Lp(a) and Incident CVD in Women

Study Questions:

Is there an association between lipoprotein(a) [Lp(a)] and incident cardiovascular disease (CVD), which is clinically meaningful?


Lp(a) was measured in three cohorts of women: the WHS (Women’s Health Study) included 24,558 women, the WHI (Women’s Health Initiative) Observational Study included a case-cohort sample of 1,815 cases and as subcohort of 1,989 controls, and the JUPITER (Justification for Use of Statins in Prevention) trial included 2,569 women. A sample of 5,161 men from JUPITER was also included in this study for the validation models. A derivation sample of 16,400 from WHS was used to examine the association of Lp(a) with incident CVD. This was then tested in WHS validation data (n = 8,158) and the other study samples. The primary outcome of interest was incident CVD. Models included traditional CV risk factors with and without Lp(a) to examine risk reclassification.


Among the 24,558 women in the full WHS sample, the average age was 54 years, 11% were current smokers, and 2% had diabetes at baseline. Mean values of total and high-density lipoprotein (HDL) cholesterol were 211 and 54 mg/dl, respectively. The distribution of Lp(a) was highly skewed, with a median of 10.5 mg/dl (25th, 75th percentiles: 4.4, 32.3 mg/dl). Age, percent black, and systolic blood pressure increased with Lp(a) level, as did total cholesterol, LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein. Use of hormone therapy was highest in those at the lowest Lp(a) level. HDL cholesterol and apolipoprotein A1 were not associated with Lp(a). A curvilinear association was observed in WHS, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol >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 total cholesterol levels in JUPITER.


The authors concluded that in three cohorts of women, Lp(a) was associated with CVD only among those with high total cholesterol, 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.


These data suggest that Lp(a) may have less clinical utility among women compared to men. However, the generalizability of these findings to nonwhite populations is limited given these cohorts are predominantly white.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Smoking

Keywords: Apolipoprotein A-I, Apolipoproteins C, Blood Pressure, Cardiovascular Diseases, Cholesterol, HDL, C-Reactive Protein, Diabetes Mellitus, Experimental, Lipoprotein(a), Primary Prevention, Risk Factors, Smoking, Women

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