Lipoprotein(a) and risk of peripheral arterial disease, abdominal aortic aneurysms, and major adverse limb events

Abstract

Abstract Background Lipoprotein(a) lowering therapy to reduce atherosclerotic cardiovascular disease is currently under investigation in clinical trials, but lipoprotein(a) may also be implicated in peripheral arterial disease (PAD), abdominal aortic aneurysms (AAA), and major adverse limb events (MALE). Yet, data from general population studies are limited, and large studies are needed to determine risk in individuals with the highest lipoprotein(a). Purpose 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 We included 108,146 individuals from a contemporary prospective cohort study of the general population. During a median follow-up of 8.6 years, 2,450 developed PAD, 1,251 AAA, and 489 MALE. We used a historic prospective cohort study of the general population (N=10,960) to replicate findings for MALE (N=116). Results High lipoprotein(a) levels and corresponding LPA risk genotypes were associated with increased risk of PAD and AAA (Figure 1). For individuals with lipoprotein(a) levels in the 100th percentile (≥143mg/dL, ≥307nmol/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 <50th percentile (≤9mg/dL, ≤17nmol/L). For individuals with peripheral arterial disease, corresponding hazard ratios for MALE were 2.70 (1.67-4.37) in the contemporary cohort, 8.12 (3.56-18.55) in the historic cohort, and 3.31 (2.21-4.95) in the two cohorts combined. The absolute 10-year risk of PAD and/or AAA increased with higher age and lipoprotein(a) level for both men and women and in smokers and non-smokers (Figure 2). The absolute risk increase conferred by high (100th percentile) versus low (<50th percentile) lipoprotein(a) was 2-3-fold in all categories of age, sex, and smoking status. Absolute 10-year risks were 23% and 9% in smoking women aged 70-79 years with lipoprotein(a) in the 100th percentile versus <50th percentile, and equivalent values in men were 38% and 15%. The percentage of events attributable to lipoprotein(a) >50th percentile was 11.6% for PAD and 15.0% for AAA. Conclusion High lipoprotein(a) levels increased risk of PAD, AAA, and MALE by 2-3-fold in the general population, opening opportunities for prevention given future lipoprotein(a) lowering therapies.Figure 1Figure 2