Safety and tolerability of nonstatin LDL-cholesterol-lowering therapies: A systematic review and pairwise meta-analysis of randomized controlled trials.

Authors

Andrea Matteucci, Michela Bonanni, Stefania Angela Di Fusco, Alessandro Aiello, Stefano Aquilani, Silvio Fedele, Federico Nardi, Furio Colivicchi

Published in

Journal of clinical lipidology. Sep 21, 2026. Epub Sep 21, 2026.

Abstract

Nonstatin low-density lipoprotein (LDL)-cholesterol-lowering therapies are increasingly used in secondary prevention, familial hypercholesterolemia, and statin-intolerant patients, but adverse-event reporting is heterogeneous, and harmonized safety evidence remains limited.
To evaluate the tolerability and safety profile of non-statin LDL-cholesterol-lowering treatments.
We performed a systematic review and pairwise meta-analysis of randomized, double-blind, placebo-controlled trials of ezetimibe, proprotein convertase subtilisin/kexin type 9 monoclonal antibodies, bempedoic acid, and inclisiran. Prespecified tolerability outcomes were any adverse event, serious adverse event, discontinuation because of adverse events, and investigator-attributed drug-related adverse events. Safety outcomes included myalgia, muscle-related and hepatic adverse events, aminotransferase elevation greater than 3 times the upper limit of normal, and neurocognitive adverse events. Random-effects Mantel-Haenszel models estimated risk ratios (RRs) with 95% CIs using restricted maximum likelihood and Hartung-Knapp adjustment.
The primary synthesis included 41 trial-level comparisons and 104,672 participants. Nonstatin LDL-cholesterol-lowering therapy was not associated with any adverse event (RR 1.003, 95% CI 0.991-1.015) or serious adverse event (RR 0.980, 0.946-1.015), but discontinuation because of adverse events (RR 1.084, 1.020-1.152) and investigator-attributed drug-related adverse events (RR 1.227, 1.120-1.344) were modestly increased. No significant pooled associations were observed for myalgia, muscle-related, hepatic, aminotransferase, or neurocognitive adverse events. The only class-specific finding remaining significant after false-discovery-rate correction was lower myalgia risk in adenosine triphosphate citrate lyase-inhibitor trials (RR 0.845, 0.769-0.927), attenuated after excluding CLEAR outcomes.
Nonstatin LDL-cholesterol-lowering therapies were not associated with excess total or serious adverse events or consistent muscle, hepatic, or neurocognitive safety signals. Modest excesses were confined to tolerability-related outcomes (discontinuation because of adverse events and investigator-attributed drug-related adverse events) rather than major toxicity.

PMID:
42844101
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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