New oral orforgliprone reduces weight by 9.2% and HbA1c by 2.2% versus semaglutide in type 2 diabetes
Orforgliprone 36 mg reduces HbA1c by 2.2% and weight by 9.2% versus 1.4% and 5.3% for semaglutide 14 mg in the ACHIEVE-3 trial published in The Lancet; Oral experimental medication does not require fasting and may simplify adherence to treatment for type 2 diabetes.
A phase 3 clinical trial directly compared Eli Lilly’s oral investigational drug orforgliprone with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin. The ACHIEVE-3 study involved 1,698 participants randomized to daily doses of orforgliprone (12 mg or 36 mg) or semaglutide (7 mg or 14 mg) for 52 weeks, with monitoring for lifestyle changes. The results demonstrated superiority of orforgliprone in all primary and main secondary outcomes.
The reduction in glycated hemoglobin (HbA1c) was greater with doses of the new medication, and the loss of body weight was also notable, with clinically relevant differences observed from the fourth week onwards and maintained until the end of the period. Orforgliprone differs in that it does not require time restrictions for food or water intake, which facilitates daily use compared to current oral semaglutide.
Results in glycemic control
The 36 mg dose of orforgliprone achieved a mean reduction of 2.2% in HbA1c from a baseline of 8.3%. Semaglutide at a dose of 14 mg recorded a 1.4% drop in the same indicator. The estimated treatment difference confirmed significant statistical superiority.
Participants on orforgliprone 12 mg achieved a 1.9% reduction in HbA1c. Mais of half of the individuals treated with the highest doses reached levels below 6.5% or 7%, important goals for controlling type 2 diabetes.
Main differences observed
- HbA1c reduction with orforgliprone 36 mg: 2.2%
- HbA1c reduction with semaglutide 14 mg: 1.4%
- Average weight loss with orforgliprone 36 mg: 9.2% (about 8.9 kg)
- Average weight loss with semaglutide 14 mg: 5.3% (about 5 kg)
- Discontinuation rate due to adverse effects on orforgliprone: 8.7% to 9.7%
- Discontinuation rate due to adverse effects in semaglutide: 4.5% to 4.9%
These data reinforce the greater potency of orforgliprone in direct comparison, especially at the highest dose evaluated.
Weight loss observed in the trial
The highest dose of orforgliprone promoted an average loss of 9.2% of body weight, equivalent to approximately 8.9 kg in participants with an average initial weight close to 97 kg. Semaglutide 14 mg resulted in a reduction of 5.3%, or approximately 5 kg. Essa difference represents a relative advantage of approximately 73.6% in weight loss in favor of orforgliprone.
The 12 mg dose also outperformed the semaglutide options by magnitude. Reduções in weight contributed to additional benefits in cardiometabolic parameters.
Improvements in cardiovascular indicators
Treatment with orforgliprone led to greater reductions in blood pressure and cholesterol levels compared with semaglutide.
These effects are associated with greater weight loss and better glycemic control achieved. Participantes reported overall improvement in cardiovascular risk factors throughout the study.
The benefits occurred regardless of the initial dose, with consistency across the treated groups.
Adverse effects and tolerability
Gastrointestinal events such as nausea, diarrhea and vomiting were more frequent with orforgliprone, affecting approximately 58-59% of participants at the doses tested. In semaglutide, the rates were between 37% and 45%. Most events occurred during the dose escalation period and tended to decrease over time.
No drug-related deaths were confirmed during the trial.
Eli Lilly regulatory perspectives
Eli Lilly awaits FDA analysis for approval of orforgliprone in the treatment of obesity, expected in the next quarter. The specific application for type 2 diabetes is scheduled for the end of 2026. The drug belongs to the class of GLP-1 receptor agonists, but stands out for being a small molecule administered orally without dietary restrictions.
Results from ACHIEVE-3 reinforce its potential as a convenient option for patients.
General safety in the study
The safety profile followed that expected for GLP-1 agonists, with a predominance of mild to moderate gastrointestinal effects. Aumento in heart rate was slightly higher with orforgliprone, but with no serious implications reported.
More than 6,000 participants have been enrolled in the global phase 3 orforgliprone program, and ACHIEVE-3 represents the first head-to-head between two oral GLP-1 agonists.
