Low-density lipoprotein cholesterol lowering and risk of major adverse cardiovascular events in primary prevention trials: A meta-analysis
Dinesh Kalra, Kausik K. Ray, Archna Bajaj, Pamela Kushner, Meredith L. Wilcox, Mary R. Dicklin, Carol F. Kirkpatrick, Kevin C. Maki
Abstract
BACKGROUND: Analyses of statin trials by the Cholesterol Treatment Trialists' Collaboration have suggested larger relative risk reduction (RRR) for major adverse cardiovascular events (MACE) per 1 mmol/L (38.7 mg/dL) low-density lipoprotein cholesterol (LDL-C) lowering in primary prevention than in secondary prevention. However, controversy remains about the value of LDL-C lowering in primary prevention. OBJECTIVE: This meta-analysis examined the relationship between LDL-C reduction and MACE risk in primary prevention with statin and nonstatin LDL-C-lowering therapies in cardiovascular outcomes trials (CVOTs). METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched from inception through August 26, 2025. The primary endpoint was the pooled RRR vs controls for 4-point composite MACE (coronary heart disease death, nonfatal myocardial infarction, fatal and nonfatal stroke, and coronary revascularization) per 1 mmol/L LDL-C lowering. RESULTS: Eleven CVOTs of solely primary prevention participants (n = 74,466) and 3 in which >80% of participants were primary prevention (n = 24,071) were identified (11 statin, 1 bempedoic acid, 1 ezetimibe, 1 statin+ezetimibe). In 13 trials, the pooled mean difference between groups in LDL-C reduction was 1.00 mmol/L (95% CI: 0.82-1.18 mmol/L) with a pooled estimate of 30% (relative risk: 0.70; 95% CI: 0.67-0.74) RRR for 4-point MACE per 1 mmol/L LDL-C reduction vs control. CONCLUSION: In CVOTs of solely or predominantly primary prevention participants, each 1 mmol/L reduction in LDL-C was associated with a 30% RRR in 4-point MACE. These results strengthen the evidence and rationale for the benefits of LDL-C lowering in primary prevention.