Factorial Mendelian randomisation in 385 917 UK Biobank participants finds Lp(a) lowering benefits add to, not multiply, LDL-C and lifestyle effects (Int J Epidemiol 2025)

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

Int J Epidemiol · 16 February 2025 · 8

Wang L, Jiang F, Sun J, Zhao J, He Y, Gill D, Burgess S, Larsson SC, Yuan S, Li X

This factorial Mendelian randomisation study in 385 917 UK Biobank participants used genetic scores to proxy Lp(a) lowering, LDL-C lowering via four separate pathways (HMG-CoA reductase, NPC1L1, PCSK9, LDLR), and improvements in BMI, blood pressure and lifestyle. Genetically predicted lower Lp(a) was associated with reduced cardiovascular disease and cardiovascular mortality, with hazard ratios per 50 mg/dL lower Lp(a) ranging from 0.73 for peripheral artery disease to 0.95 (95% CI 0.92-0.99) for venous thromboembolism. Combining low Lp(a) with low LDL-C or with favourable lifestyle showed no consistent departure from a simple additive model for any outcome (P for interaction > 0.05 in nearly all analyses), with one exception for the LDLR score and peripheral artery disease (P for interaction = 0.006). The results suggest Lp(a)-lowering therapy should deliver a similar relative cardiovascular benefit whether given alone or alongside LDL-C-lowering and lifestyle interventions.

Original abstract

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.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.