Potential Mediators of Efpeglenatide's Cardiovascular Benefit: An Exploratory Analysis of the <scp>AMPLITUDE</scp> ‐O Trial

AIMS: In the AMPLITUDE O trial, efpeglenatide reduced major cardiovascular events by 27% in 4076 individuals with Type 2 diabetes and established cardiovascular or kidney disease compared to placebo during a median follow-up of 1.81 years. This exploratory mediation analysis evaluates the degree to which changes in measured clinical variables and biomarkers during the trial might explain the observed reduction in MACE. MATERIALS AND METHODS: Measured variables were considered potential mediators if they were significantly changed by the intervention. The hazard (95% CI) per 1-unit increase in each time-updated mediator (change from baseline or updated mean) was estimated using Cox models adjusted for the same variables as in the main AMPLITUDE-O results. Mediators whose hazard-ratio CIs excluded 1.0 were then included in the MACE Cox model to estimate how much of efpeglenatide's effect on MACE could be statistically explained by its effect on that mediator in uni- and multivariable analyses. RESULTS: Change in HbA1c, weight, pulse pressure, LDL cholesterol, urinary albumin: creatinine ratio (UACR), eGFR, heart rate, lipase and amylase were modified by efpeglenatide. Of these, univariable analyses showed that only changes in HbA1c, LDL cholesterol, UACR and amylase accounted for 14%, 11%, 16% and 10%, respectively, of the effect of efpeglenatide on MACE. In the multivariable analysis, LDL cholesterol together with UACR accounted for 29.6% mediation of this effect. CONCLUSION: In this post hoc analysis from the AMPLITUDE-O trial, changes in LDL cholesterol together with UACR but not weight were estimated to statistically account for a modest portion of the reduction in risk of MACE with efpeglenatide.