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. 2023 Dec 12;82(24):2265-2276.
doi: 10.1016/j.jacc.2023.10.009.

Lipoprotein(a) and Risks of Peripheral Artery Disease, Abdominal Aortic Aneurysm, and Major Adverse Limb Events

Peter E Thomas  1 , Signe Vedel-Krogh  1 , Sune F Nielsen  2 , Børge G Nordestgaard  1 , Pia R Kamstrup  3
Affiliations
Free article

Lipoprotein(a) and Risks of Peripheral Artery Disease, Abdominal Aortic Aneurysm, and Major Adverse Limb Events

Peter E Thomas et al. J Am Coll Cardiol. .
Free article

Abstract

Background: Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE).

Objectives: The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE.

Methods: The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study.

Results: Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men.

Conclusions: High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies.

Keywords: abdominal aortic aneurysm; lipoprotein(a); lower-extremity amputation; major adverse limb event; peripheral artery disease.

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Conflict of interest statement

Funding Support and Author Disclosures The study was founded by the Department of Clinical Biochemistry, Copenhagen University Hospital–Herlev and Gentofte, Gangstedfonden, and was supported by a research grant from the Danish Cardiovascular Academy (grant number 2022007-HF), which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and The Danish Heart Foundation. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the paper, or decision to submit the manuscript for publication. Dr Nordestgaard has consultancies with Abbott, Akcea, Amarin, Amgen, AstraZeneca, Denka, Esperion, Kowa, Lilly, Mankind, Novartis, Novo Nordisk, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx. Dr Kamstrup has lecture honoraria or consultancies from Physicians’ Academy for Cardiovascular Education, PCSK9 Forum, Silence Therapeutics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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