Eli Lilly and Company (NYSE:LLY) said its experimental oral diabetes treatment orforglipron delivered superior blood sugar reduction and weight-loss outcomes compared with oral semaglutide in a head-to-head clinical study published in The Lancet.
The findings come from the 52-week ACHIEVE-3 trial, which enrolled 1,698 patients with type 2 diabetes and compared multiple dosing regimens of the two oral GLP-1 therapies.
Patients receiving a 36 mg dose of orforglipron achieved an average A1C reduction of 2.2%, compared with a 1.4% decline among participants taking oral semaglutide at a 14 mg dose. Weight loss was also greater with Lilly’s drug, with participants losing an average of 19.7 pounds, or 9.2% of body weight, versus 11.0 pounds, or 5.3%, in the semaglutide group.
Trial design and outcomes
The study evaluated four treatment arms, including orforglipron at 12 mg and 36 mg doses and oral semaglutide at 7 mg and 14 mg doses. Across both primary and secondary endpoints — including the proportion of patients reaching target A1C levels below 7% — both orforglipron doses outperformed the semaglutide regimens.
Dr. Julio Rosenstock, clinical professor at the University of Texas Southwestern Medical Center and lead investigator of the trial, said the differences were “clinically meaningful” and noted that improvements became visible as early as four weeks into treatment.
Safety profile and side effects
Discontinuation rates linked to adverse events were higher among patients receiving orforglipron, reaching 8.7% for the 12 mg dose and 9.7% for the 36 mg dose, compared with 4.5% and 4.9% for oral semaglutide at 7 mg and 14 mg respectively.
Common side effects observed for both treatments included nausea, diarrhea, vomiting and reduced appetite.
Regulatory pathway underway
Lilly has already submitted orforglipron for regulatory review in more than 40 countries. The company expects potential U.S. regulatory action related to obesity treatment during the second quarter of 2026, with a submission for type 2 diabetes anticipated later this year.
Unlike existing oral semaglutide therapies, orforglipron is designed as a once-daily pill that can be taken without restrictions related to food or water intake, which could simplify dosing for patients if approved.