Efficacy and safety of lipid-lowering therapies in combination with or without statin to reduce the cardiovascular risk: A systematic review of randomised controlled trials.

Background and aims: Cardiovascular diseases (CVD) pose a significant global health burden. Lowering low-density lipoprotein-cholesterol is the primary therapeutic aim for preventing primary and secondary CVD events. While statins are the standard treatments, their limitations, such as side effects and intolerance in certain patient groups, necessitate exploration of alternative lipid-lowering therapies (LLTs). We systematically reviewed randomised controlled trials (RCTs) evaluating cardiovascular outcomes associated with non-statin LLTs (bempedoic acid, alirocumab, evolocumab, ezetimibe, and inclisiran) in adults with CVD or high cardiovascular risk. Methods: EMBASE, Medline, Cochrane Library, and clinical trial registries were systematically searched for eligible studies, from inception until February 08, 2023. Two reviewers independently screened the studies, with discrepancies resolved by a third reviewer. Data extraction and validation were conducted, and the risk of bias was assessed using the Cochrane Risk-of-Bias tool-2 for RCTs. Results: The search strategy yielded 2104 citations. Post screening for eligibility, nine unique trials/studies (84 publications) were identified. Among these, one trial each was identified for bempedoic acid and alirocumab, three for evolocumab, and four for ezetimibe. No published literature documenting the cardiovascular outcomes of inclisiran was identified. Only one trial (CLEAR Outcomes) included statin-intolerant patients at baseline. Most studies evaluated a 3-component, 4-component, or 5-component major adverse cardiovascular events composite as an outcome along with individual components. The quality of the included trials was found to be fair-to-good. Conclusions: The systematic review findings emphasise the significance of considering non-statin LLTs as viable treatment options for individuals with CVD or high cardiovascular risk who cannot tolerate or achieve optimal lipid control with statin therapy alone.