Lipoprotein(a) lowering and risk of cardiovascular disease in primary and secondary prevention

Background and aims High lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease, and therapies lowering lipoprotein(a) by up to 98% are in phase 3 trials. However, the clinical benefit of lipoprotein(a) reduction remains uncertain. We estimated the effect of lipoprotein(a) lowering on major adverse cardiovascular events (MACE) in the context of ongoing trials and in hypothetical primary prevention trials. Methods Using real-world data from two large general population based cohorts (n=522,494), we constructed sub-cohorts mimicking Lp(a)HORIZON, ACCLAIM-Lp(a), and OCEAN(a), and hypothetical primary prevention trials across combinations of conventional cardiovascular risk factors and lipoprotein(a) inclusion thresholds (≥70, ≥82, or ≥94 mg/dL). High lipoprotein(a) was compared with 80% or 98% lower levels to simulate pharmacologic reduction. The outcome was 5-year MACE (myocardial infarction, ischemic stroke, coronary revascularization, or coronary death). Results In ongoing trials, 5-year absolute risk reductions were 2.3%(95% CI -0.5%-5.1%; p=0.16) in Lp(a)HORIZON, 3.4%(1.0%-5.9%; p=0.0003) in ACCLAIM-Lp(a), and 3.7%(1.0%-6.5%; p=0.008) in OCEAN(a), with corresponding hazard ratios 0.86(0.69–1.07), 0.74(0.63–0.87), and 0.76(0.61–0.93). In primary prevention trials, absolute risk reductions ranged 1.1%–4.2%, increasing with additional baseline risk factors and with more potent lowering, while hazard ratios were similar across lipoprotein(a) inclusion thresholds and number of baseline risk factors, ranging 0.53-0.71 for 80% lowering and 0.43-0.57 for 98%. Conclusion Using real-world data, lipoprotein(a) lowering was associated with clinically meaningful reductions in 5-year MACE risk in both ongoing trials and in hypothetical primary prevention settings, supporting ongoing trials and informing design of future primary prevention trials.