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

Background

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.

Objective

To evaluate the tolerability and safety profile of non-statin LDL-cholesterol-lowering treatments.

Methods

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.

Results

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.

Conclusion

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.