Sex differences and sex-specific associations between Lipoprotein(a) and risk of cardiovascular outcomes in primary prevention: a systematic review and meta-analysis

Background Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, whether the magnitude of Lp(a)-associated risk differs between women and men remains uncertain. Purpose To evaluate sex differences and sex-specific associations between Lp(a) levels and cardiovascular outcomes. Methods We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. PubMed, Embase and Scopus were searched to 20 February 2026 for longitudinal studies reporting sex-specific associations between Lp(a) and cardiovascular outcomes. Fully adjusted hazard ratios (HRs) were pooled separately for women and men using random-effects models (REML), with heterogeneity assessed by I². Analyses were prespecified according to Lp(a) definition: high-risk cut-offs (≥50 mg/dL or ≥125 nmol/L) and percentile-based comparisons (highest versus lowest categories). The primary outcome was composite ASCVD; secondary outcomes were stroke and coronary heart disease (CHD). Sex differences were assessed by pooling the between-sex difference in log-transformed HRs and exponentiating summary estimates to derive the ratio of hazard ratios (RHR). Results Twenty-four studies met the inclusion criteria, and eleven were included in the meta-analysis. For the primary ASCVD composite, elevated Lp(a) defined by high-risk cut-offs was associated with increased risk in both men (HR 1.38, 95% CI 1.14–1.66; I²=77.5%) and women (HR 1.40, 95% CI 1.04–1.87; I²=64.1%), without significant sex differences (RHR 1.11, 95% CI 0.81–1.51; I²=50.2%). In percentile-based analyses, ASCVD risk was similarly increased in men (HR 1.38, 95% CI 1.07–1.78; I²=90.2%) and women (HR 1.37, 95% CI 1.08–1.74; I²=90.2%); an initial modest sex difference was not sustained after sensitivity analysis excluding one influential study (RHR 0.97, 95% CI 0.85–1.11; I²=0%). Elevated Lp(a) was also associated with higher stroke risk in men (HR 1.83, 95% CI 1.06–3.16; I²=63.5%) and women (HR 1.44, 95% CI 1.12–1.85; I²=34.2%), without significant sex difference (RHR 0.73, 95% CI 0.39–1.35; I²=50.7%). For CHD, elevated Lp(a) was associated with higher risk in both sexes (men HR 1.89, 95% CI 1.09–3.28; women HR 1.59, 95% CI 1.08–2.33), with a significantly stronger association in men (RHR 0.76, 95% CI 0.61–0.95; I²=0%). Conclusion Elevated Lp(a) is associated with increased ASCVD risk in both women and men, with no consistent evidence of sex differences across Lp(a) definitions. These findings support a broadly similar clinical interpretation of elevated Lp(a) in both sexes and reinforce its role as a genetically determined, independent risk factor that should be incorporated into preventive cardiovascular risk assessment. The stronger association observed for CHD in men should be interpreted with caution and considered hypothesis-generating.