MON-738 - Orforglipron and the 10-year Predicted Risk of Cardiovascular Disease and Type 2 Diabetes: A Post Hoc Analysis from the ATTAIN-1 Trial

Background: In the ATTAIN-1 phase 3 trial, once-daily orforglipron, a small-molecule, nonpeptide oral glucagon-like peptide-1 receptor agonist, demonstrated clinically meaningful weight loss and improvements in cardiometabolic parameters at 72 weeks. This study describes relative change from baseline in predicted 10-year risk for cardiovascular disease (CVD) and type 2 diabetes (T2D) in adults with obesity or overweight without T2D receiving orforglipron or placebo.

Methods: In the ATTAIN-1 trial, 3127 participants were randomized to receive orforglipron 6 mg, 12 mg, or 36 mg capsules, or placebo (3:3:3:4 ratio) for 72 weeks. Orforglipron capsular doses were equivalent to US-approved 5.5 mg, 9 mg, and 17.2 mg tablets. This post hoc analysis of individual patient-level data from the trial used 3 clinically validated risk prediction models: 1) the Framingham risk engine for total CVD; 2) the Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) engine as a sensitivity analysis; and 3) the enhanced Cardiometabolic Disease Staging (CMDS) model for T2D risk. Excluded data included participants with CVD at baseline and data collected for participants with post-randomization CVD- or T2D-related events. Mixed models for repeated measures were used to analyze change from baseline in risk scores, with treatment group, geographic region, and baseline risk score as covariates, and sex and prediabetes status as stratification factors. Framingham model risk factors (covariates/stratification factors) were assessed for treatment effect/impact on predicted overall CVD risk. Hazard ratios (HRs) were approximated using the ratio of the negative logarithms of the group-level predicted 10-year survival, based on the assumption of proportional hazard.

Results: Mean baseline Framingham CVD risk scores (range: 8.5%–8.9%) were comparable between orforglipron and placebo treatment groups. At 72 weeks, orforglipron 36 mg capsule (tablet equivalent: 17.2 mg) reduced predicted total CVD risk (−6.7% of baseline risk) vs an increase with placebo (15.3% of baseline risk; HR, 0.82; 95% confidence interval [CI], 0.79–0.86]). PREVENT model sensitivity analyses were consistent with Framingham at 72 weeks; orforglipron 36 mg had −10.3% relative change from baseline in predicted total CVD risk vs an increase with placebo (11.3%; HR, 0.80; 95% CI, 0.77–0.84). At 72 weeks, CMDS analyses showed that orforglipron 36 mg was associated with a lower percent change from baseline in predicted T2D risk of −59.4% vs placebo (−10.5%; HR, 0.43; 95% CI, 0.40–0.47). Reductions in CVD or T2D risk were observed with all orforglipron doses across all 3 models.

Conclusions: In this post hoc analysis of the ATTAIN-1 trial, orforglipron treatment was associated with reduced long-term predicted risks of CVD and T2D compared with placebo, suggesting potential preventive benefits in adults with obesity or overweight.

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