Effect of Orforglipron vs. Placebo and Dulaglutide on Glycemic Control and Body Weight in Patients with Type 2 Diabetes

Orforglipron [OFG (LY3502970)] is an oral, non-peptide, glucagon-like peptide-1 receptor agonist (GLP-1 RA). The 26-week, randomized, double-blind, double placebo, phase 2 study enrolled 383 patients with type 2 diabetes (T2D) treated with diet, exercise, ± metformin. At baseline, mean age was 58.9 yr, HbA1c was 8.1%, and body weight (BW) was 100.3 kg. Patients were randomly assigned to OFG 3, 12, 24, 36, or 45 mg once daily, placebo (PBO), or dulaglutide 1.5 mg (dula). Protocols guided the initial OFG dose and escalation schemes. Primary endpoint was HbA1c change from baseline (CFB) at wk 26 for OFG vs PBO. Secondary endpoints included CFB at wk 26 in HbA1c for OFG vs dula, and CFB in fasting blood glucose (FBG) and body weight (BW) for OFG vs PBO and dula. OFG resulted in improvements in glycemic control and BW (table). At wk 26, HbA1c reduction with OFG ranged from 1.19 to 2.10% vs PBO 0.43% (P<0.001, all doses vs PBO). Significantly greater reductions in HbA1c were also noted with 12, 24, 36, and 45 mg OFG vs dula (p<0.001). Most adverse events (AE) were gastrointestinal (nausea: PBO 5.5%, OFG 30.6%, dula 18.0%) and mild or moderate in severity. OFG resulted in significant reductions in HbA1c, FBG, and BW with an AE profile consistent with other GLP-1RAs. OFG does not have food or water administration restrictions and may provide a safe, effective, and convenient oral treatment option for patients with T2D. Disclosure J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.A.Robins: None. S.H.Hsia: Research Support; Eli Lilly and Company. S.Eyde: None. R.Liu: None. X.Ma: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Konig: None. C.M.Kazda: Employee; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company.