Predicting the Long‐Term Risk of Type 2 Diabetes and Cardiovascular Disease With Orforglipron in People With Overweight or Obesity: A Post Hoc Analysis of the ATTAIN ‐1 Trial

OBJECTIVE: To assess change in long-term predicted 10-year cardiometabolic risk (Type 2 diabetes [T2D] and cardiovascular disease [CVD]) in adults with overweight or obesity without T2D. METHODS: with ≥ 1 obesity-related complication) without T2D. Participants received orforglipron 5.5 mg, 9 mg, or 17.2 mg, or placebo for 72 weeks. Changes in predicted risk from baseline to 72 weeks were assessed using three validated risk prediction engines: Cardiometabolic Disease Staging (T2D risk), Framingham (total CVD risk), and PREVENT (total CVD, ASCVD, and HF risk). Mixed models for repeated measures compared change from baseline risk scores between groups. RESULTS: At week 72, mean relative reduction from baseline (median baseline scores: 16.0%-17.3%) in T2D risk score was significantly greater with orforglipron than placebo (-48.6% to -59.4% vs. -10.5%; p < 0.0001; HR-range 0.43-0.55). Using Framingham, at week 72, orforglipron was associated with a significant decrease in mean absolute change in total CVD risk vs placebo (-0.6% to -1.00% vs. +0.6%; p < 0.0001; HR range: 0.82-0.87). Similarly, at week 72, orforglipron was associated with reduced predicted ASCVD, HF, and total CVD risks compared to placebo, assessed using PREVENT (p < 0.0001). CONCLUSIONS: In this post hoc analysis, once-daily oral orforglipron was associated with statistically significant improvements in predicted 10-year risk of incident T2D and CVD compared with placebo over 72 weeks using three validated risk prediction models. TRIAL REGISTRATION: ATTAIN-1: NCT05869903.