Very high Lp(a) levels associated with increased 30-year CVD risk in healthy women

In a prospective cohort study, increasing Lp(a) levels at baseline were associated with increased 30-year risks of MACE and CHD in healthy US women. However, higher cumulative risks of ischemic stroke and CV death were only seen for very high Lp(a) levels.

This summary is based on the publication of Nordestgaard AT, Chasman DI, Moorthy V, et al. - Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a). JAMA Cardiol. 2026 Jan 7:e255043 [Online ahead of print]. doi: 10.1001/jamacardio.2025.5043

Introduction and methods

Background

Elevated Lp(a) levels are a strong, independent, and lifelong risk factor for CVD [1-3]. Previously, a prospective cohort study based on data from the Women’s Health Study showed that the incidence of CV events over 30 years increased gradually across quintiles of baseline LDL-c and hs-CRP levels in healthy US women [4]. However, only the highest Lp(a) quintile was predictive of 30-year CVD risk.

Aim of the study

The study aim was to further examine the clinical utility of Lp(a) levels as a predictor of long-term CVD risk in healthy women.

Methods

For this cohort study, data were collected from female health professionals aged ≥45 years who were enrolled in the Women’s Health Study and were followed up prospectively from 1993 to 2023 [5,6]. Exclusion criteria were a history of CVD, cancer, or other major chronic illnesses. Women with available baseline plasma Lp(a) measurements (n=27,748) and/or genotype information on single-nucleotide variants (including in LPA rs3798220) were included in the current analysis. To limit known ancestry-related genotype–phenotype heterogeneity at the LPA locus, only women with genetically verified European ancestry were included in analyses of the LPA rs3798220 variant (n=23,179). Median follow-up time in the entire cohort was 27.8 years (IQR: 22.8–29.4).

Outcomes

The primary endpoint was the first occurrence of MACE, a composite outcome of incident MI, coronary revascularization, incident ischemic stroke, or CV death. Secondary endpoints were CHD, including fatal and nonfatal MI and coronary revascularization, fatal and nonfatal ischemic stroke, and CV death.

Main results

Major adverse cardiovascular events

• Cox proportional hazards regression analysis adjusted for possible confounders indicated that women with Lp(a) ≥30 mg/dL at baseline had a higher 30-year risk of MACE compared with those with Lp(a) <30 mg/dL, with a stepwise cumulative risk increase with increasing Lp(a) levels (P for trend<0.01).
• A similar increase in cumulative MACE risk was observed for Lp(a) >75th percentile (≥33 mg/dL) versus Lp(a) ≤75th percentile (<33 mg/dL).
• The age-adjusted HR for women with Lp(a) ≥120 mg/dL compared with those with Lp(a) <10 mg/dL was 1.75 (95%CI: 1.42–2.17), whereas that for Lp(a) >99th percentile (≥131 mg/dL) versus Lp(a) ≤50th percentile (<11 mg/dL) was 1.98 (95%CI: 1.54–2.53).
• The multivariable adjusted HR for Lp(a) ≥120 mg/dL versus <10 mg/dL was 1.54 (95%CI: 1.24–1.92), whereas that for >99th percentile versus ≤50 percentile was 1.74 (95%CI: 1.35–2.25).

Coronary heart disease

• A stepwise increase in the cumulative incidence of CHD was observed starting from the Lp(a) clinical threshold of 30 mg/dL or the 76th Lp(a) percentile.
• The multivariable-adjusted HR for Lp(a) ≥120 mg/dL versus <10 mg/dL was 1.80 (95%CI: 1.36–2.37), and that for >99th percentile versus ≤50 percentile was 2.06 (95%CI: 1.49–2.84).

Ischemic stroke and cardiovascular death

• For ischemic stroke and CV death, only very high Lp(a) levels (≥120 mg/dL or >99th percentile) were associated with increased 30-year risks compared with the respective reference groups.
• Multivariable-adjusted HRs for Lp(a) ≥120 mg/dL versus <10 mg/dL were 1.41 (95%CI: 0.93–2.15) for ischemic stroke and 1.63 (95%CI: 1.16–2.28) for CV death.
• Multivariable-adjusted HRs for >99th percentile versus ≤50 percentile were 1.85 (95%CI: 1.17–2.93) for ischemic stroke and 1.86 (95%CI: 1.26–2.75) for CV death.

Cardiovascular disease risk across rs3798220 genotypes

• Of the 23,179 women of European ancestry with rs3798220 genotype information, 22,349 (96.4%) were homozygous for the major allele, whereas 817 (3.5%) were heterozygous for the Lp(a)-increasing minor allele.
• The 30-year risk of MACE was higher for heterozygous carriers of the minor allele than homozygous carriers of the major allele (age-adjusted HR: 1.27; 95%CI: 1.07–1.51).

Conclusion

In this prospective cohort study among ~28,000 healthy US women, increasing Lp(a) levels (≥30 mg/dL or >75th percentile) at baseline were associated with increased 30-year risks of MACE and CHD. However, higher cumulative risks of ischemic stroke and CV death were only seen for very high Lp(a) levels (≥120 mg/dL or >99th percentile). Furthermore, women of European ancestry carrying the Lp(a)-increasing minor allele of the LPA rs3798220 variant had a higher 30-year MACE risk than homozygous carriers of the major allele.

The authors believe their findings “support the case for screening for elevated Lp(a) among healthy individuals [...]. Most importantly, such screening could help identify individuals with very high Lp(a) levels, as these individuals may benefit from primary preventive efforts, including possible future Lp(a)-lowering therapies.”

Find this article online at JAMA Cardiol.

References

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