Sources of Heterogeneity in the Efficacy of Statins for Primary Prevention of Cardiovascular Diseases: A Systematic Review with Meta-Regression and Meta-Analysis of Within-Study Subgroup Differences.

PURPOSE: Evidence regarding sources of heterogeneity in the efficacy of statins for primary prevention of cardiovascular disease (CVD) remains limited. This study aimed to identify trial-level factors contributing to such heterogeneity. METHODS: Relevant studies were systematically identified from a previous systematic review and through searches in PubMed, Embase, and Cochrane up to 20 January 2026. The protocol was registered in PROSPERO (CRD42024579932). Randomized controlled trials (RCTs) in adults without prior CVD that investigated statin treatment were included. Risk of bias was assessed using the Cochrane Risk of Bias tool. Meta-analyses were conducted to pool risk ratios (RRs) and 95% confidence intervals (CIs) for major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and cardiovascular death. Univariate meta-regression analyses were conducted to assess the impact of trial-level covariates on the effect sizes, expressed as the ratio of risk ratios (RRR). Within-study subgroup differences were meta-analyzed by pooling ratio of effect sizes. Meta-regression analyses were conducted using complete-case trial-level data. RESULTS: 25 RCTs (102,667 participants) were included. Compared to no statin treatment, statin treatment was associated with a reduced risk of MACE (RR, 0.73[95% CI, 0.67 to 0.80], P < 0.001), MI (RR, 0.68[95% CI, 0.60 to 0.77], P < 0.001), stroke (RR, 0.76[95% CI, 0.65 to 0.89], P = 0.001) and cardiovascular death (RR, 0.81[95% CI, 0.71 to 0.95], P = 0.008). Univariate meta-regression indicated that higher baseline total cholesterol (RRR, 1.29 [95% CI, 1.07 to 1.57], P = 0.008), higher low-density lipoprotein cholesterol (LDL-C) (RRR, 1.31 [95% CI, 1.07 to 1.62], P = 0.010), higher triglycerides (RRR, 1.81 [95% CI, 1.17 to 2.81], P = 0.008) and lower statin intensity (RRR, 0.74 [95% CI, 0.59 to 0.94], P = 0.015) were significantly associated with reduced efficacy of statins for stroke prevention at the trial level. CONCLUSIONS: Statin therapy demonstrated consistent efficacy in CVD prevention across diverse populations, except that baseline lipid profiles and statin intensity may represent exploratory, hypothesis-generating signals of potential effect modification for stroke prevention, warranting further investigation.