Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial.
Level 2 - randomized trial
Individual double-blind randomized controlled phase 3 trial
PubMed 41275875 · doi:10.1016/S0140-6736(25)02165-8
What was done
In a 72-week, phase 3, double-blind, placebo-controlled trial conducted across 136 sites in ten countries, 1613 adults with a BMI of 27 kg/m² or higher and an HbA1c of 7–10% were randomly assigned (1:1:1:2) to once-daily oral orforglipron (6 mg [n=329], 12 mg [n=332], or 36 mg [n=322]) or placebo (n=630) following a dose-escalation phase, as an adjunct to lifestyle modification. The primary outcome was the mean percent change in bodyweight from baseline to week 72 assessed using the treatment regimen estimand.
What was found
Baseline bodyweight averaged 101.4 kg (SD 22.5), BMI 35.6 kg/m² (SD 6.6), and HbA1c 8.05% (SD 0.75); 1444 (89.5%) participants completed the study. For the treatment regimen estimand, the mean percent change in bodyweight at week 72 was -5.1% (95% CI -6.0 to -4.2) for 6 mg (estimated treatment difference [ETD] vs placebo -2.7 [95% CI -3.7 to -1.6]; p<0.0001), -7.0% (-7.8 to -6.2) for 12 mg (ETD -4.5 [-5.5 to -3.6]; p<0.0001), and -9.6% (-10.5 to -8.7) for 36 mg (ETD -7.1 [-8.2 to -6.1]; p<0.0001), compared to -2.5% (-3.0 to -1.9) with placebo. Discontinuations due to adverse events occurred in 6.1–9.9% of orforglipron participants versus 4.1% on placebo, mainly driven by mild-to-moderate gastrointestinal events during dose escalation. Ten deaths occurred (six in the orforglipron groups, four in placebo).
Why it matters
Orforglipron provides an effective, non-peptide oral GLP-1 receptor agonist alternative for chronic weight management and cardiometabolic improvement in adults with obesity and type 2 diabetes without requiring subcutaneous injections.
Limits
The abstract reports statistical significance for cardiometabolic markers and HbA1c but does not provide exact numerical changes. The trial only included adults with baseline HbA1c between 7% and 10%, and long-term efficacy or weight maintenance beyond 72 weeks was not evaluated.
Cited by
- supports Orforglipron is a non-peptide GLP-1 receptor agonist.