BACKGROUND: Type 2 diabetes is a complex metabolic disorder often requiring combination therapy for optimal glycaemic control. This study assessed the efficacy and safety of orforglipron, an oral, non-peptide GLP-1 receptor agonist, versus dapagliflozin, an oral SGLT2 inhibitor, in participants with type 2 diabetes and inadequate glycaemic control with metformin.
METHODS: This 40-week, phase 3, multicentre, open-label (orforglipron dose-blinded), randomised study was conducted in 73 sites across six countries. The study included adults with type 2 diabetes using metformin (≥1500 mg/day) with glycated haemoglobin (HbA) concentrations between 7·0% and 10·5% (53-91 mmol/mol), stable bodyweight (±5%), and a BMI of 23·0 kg/mor more. Participants were randomly assigned in a 1:1:1:1 ratio to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg) or dapagliflozin 10 mg. The primary endpoint was change from baseline in HbAat week 40, using a non-inferiority margin of 0·3% for orforglipron versus dapagliflozin; analysis was based on the treatment-regimen estimand (data obtained regardless of study intervention discontinuation or initiation of additional glucose-lowering agents). The treatment regimen estimand was the primary estimand, with the efficacy estimand considered supportive. Safety was assessed in all randomised participants who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov (NCT06192108, completed). 1c1c2
FINDINGS: From Jan 10, 2024, to Sept 26, 2025, 1404 adults were assessed and 962 participants were randomly assigned to orforglipron 3 mg (n=240), 12 mg (n=241), or 36 mg (n=241), or dapagliflozin 10 mg (n=240). The baseline population included 474 (49%) females and had a mean age of 56·1 years (SD 11·5), HbAof 8·14% (1·04), type 2 diabetes duration of 8·0 years (6·7), and BMI of 32·6 kg/m(6·6). At week 40, for the treatment regimen estimand, all orforglipron doses were non-inferior to dapagliflozin in reducing HbA. Change from baseline in mean HbAwas -1·23% (SE 0·08), -1·50% (0·08), and -1·56% (0·09) with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus -0·81% (0·07) with dapagliflozin 10 mg; estimated treatment difference versus dapagliflozin was -0·42% (95% CI -0·62 to -0·23), -0·70% (-0·90 to -0·49), and -0·75% (-0·96 to -0·55) with orforglipron 3 mg, 12 mg, and 36 mg, respectively (all p<0·0001). The most frequent adverse events associated with orforglipron were mild-to-moderate gastrointestinal events, observed in 112 (47%) of 240 participants receiving orforglipron 3 mg, 112 (46%) of 241 receiving 12 mg, and 130 (54%) of 241 receiving 36 mg, versus 29 (12%) of 240 receiving dapagliflozin. More study intervention discontinuations were observed with orforglipron 3 mg (35 [15%] of 240), 12 mg (44 [18%] of 241), and 36 mg (47 [20%] of 241) than with dapagliflozin (14 [6%] of 240). No severe episode of hypoglycaemia was reported. 1c1c1c2
INTERPRETATION: Orforglipron demonstrated superior glycaemic control compared with dapagliflozin, with a tolerability profile consistent with the GLP-1 receptor agonist class, including increased rates of discontinuation due to adverse events, positioning it as a potential effective oral treatment option for type 2 diabetes.
FUNDING: Eli Lilly and Company.
