, precision, and baseline uniformity of studies designed specifically for statin-intolerant patients.This may compromise the accuracy of findings for this population. These observations underscore the need for targeted research on statin-intolerant patients, with a rigorous evaluation of both efficacy and safety.

This systematic review and network meta-analysis aims to provide an updated comparison of non-statin lipid-lowering therapies in statin-intolerant patients, focusing on both efficacy and safety. Ezetimibe is used as the standard of care due to its favorable safety profile, despite being relatively less effective in LDL-C reduction according to previous network meta-analyses.(12,13) By evaluating LDL-C reduction and withdrawal due to adverse effects, this study seeks to inform clinical decision-making for optimal management of this patient population.