Lp(a) predicts cardiovascular risk in women only when total cholesterol is high, an analysis of over 24,000 Women's Health Study participants plus WHI and JUPITER cohorts (J Am Coll Cardiol 2018)

Original title: Lipoprotein(a) and Cardiovascular Risk Prediction Among Women

J Am Coll Cardiol · 9 July 2018 · 8

Cook NR, Mora S, Ridker PM

This study examined Lp(a) association with incident cardiovascular disease (CVD) and its value for risk prediction in women, using the Women's Health Study (WHS, N=24,558), a case-cohort sample from the Women's Health Initiative (WHI, 1,815 cases, subcohort 1,989), the JUPITER trial (women n=2,569), and men from JUPITER (n=5,161). In the WHS, a curvilinear association showed increased CVD risk with Lp(a) above 50 mg/dL, but only among women with total cholesterol above 220 mg/dL; adding Lp(a) produced a small but significant change in the C-statistic (0.790 to 0.797, P=0.035) with no improvement in reclassification measures, a pattern replicated in the WHI and JUPITER women's cohorts. In contrast, Lp(a) showed a strong association with CVD among men with low total cholesterol in JUPITER. The findings show Lp(a) is associated with CVD in women only when total cholesterol is high, with minimal improvement in risk prediction, informing how Lp(a) should be used in clinical practice and Lp(a)-lowering trials for women.

Original abstract

Background: Although lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial.

Objectives: This study examined the association and clinical utility of Lp(a) with incident CVD in women.

Methods: A turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women's Health Study] [N = 24,558], a case-cohort sample from the WHI [Women's Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification.

Results: In the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER.

Conclusions: In 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.