Mitigating Atherosclerotic Cardiovascular Disease Risk in Individuals with Elevated Lipoprotein(a): The Role of Modifiable Risk Factors

ImportanceLipoprotein(a) [Lp(a)] is a primarily hereditary lipid linked to an increased risk of atherosclerotic cardiovascular disease (ASCVD). Currently, there are no pharmacological treatments specifically targeting elevated Lp(a) to reduce ASCVD risk. ObjectiveTo examine whether achieving optimal levels of modifiable risk factors could attenuate the ASCVD risk associated with elevated Lp(a). Design, Setting, and ParticipantsProspective cohort analysis of 289,186 ASCVD-free participants from the UK Biobank, including 57,813 individuals with elevated circulating Lp(a) and 231,373 individuals with non-elevated Lp(a) (control group). Findings were further validated in the ARIC study. ExposuresElevated Lp(a) was defined as either the highest ethnicity-/race-specific quintile of circulating Lp(a) levels or based on an Lp(a) polygenic risk score (PRS). Modifiable risk factor within target ranges included body mass index, diet quality, physical activity, smoking status, sleep duration, blood pressure, glycemic control, and low-density lipoprotein cholesterol (LDL-C). Main Outcomes and MeasuresThe primary outcome was ASCVD. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsOver a median follow-up of 12.6 years, 12,592 ASCVD events were recorded. Among participants with elevated Lp(a), the risk of ASCVD progressively decreased as the number of modifiable risk factor within target ranges increased. Individuals with 7-8 risk factor within target ranges had a 24% lower risk of ASCVD (HR, 0.76; 95% CI, 0.70-0.82) compared with the control group. The most significant risk factors were smoking, systolic blood pressure, and LDL-C. The beneficial effects of controlling risk factors may be partly mediated through inflammatory pathways. Results were consistent when analyzed using the Lp(a) PRS in the UK Biobank and were confirmed in the ARIC study. Conclusions and RelevanceOptimal management of modifiable risk factors may reduce the excess ASCVD risk associated with elevated Lp(a). These findings underscore the importance of comprehensive risk factor control in individuals with high Lp(a) levels.