Background: Scarce evidence exists comparing clinical outcomes of novel lipid-lowering monotherapy with standard statin therapy for primary prevention. We compared clinical outcomes among primary prevention patients treated with novel lipid-lowering monotherapy versus statin monotherapy.
Methods: We performed a retrospective matched cohort study using the TriNetX network comprising 107 predominantly U.S. healthcare organizations. Adults with LDL-C > 100 mg/dL, between 2015 and 2024, and no prior ischemic heart disease, heart failure, cerebral infarction, or peripheral vascular disease were included. Exposure was treatment with evolocumab, alirocumab, or inclisiran without concomitant statins within 1 year of the qualifying LDL-C, compared with initiation of statin monotherapy. Propensity score matching was performed 1:1 across 28 covariates. Follow-up began 7 days after treatment initiation and extended to 2 years. Primary outcomes were all-cause mortality and acute myocardial infarction (AMI). Secondary outcomes included hospitalization, acute heart failure, ventricular tachycardia, atrial fibrillation, cerebral infarction, and MACE.
Results: After matching, 5844 patients remained in each cohort. Median follow-up was 675 days. All-cause mortality (0.8% vs 1.1%; HR 0.79, 95% CI 0.54-1.15) and AMI (0.3% vs 0.3%; HR 1.31, 95% CI 0.65-2.62) were similar between novel therapy and statin cohorts. Hospitalizations, stroke, atrial fibrillation, ventricular tachycardia, and MACE did not differ significantly. Novel therapies were associated with lower acute heart failure events (0.7% vs 1.2%; HR 0.63, 95% CI 0.42-0.93).
Conclusions: Among patients without prior ASCVD, novel lipid-lowering monotherapy achieved comparable short-term outcomes to statin monotherapy, with fewer acute heart failure events, complementing the VESALIUS trial.
Keywords: Cardiovascular medicine; Lipid-lowering; Population health; Prevention.
Copyright © 2026 Elsevier Inc. All rights reserved.