A new non-peptide GLP-1 receptor agonist pill, orforglipron, has demonstrated superior effectiveness for weight loss and blood glucose control compared to oral semaglutide in patients with Type 2 diabetes. A 2026 Phase III trial found orforglipron 36 mg to be better than semaglutide 14mg in reducing glycated haemoglobin (HbA1c) levels over 52 weeks in patients inadequately controlled with metformin.
Orforglipron offers the convenience of daily oral administration without food or water restrictions. In contrast, oral semaglutide requires taking the medication on an empty stomach with specific waiting periods before consuming food or drinks.
The multinational trial, involving nearly 1,700 adults across multiple research centers, assigned participants to receive either orforglipron (12mg or 36mg) or semaglutide (7mg or 14mg) daily for 52 weeks. The average baseline HbA1c was 8.3%.
Both doses of orforglipron led to greater reductions in HbA1c than both doses of semaglutide. Specifically, orforglipron 12 mg lowered HbA1c by 0.48% more than semaglutide 7 mg, and orforglipron 36 mg showed a 0.33% greater reduction than semaglutide 14 mg.
While both drugs are consistent with the GLP-1 receptor agonist class, orforglipron was associated with a higher incidence of gastrointestinal events, including nausea, diarrhea, and vomiting, leading to more discontinuations due to adverse events. Orforglipron also resulted in a greater increase in heart rate compared to semaglutide.
Eli Lilly is preparing to submit orforglipron to the FDA for Type 2 diabetes treatment later this year.