A NOVEL non-peptide glucagon-like peptide-1 receptor agonist (GLP-1) pill is more effective for weight loss than oral semaglutide in patients with Type 2 diabetes, a 2026 Phase III trial has found.
Orforglipron 36 mg was superior to semaglutide 14mg with respect to mean change in glycated haemoglobin (HbA1c) in patients with Type 2 diabetes inadequately controlled with metformin over 52 weeks.
Orforglipron is designed for daily oral administration without food or water restrictions, whereas oral semaglutide must be taken on an empty stomach with water followed by a minimum 30-minute wait before consuming other food, drinks, or medications.
Orforglipron Versus Semaglutide
Researchers enrolled nearly 1,700 adults with Type 2 diabetes inadequately controlled with metformin and HbA1c levels between 53 and 91 mmol/mol. Participants were from 131 medical research centres and hospitals across Argentina, China, Japan, Mexico, and the USA.
Patients were randomly assigned to orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg) with a treatment period of 52 weeks, from 22 September 2022 to 22 August 2025, and drugs were administered orally once per day.
The baseline average HbA1c was 8.3%. Both doses of orforglipron lowered blood sugar more than both doses of semaglutide.
Orforglipron 12 mg lowered HbA1c 0.48% more than semaglutide 7 mg. Orforglipron 36 mg lowered HbA1c 0.33% more than semaglutide 14 mg. Even the smaller dose of orforglipron lowered HbA1c 0.24 percentage points more than the higher dose of semaglutide.
Side Effects and Future Treatment
More participants in the orforglipron groups discontinued study treatment due to adverse events than in the semaglutide groups. Most events included nausea, diarrhoea, and vomiting and were mild to moderate.
In the orforglipron groups, 9% and 10% of patients stopped treatment in the 12 mg and 36 mg doses respectively. In the semaglutide cohorts, 4% and 5% stopped taking the drug due to side effects in the 7 mg and 14 mg doses respectively.
Orforglipron was also associated with a greater increase in heartrate than semaglutide.
Average pulse rate increased by 3.7 bpm and 4.7 bpm with orforglipron 12 mg and 36 mg doses respectively. Patients taking semaglutide 7 mg and 14 mg doses only experienced an increase in heart rate by 1 bpm and 1.5 bpm respectively.
Researchers found that the safety profiles of both drugs were generally consistent with the GLP-1 receptor agonist class.
However, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide.
Eli Lilly is due to submit orforglipron for Type 2 diabetes to the FDA later this year.
Reference
Rosenstock J et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. The Lancet. 2026;DOI:10.1016/S0140-6736(26)00202-3.
Featured image: Andreas Prott on Adobe Stock
