Factorial Mendelian randomization of lipoprotein (a) lowering, low-density lipoprotein cholesterol lowering, and lifestyle improvements: joint associations with cardiovascular risk.

Background: High levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease (CVD); however, the effects of Lp(a)-lowering therapy in combination with low-density lipoprotein cholesterol (LDL-C)-lowering treatment or lifestyle improvements on CVD risk remain unexplored.

Methods: We conducted a factorial Mendelian randomization study among 385 917 participants in the UK Biobank. Separate genetic scores were constructed to proxy the effects of Lp(a) lowering, LDL-C lowering through different targets [HMG-CoA reductase, NPC1-like intracellular cholesterol transporter 1, proprotein convertase subtilisin/kexin Type 9, and low-density lipoprotein receptor (LDLR)], as well as improvements in body mass index (BMI), systolic blood pressure (SBP), and lifestyle factors (cigarette smoking, alcohol consumption, and physical activity).

Results: Genetically predicted lower Lp(a) levels were associated with a decreased risk of CVD and CVD-specific mortality. Per 50-mg/dl, the hazard ratio ranged from 0.73 [95% confidence interval (CI): 0.73, 0.73] for peripheral artery disease (PAD) to 0.95 (95% CI: 0.92, 0.99) for venous thromboembolism. In factorial analyses exploring combined exposure to low-level Lp(a) and low-level LDL-C, there was no consistent evidence for departure from an additive model for any outcome (Pinteraction > .05), with the exception of the analysis using the LDLR score and PAD (Pinteraction = .006). In factorial analyses exploring combination therapies integrating Lp(a) lowering with interventions on BMI, SBP, and lifestyle factors, there was no evidence for departure from an additive model in any analysis (Pinteraction > .05).

Conclusions: Our study suggests that Lp(a) lowering will have a similar magnitude for reducing cardiovascular events whether it is considered alone, or in conjunction with LDL-C reduction or lifestyle improvements.