Low-density lipoprotein cholesterol lowering and risk of major adverse cardiovascular events in primary prevention trials: A meta-analysis.

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.