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.
Orforglipron was associated with significant reductions in predicted 10-year risks for Type 2 diabetes and cardiovascular disease compared to placebo over 72 weeks, but the clinical relevance of these findings needs further evaluation.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This study assessed changes in long-term predicted 10-year cardiometabolic risk for Type 2 diabetes and cardiovascular disease in adults with overweight or obesity. Participants received orforglipron at doses of 5.5 mg, 9 mg, or 17.2 mg, or placebo for 72 weeks. The analysis reported significant reductions in predicted risk scores for T2D and CVD with orforglipron compared to placebo.
Abstract
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 This post hoc analysis used data from ATTAIN-1, a Phase 3 trial in adults (≥ 18 years) with obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2 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.
Background
This paper addresses the long-term predicted risk of Type 2 diabetes and cardiovascular disease in adults with overweight or obesity, a population at increased risk for these conditions. Prior studies have shown that weight management can influence these risks, but the specific effects of orforglipron on long-term outcomes were not well established. This study is significant as it utilizes validated risk prediction engines to assess the impact of orforglipron on these risks over a 72-week period.
Methods
This post hoc analysis utilized data from the ATTAIN-1 Phase 3 trial, involving adults aged 18 years and older with obesity or overweight without Type 2 diabetes. Participants were administered orforglipron at doses of 5.5 mg, 9 mg, or 17.2 mg, or a placebo for 72 weeks. The primary outcome measures included changes in predicted risk scores for T2D and cardiovascular disease assessed using three validated risk prediction engines.
Results
At week 72, the mean relative reduction in T2D risk score was significantly greater with orforglipron compared to placebo, with reductions ranging from -48.6% to -59.4% versus -10.5% for placebo (p<0.0001). For total CVD risk, the mean absolute change was -0.6% to -1.00% for orforglipron compared to +0.6% for placebo (p<0.0001). Additionally, significant reductions in predicted ASCVD, HF, and total CVD risks were observed with orforglipron compared to placebo.
Interpretation
The findings suggest that orforglipron may have a statistically significant impact on reducing predicted risks for Type 2 diabetes and cardiovascular disease. However, the clinical significance of these reductions, particularly given the reliance on predictive models, remains uncertain. Limitations such as the post hoc nature of the analysis and the absence of direct clinical outcomes may confound the conclusions drawn from this study.
Key findings
- -48.6% to -59.4% relative reduction in T2D risk score vs placebo (-10.5%; p<0.0001; HR-range 0.43-0.55)
- -0.6% to -1.00% absolute change in total CVD risk vs placebo (+0.6%; p<0.0001; HR range: 0.82-0.87)
- Median baseline scores for T2D risk were 16.0%-17.3%.
Limitations
- Post hoc analysis may introduce bias.
- Findings based on predictive models rather than direct clinical outcomes.
- No long-term follow-up beyond 72 weeks.