High Lp(a) associated with increased risks of peripheral vascular diseases

23/01/2024

In a general Danish population, high Lp(a) levels were associated with 2–3-fold increased risks of peripheral artery disease, abdominal aortic aneurysm, and major adverse limb events.

This summary is based on the publication of Thomas PE, Vedel-Krogh S, Nielsen SF, et al. - Lipoprotein(a) and Risks of Peripheral Artery Disease, Abdominal Aortic Aneurysm, and Major Adverse Limb Events. J Am Coll Cardiol. 2023 Dec 12;82(24):2265-2276. doi: 10.1016/j.jacc.2023.10.009

Introduction and methods

Background

The association of Lp(a) with risk of coronary heart disease and aortic valve stenosis has been well-described in primary and secondary prevention populations. However, research data, especially those from general population studies, are scarce for peripheral artery disease (PAD) and abdominal aortic aneurysm (AAA). At the same time, current treatment options for late-stage PAD and AAA are limited to surgical interventions, with associated health care costs and morbidity [1,2].

Aim of the study

The authors investigated the association of high plasma Lp(a) levels and corresponding LPA risk genotypes with risk of PAD, AAA, and major adverse limb events (MALE).

Methods

Data were collected for 108,446 individuals from the Copenhagen General Population Study, a Danish, contemporary, prospective cohort study. Lp(a) measurements were available for 70,317 individuals. Risk of MALE was also assessed in 901 individuals with PAD at baseline using data from the historic Copenhagen City Heart Study.

Outcomes

The outcomes were hospital-diagnosed PAD (and/or lower-extremity amputation) and AAA, as well as MALE. The latter was defined as thrombectomy, bypass surgery, stenting of lower-extremity arteries, balloon angioplasty, drug-coated balloon angioplasty, thrombolysis, atherectomy, or lower-extremity amputation.

Main results

Risks of peripheral artery disease and abdominal aortic aneurysm

  • Higher Lp(a) levels were associated with a stepwise increase in risk of incident hospital-diagnosed PAD and AAA (both P for trend<0.001).
  • Observational analyses demonstrated that for individuals with Lp(a) ≥99th percentile (≥143 mg/dL; ≥307 nmol/L) versus <50th percentile (≤9 mg/dL; ≤17 nmol/L), the multivariable-adjusted HR for PAD was 2.99 (95%CI: 2.09–4.30) and that for AAA was 2.22 (95%CI: 1.21–4.07).
  • Genetic analyses also showed increased risks of PAD and AAA in individuals with LPA Kringle IV type 2 number of repeats ≤5th percentile (vs. >50th percentile) and carriers of LPA rs3798220 or LPA rs10455872 (vs. noncarriers).
  • Per 50 mg/dL (105 nmol/L) genetically higher Lp(a), the sex- and age-adjusted causal risk ratio was 1.39 (95%CI: 1.24–1.56) for PAD and 1.21 (95%CI: 1.01–1.44) for AAA. These causal risk estimates were consistent with the observational HRs of 1.33 (95%CI: 1.24–1.43) and 1.27 (95%CI: 1.15–1.41), respectively.
  • For individuals with Lp(a) >50th percentile (>9 mg/dL; >17 nmol/L), the population attributable risk (i.e., percentage of events attributed to this Lp(a) percentile threshold) was 12% for PAD and 15% for AAA.
  • Absolute 10-year risks of PAD and AAA increased with higher age and higher Lp(a) levels in both men and women and in smokers and nonsmokers. For example, the absolute 10-year risk of PAD in a female smoker aged 70–79 years with Lp(a) <50th percentile was 8%, and 21% when she had Lp(a)≥99th percentile. Equivalent 10-year risks in a male smoker aged 70–79 years were 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4%, respectively, in women and 5% and 12%, respectively, in men.

Risk of major adverse limb events

  • In individuals with PAD at baseline, higher Lp(a) levels were associated with increased risk of MALE (P for trend in combined Copenhagen studies=0.006).
  • Among individuals with PAD at baseline, the multivariable-adjusted incidence rate ratio for MALE in those with Lp(a) ≥99th versus <50th percentile was 3.04 (95%CI: 1.55–5.98) in the combined Copenhagen studies.

Conclusion

In these combined Danish general population studies, high Lp(a) levels and corresponding LPA risk genotypes were associated with 2–3-fold increased risks of PAD and AAA. According to the authors, “[t]he inclusion of LPA genotypes enables a strong argument for causality.” In addition, high Lp(a) levels were associated with a 3-fold elevated risk of MALE in individuals with established PAD. The absolute 10-year risk estimates the authors provided for PAD and AAA by Lp(a) level “may, in addition to improved risk stratification, open opportunities for prevention given future Lp(a)-lowering therapy presently in phase III clinical trials.”

References

1. Aboyans V, Ricco J-B, Bartelink M-LEL, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur Heart J. 2017;39:763–816.

2. Sakalihasan N, Michel J-B, Katsargyris A, et al. Abdominal aortic aneurysms. Nat Rev Dis Primers. 2018;4:34.

Find this article online at J Am Coll Cardiol.

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