September 17, 2025
2 min read
Key takeaways:
- Orforglipron, a novel oral GLP-1, was superior to oral semaglutide for lowering HbA1c and weight in patients with type 2 diabetes.
- Regulatory approval for orforglipron will be sought in 2026.
In a trial comparing two oral GLP-1s, orforglipron was superior to semaglutide for glycemic control and weight loss in patients with type 2 diabetes, according to topline results announced by Eli Lilly.
For the ACHIEVE-3 trial, researchers randomly assigned 1,698 adults with type 2 diabetes inadequately controlled with metformin (mean HbA1c at baseline, 8.3%) to orforglipron (Eli Lilly) 12 mg, orforglipron 36 mg, oral semaglutide (Rybelsus, Novo Nordisk) 7 mg or oral semaglutide 14 mg, according to a press release from Eli Lilly.
Orforglipron conferred greater HbA1c and body weight reductions than oral semaglutide in the ACHIEVE-3 trial.
In the efficacy estimand, the primary endpoint of change in HbA1c at 52 weeks was –1.9 percentage points for orforglipron 12 mg, –2.2 percentage points for orforglipron 36 mg, –1.1 percentage points for semaglutide 7 mg and –1.4 percentage points for semaglutide 14 mg, whereas for the treatment regimen estimand, those figures were –1.7 percentage points for orforglipron 12 mg, –1.9 percentage points for orforglipron 36 mg, –1.2 percentage points for semaglutide 7 mg and –1.5 percentage points for semaglutide 14 mg, according to the release.
Change in weight from baseline to 52 weeks in the efficacy estimand was –6.7% for orforglipron 12 mg, –9.2% for orforglipron 36 mg, –3.7% for semaglutide 7 mg and –5.3% for semaglutide 14 mg, whereas in the treatment regimen estimand, those figures were –6.1% for orforglipron 12 mg, –8.2% for orforglipron 36 mg, –3.9% for semaglutide 7 mg and –5.3% for semaglutide 14 mg, Lilly stated in the release.
The percentage of patients achieving HbA1c less than 5.7% at 52 weeks in the efficacy estimand was 25.4% in the orforglipron 12 mg group, 37.1% in the orforglipron 36 mg group, 7.8% in the semaglutide 7 mg group and 12.5% in the semaglutide 14 mg group, whereas for the treatment regimen estimand, those figures were 21.4% in the orforglipron 12 mg group, 31.4% in the orforglipron 36 mg group, 7.4% in the semaglutide 7 mg group and 11.7% in the semaglutide 14 mg group, according to the release.
Orforglipron also conferred clinically meaningful improvements in cardiovascular risk factors such as systolic blood pressure, non-HDL cholesterol and triglycerides, according to the release.
Safety and tolerability were similar to that seen with orforglipron in previous trials, with most adverse events gastrointestinal-related and of mild to moderate severity, and treatment discontinuation rates due to adverse events were 8.7% in the orforglipron 12 mg group, 9.7% in the orforglipron 36 mg group, 4.5% in the semaglutide 7 mg group and 4.9% in the semaglutide 14 mg group, Lilly stated in the release.
“Head-to-head trials are a gold standard for comparing potential treatments,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in the release. “In this type 2 diabetes trial, orforglipron, even at the lower dose, outperformed both doses of oral semaglutide in reducing A1c. At the highest dose, orforglipron helped nearly three times as many participants reach near-normal blood sugar vs. the highest dose of oral semaglutide. These results, combined with orforglipron’s once-daily oral dosing and broad scalability, reinforce its potential as a foundational treatment for type 2 diabetes.”
The full results will be presented at a future medical meeting and published in a peer-reviewed journal, according to the release.
Orforglipron is not yet approved for commercial use in the United States. Lilly stated in the release that it will seek approval for orforglipron for treatment of type 2 diabetes in 2026.
