Alirocumab lowers both Lp(a) and LDL-C but they pull new-onset diabetes risk in opposite directions, cancelling out net effect, ODYSSEY OUTCOMES post-hoc analysis finds (Diabetes Care 2025)

Original title: Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial

Diabetes Care · 1 April 2025 · 8

Schwartz GG, Szarek M, Jukema JW, Cobbaert CM, Reijnders E, Bittner VA, Schwertfeger M, Bhatt DL, Fazio S, Garon G, Goodman SG, Harrington RA et al.

This post-hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402) examined 8,107 patients with recent acute coronary syndrome on optimised statin therapy, without baseline diabetes, randomised to alirocumab or placebo (median follow-up 2.4 years), to disentangle how PCSK9-inhibitor-driven changes in Lp(a) and LDL-C relate to new-onset diabetes (NOD) risk. Lower baseline Lp(a) and higher baseline insulin or HOMA-IR independently predicted the 782 NOD cases observed; baseline LDL-C did not predict NOD. Alirocumab lowered both Lp(a) and LDL-C without affecting insulin or overall NOD risk (OR vs. placebo 0.998, 95% CI 0.860-1.158), but in regression modelling, alirocumab-driven Lp(a) and LDL-C reductions were independent, opposite predictors of NOD: 25% and 50% Lp(a) reductions raised NOD odds (OR 1.12 and 1.24), while equivalent LDL-C reductions lowered them (OR 0.88 and 0.77). The authors conclude these opposing effects cancelled out in the overall trial, and that ongoing trials with larger, more sustained Lp(a) reductions will need to clarify the net diabetes impact of potent Lp(a)-lowering therapies.

Original abstract

Objective: Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD.

Research Design And Methods: In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA-insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models.

Results: Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94).

Conclusions: Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.

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