Achieving BMI <25 kg/m² was associated with reduced predicted risk of atherosclerotic cardiovascular disease in people with obesity or overweight on tirzepatide or placebo: a post hoc analysis of SURMOUNT-1, -3, and -CN.

BACKGROUND: Effective weight reduction interventions may significantly reduce obesity-related atherosclerotic cardiovascular disease (ASCVD) risk. However, evidence on the association between optimal body mass index (BMI) target and long-term ASCVD risk was limited. METHODS: Pooled individual-level data from participants with obesity/overweight randomized to tirzepatide or placebo in SURMOUNT-1 (December 2019-April 2022; NCT04184622), -3 (March 2021-April 2023; NCT04657016), and -CN trials (September 2021-December 2022; NCT05024032) were analyzed. Ten-year ASCVD risk was calculated using the American College of Cardiology/American Heart Association Pooled Cohort Equations. A mixed model for repeated measures analysis was used to compare percent change in ASCVD risk from baseline by achieved BMI group (<25 kg/m, ≥25 kg/m) at trial end, with terms including achieved BMI group, time point, achieved-BMI-group-by-time-point interaction, and baseline covariates. FINDINGS: Among 2691 participants included, 495 (18.4%) achieved BMI <25 kg/m at trial end. In addition to a significantly higher proportion being treated with tirzepatide (98.2% vs 66.8%), the BMI <25 kg/m group also had a higher proportion of females and lower mean BMI at baseline compared with the BMI ≥25 kg/m group ( < 0.001 for all). After adjusting for baseline covariates, relative to baseline, participants achieving BMI <25 kg/m had a significantly greater percent reduction in predicted ASCVD risk (39.4% vs 10.6%, < 0.001) compared to the BMI ≥25 kg/m group. Among those with baseline intermediate-to-high ASCVD risk, reduction remained greater in the BMI <25 kg/m group (25.6%) than the BMI ≥25 kg/m group (9.0%; < 0.001). Significantly greater improvements were also observed in blood pressure and lipids for the BMI <25 kg/m group ( < 0.001). INTERPRETATION: Achieving BMI <25 kg/m, primarily with tirzepatide, was associated with a significantly greater 10-year ASCVD risk reduction compared with those whose BMI remained at 25 kg/m or greater. These findings suggest potential cardiovascular benefits associated with targeting BMI <25 kg/m in the long-term weight management. FUNDING: This study was funded by Eli Lilly and Company.