Eli Lilly has reported positive Phase III results from its ACHIEVE-3 trial, demonstrating that its investigational small-molecule oral GLP-1 receptor agonist, orforglipron, outperformed oral semaglutide in adults with type 2 diabetes inadequately controlled on metformin.
The 52-week, head-to-head study enrolled 1698 participants across four treatment arms: orforglipron 12 mg and 36 mg and oral semaglutide 7 mg and 14 mg.
According to data published in The Lancet, orforglipron met the primary endpoint and all key secondary endpoints, showing statistically and clinically significant improvements in glycaemic control and weight reduction.
The results
At the highest tested dose, orforglipron 36 mg reduced HbA1c by 2.2% compared with a 1.4% reduction seen with oral semaglutide 14 mg.
In a key secondary endpoint, participants receiving orforglipron 36 mg achieved an average weight loss of 19.7 lbs (9.2%) versus 11.0 lbs (5.3%) with oral semaglutide 14 mg, representing a 73.6% greater relative weight reduction.
Improvements were observed as early as four weeks and sustained throughout the study period.
Orforglipron also delivered clinically meaningful changes in several cardiovascular risk markers, including non-HDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.
Unlike peptide-based oral GLP-1 therapies, orforglipron is a non-peptide small molecule and can be taken without food or water timing restrictions, a potential advantage for patient adherence and lifecycle management.
For manufacturers, its small-molecule profile may also offer supply chain and formulation flexibility compared with peptide-based alternatives.
The overall safety and tolerability profile was consistent with the GLP-1 class.
The most common adverse events for both treatments included nausea, diarrhoea, vomiting, dyspepsia and decreased appetite.
Discontinuation rates due to adverse events were higher with orforglipron (8.7% for 12 mg and 9.7% for 36 mg) than with oral semaglutide (4.5% for 7 mg and 4.9% for 14 mg).
Lilly has submitted orforglipron to regulators in more than 40 countries.
A US regulatory decision for obesity is anticipated in Q2 2026, with a type 2 diabetes submission planned later this year, positioning the candidate as a potential new entrant in the rapidly expanding oral GLP-1 market.