Impact of Lipid-Lowering Combination Therapy With Statins and Ezetimibe vs Statin Monotherapy on the Reduction of Cardiovascular Outcomes: A Meta-analysis

Abstract

Objective: To evaluate the efficacy of combination lipid-lowering therapy (LLT) compared with statin monotherapy for low-density lipoprotein cholesterol (LDL-C) reduction, associated adverse events, and outcomes.

Methods: A systematic literature search was conducted using PubMed, Embase, and ClinicalTrials.gov to identify relevant articles published from inception until the end of June 2024. The outcomes were assessed using pooled odds ratios (ORs) for categorical data and mean difference for continuous data, with corresponding 95% CIs.

Results: A total of 14 studies (11 randomized controlled trials and 3 cohort studies) with 108,373 very high-risk patients were included in the final analysis. The mean age of the patients in the combination LLT group and the statin monotherapy group was 67.31 and 67.89 years, respectively. Pooled analysis revealed that combination LLT significantly more effectively reduced the LDL-C level from baseline (mean difference, -12.96 mg/dL; 95% CI, -17.27 to -8.65; P<.001) and significantly reduced all-cause mortality (OR, 0.81; 95% CI, 0.67 to 0.97; P=.02), major adverse cardiovascular events (OR, 0.82; 95% CI, 0.69 to 0.97; P=.02), and stroke incidence (OR, 0.83; 95% CI, 0.75 to 0.91; P<.001), with an insignificant effect on cardiovascular mortality (OR, 0.86; 95% CI, 0.65 to 1.12; P=.26) when compared with statin monotherapy. The risk of adverse events and the therapy discontinuation rate were comparable between groups.

Conclusion: Combination LLT was associated with an overall greater reduction in LDL-C, the same risk of adverse effects, and significantly lower risk of all-cause mortality, major adverse cardiovascular events, and stroke compared with statin monotherapy. Forthcoming guidelines should consider the lipid-lowering combination therapy as early as possible, preferably up-front, for more effective LDL-C goal achievement and significant reduction of cardiovascular disease outcomes and mortality in high- and very high-risk patients.