Comparative Efficacy of Nonstatin Lipid-Lowering Therapies in Patients With Hypercholesterolemia at Increased Cardiovascular Risk: An Updated Network Meta-Analysis

Abstract: Hypercholesterolemia is associated with atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality. Nonstatin lipid-lowering therapies (LLTs) such as ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), bempedoic acid, and inclisiran have been recommended in clinical guidelines to treat patients with ASCVD and/or high cardiovascular (CV) risk having elevated low-density lipoprotein cholesterol (LDL-C) despite being treated with maximally tolerated doses (MTD) of statins. Our previously published network meta-analysis (NMA) 1 was updated in this study to evaluate comparative efficacy of nonstatin LLTs in reducing LDL-C among patients with ASCVD and/or high CV risk receiving MTD statins. The systematic literature review previously conducted to inform our NMA was updated through January 2023, wherein more recent clinical trials of nonstatin LLTs (ORION-15, ORION-18, and HUA TUO) and additional data on monthly dosing regimens for PCSK9 mAbs were included. The outcome of interest was percentage change in LDL-C at week 24. Random-effects Bayesian NMA was performed. Comparative efficacy was estimated as mean difference (MD) with 95% credible intervals (CrIs). A total of 20 trials were deemed relevant for the NMA. Consistent with the previous findings from our NMA, this study demonstrated that inclisiran provided superior efficacy in LDL-C lowering compared with ezetimibe and bempedoic acid (MD: −44.24 [95% CrI: −51.84 to −36.70]). This NMA further reaffirmed that inclisiran provided comparable LDL-C reduction versus alirocumab (MD: −1.93% [95% CrI: −8.56 to 4.20]) and evolocumab (MD: 2.00% [95% CrI: −4.58 to 8.60]) among patients with ASCVD and/or high CV risk on MTD statins.