High lipoprotein(a) and high BMI jointly confer the highest risk of ASCVD in both primary and secondary prevention

Aims Novel pharmaceuticals lower body mass index (BMI) and reduce risk of atherosclerotic cardiovascular disease (ASCVD), yet treatment indications for BMI 27–30 kg/m² require additional risk factors. High lipoprotein(a), present in one in five individuals, is a risk factor for ASCVD not included in overweight treatment guidelines. We hypothesized that high lipoprotein(a) and BMI jointly confer the highest risk of ASCVD. Methods and results Prospective cohort study of 512 687 women and men without and 14 161 with ASCVD from the Copenhagen General Population Study (CGPS) and the UK Biobank. During follow-up, 39 255 and 3501 developed ASCVD in primary and secondary prevention. In primary prevention, hazard ratios for ASCVD for individuals with high lipoprotein(a) (95th–100th percentile) and BMI > 30 were 1.97 (95% CI:1.61–2.40) in the CGPS and 2.19 (2.01–2.37) in the UK Biobank when compared to low lipoprotein(a) (1st–49th percentile) and BMI of 18.5–26.9 kg/m². Absolute risks were higher for concomitant high lipoprotein(a) and BMI 27–30 kg/m² than for BMI > 30 kg/m² and low lipoprotein(a), with 10-year absolute risks for ages 70–79 of 25% in women and 41% in men for lipoprotein(a) 95th–100th percentiles and BMI 27–30 kg/m², and correspondingly 17% and 28% for lipoprotein(a) 1st–49th percentiles and BMI > 30 kg/m². In secondary prevention, overall results were similar, with higher risks for individuals with high lipoprotein(a) and BMI 18.5–26.9 kg/m², than for BMI ≥ 27 kg/m2 and low lipoprotein(a). Conclusion High lipoprotein(a) and high BMI jointly confer the highest risk of ASCVD in primary and secondary prevention. Lay summary New medications that lower body weight also reduce the risk of heart disease, but current guidelines only recommend them for people with a body mass index (BMI) between 27 and 30 kg/m² if they have risk factors for heart disease. High levels of lipoprotein(a), a cholesterol particle in the blood, are a risk factor for heart disease, present in 1 out of 5, which is not included in these guidelines. This study investigated whether having both high lipoprotein(a) and high BMI increases the risk of heart disease more than either factor alone.In two general population cohorts, including 526 848 women and men, both with and without prior heart disease, those with high lipoprotein(a) and high BMI had the highest risk of heart disease.Individuals with high lipoprotein(a) and BMI between 27 and 30 kg/m² had a higher risk of heart disease than those with BMI above 30 kg/m² and low lipoprotein(a), supporting that high lipoprotein(a) could be considered when deciding on weight-lowering treatment for people with BMI between 27 and 30 kg/m².