Background and Aims

Background: Lipoprotein(a) may be implicated in peripheral arterial disease (PAD) and abdominal aortic aneurysms (AAA), yet data from general population studies are limited, and large studies are needed to determine risk in individuals with the highest levels and associated risk of major adverse limb events (MALE).

Aims: To test whether high lipoprotein(a) levels associate with increased risk of PAD, AAA, and MALE, and to provide genetic evidence of causality using LPA genotypes.

Methods

Methods: We included 108,146 individuals from the contemporary Copenhagen General Population Study (CGPS). During follow-up, 2,450 developed PAD, 1,251 AAA, and 489 MALE. We used the historic Copenhagen City Heart Study (CCHS, N=10,960) to replicate findings for MALE (N=116).

Results

Results: High lipoprotein(a) levels and corresponding LPA risk genotypes associated with increased risk of PAD and AAA in the CGPS (Figure 1). For individuals with lipoprotein(a) levels >99^th percentile (≥143mg/dL,≥306nmol/L), multivariable adjusted hazard ratios were 2.99(95% confidence interval:2.09-4.30) for PAD and 2.22(1.21-4.07) for AAA compared to individuals with levels <50^th percentile (≤9mg/dL,≤17nmol/L). Corresponding hazard ratios for MALE were 2.70(1.67-4.37) in the CGPS and 8.12(3.56-18.55) in the CCHS. Absolute 10-year risks of PAD and/or AAA were 11% and 29% in smoking women aged 70-79 years with lipoprotein(a) <50^th vs. >99^th percentile. Equivalent values in men were 19% and 47%. The percentage of events attributable to lipoprotein(a) >50^th percentile was 9.5% and 12.3% for PAD and AAA.

Conclusions

Conclusion: High lipoprotein(a) levels increased risk of PAD, AAA, and MALE in the general population, opening opportunities for prevention given future lipoprotein(a) lowering therapies.