Introduction and Objective: ACHIEVE-2 (NCT06192108) assessed the efficacy and safety of orforglipron (OFG), an oral non-peptide GLP-1 receptor agonist (RA), versus dapagliflozin (DAPA), an SGLT2 inhibitor, in people with T2D inadequately controlled with metformin.Methods: This 40-week, phase 3, open-label (OFG dose-blinded), randomized study included adults with T2D (HbA1c ≥7.0 to ≤10.5%) taking metformin (≥1500 mg/day) with a BMI ≥23.0 kg/m2. Participants were randomized 1:1:1:1 to once daily OFG 3, 12, 36 mg, or DAPA 10 mg. The primary endpoint was change from baseline in HbA1c at week 40. Key secondary endpoints are listed in the Table.Results: The 962 randomized participants had a mean baseline age 56 years, HbA1c 8.1%, T2D duration 8.0 years, and BMI 32.6 kg/m2. At week 40, all OFG doses were superior to DAPA in reducing HbA1c; OFG 12 and 36 mg were superior for reductions in body weight (BW); and OFG 36 mg was superior for reductions in triglycerides, non-HDL-C and systolic blood pressure. The most frequent adverse events (AEs) associated with OFG were mild to moderate gastrointestinal (GI) AEs occurring mostly during dose escalation. Treatment discontinuations due to GI AE were 5.8-8.3% with OFG and 0.4% with DAPA. No severe hypoglycemia episodes were reported.Conclusion: Compared with dapagliflozin, orforglipron demonstrated superior glycemic control, BW reduction and improvements in cardiometabolic parameters, with a safety profile consistent with the GLP-1 RA class.
M.D. Welch: Stock/Shareholder; Current; Abbott, Eli Lilly and Company. Speaker’s Bureau; Current; Eli Lilly and Company, Amgen Inc. T.A. Forst: Speaker’s Bureau; Current; AstraZeneca. Advisory Panel; Current; Bayer AG. Speaker’s Bureau; Current; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Lilly, Novo Nordisk. W. Jia: None. P. Orozco del Pino: Employee; Current; Eli Lilly and Company. M. Denning: Employee; Current; Eli Lilly and Company. W. Wu: Employee; Current; Eli Lilly and Company. R. Liu: None. J. Li: Employee; Current; Eli Lilly and Company. M. Eifu: None. Y. Chen: None.
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