Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes with Alirocumab: Post-Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial
Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL cholesterol 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 cholesterol, and insulin (or HOMA-IR) and their changes with alirocumab treatment. Analyses included 8107 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 cholesterol did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL cholesterol without affecting insulin or NOD risk (odds ratio versus placebo [OR] 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL cholesterol on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL cholesterol reductions were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94).
Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL cholesterol 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.
