Associations of Very Low Lipoprotein(a) Levels With Risks Of New-Onset Diabetes And Non-Alcoholic Liver Disease

Background and aims We aimed to study the association of very low serum Lipoprotein(a) [Lp(a)] concentrations with new-onset type 2 diabetes (T2D) and non-alcoholic liver disease (NAFLD) in the context of statin usage in the UK Biobank, a large prospective population cohort. Methods Using an extended biomarker dataset, we identified 47,362 participants with very low Lp(a) concentrations (<3.8 nmol/L) from a total of 451,479 participants. With a median follow-up of 12.3 years, we assessed the risk of new-onset cardiometabolic diseases in participants stratified by statin usage with Cox proportional hazards models. We performed two-sample Mendelian randomization MR analyses to test causal relationship between genetically predicted Lp(a) and T2D and NAFLD. Results Taking the participants with Lp(a) within reportable range as the reference group, the hazard ratios (HR) for T2D were 1.06 (95% confidence interval, CI 1.01-1.12) and for NAFLD 1.35 (95% CI 1.26-1.45) respectively for participants with very low Lp(a) (<3.8 nmol/L). The risk for new-onset T2D was higher in participants using statin (adjusted HR 1.14; 95% CI 1.05-1.24). This was contrasted by higher risk of NAFLD in participants not on statin (HR 1.40; 95%CI 1.28-1.53). There was no evidence for causal links between genetically predicted Lp(a) and T2D nor NAFLD in two-sample MR analyses. Conclusions Very low Lp(a) was associated with higher risks of T2D and NAFLD in a prospective analysis of the UK Biobank. These associations were influenced by lipid lowering medication usage. MR analyses did not support causality for these inverse associations.