OBJECTIVES: To update the published network meta-analysis (NMA) from Burnett et al. 2022 comparing the efficacy of non-statin lipid-lowering therapies inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or increased cardiovascular risk having elevated low-density lipoprotein cholesterol (LDL-C) despite taking maximally-tolerated dose statins.

METHODS: A systematic review was conducted using OvidSP (MEDLINE and Embase), Cochrane (Wiley), Pubmed, and Web of Science databases to identify more recently published randomized controlled trials through January 2023. The primary outcome of interest was the percentage change in LDL-C from baseline to week 24 (or closest available time point). A random-effects Bayesian NMA was performed to estimate the mean differences (MD) and 95% credible intervals (CrI) for the included therapies.

RESULTS: A total of 20 studies were included in the analysis (inclisiran: 4 studies, evolocumab: 5 studies, alirocumab: 8 studies, ezetimibe: 2 studies, bempedoic acid: 3 studies, bempedoic acid + ezetimibe: 1 study). Inclisiran, evolocumab, and alirocumab delivered superior efficacy over placebo, bempedoic acid, and ezetimibe in reducing LDL-C from baseline at week 24. In particular, inclisiran provided statistically significant benefit over bempedoic acid, ezetimibe, and bempedoic acid + ezetimibe (MD: -44.24% [95% CrI: -51.84, -36.70], MD: -35.66% [95% CrI: -43.10, -28.49], and MD: -20.79% [95% CrI: -33.69, -7.98], respectively). There was no significant difference in LDL-C reduction between inclisiran and PCSK9 inhibiting monoclonal antibodies. (vs. alirocumab, MD: -1.93% [95% CrI: -8.56, 4.20]; vs. evolocumab, MD: 2.00% [95% CrI: -4.58, 8.60]).

CONCLUSIONS: This updated NMA reaffirms that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in LDL-C in patients with hypercholesterolemia on maximally-tolerated statins who are at increased cardiovascular risk; while they delivered superior efficacy over placebo, bempedoic acid, and ezetimibe in reducing LDL-C.