Comparative Efficacy of Non-Statin 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. Non-statin 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 non-statin 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 non-statin LLTs (ORION-15, ORION-18, 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 interval (CrI). 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, -36.70]). This NMA further reaffirmed that inclisiran provided comparable LDL-C reduction vs. alirocumab (MD: -1.93% [95% CrI: -8.56, 4.20]) and evolocumab (MD: 2.00% [95% CrI: -4.58, 8.60]) among patients with ASCVD and/or high CV risk on MTD statins.