1253-OR: ADA Presidents' Select Abstract: Efficacy and Safety of Orforglipron vs. Placebo Added to Titrated Insulin Glargine in Adults with Long-Standing Type 2 Diabetes: ACHIEVE-5

Introduction and Objective: The efficacy and safety of the daily oral, non-peptide GLP-1RA orforglipron (OFG) were assessed as add-on to insulin glargine with/without metformin and/or SGLT-2 inhibitors in adults with type 2 diabetes (T2D) (ACHIEVE-5; NCT06109311). Methods: In this 40-week double-blind, randomized, placebo-controlled, phase 3 study, participants with T2D and inadequate glycemic control were randomized (1:1:1:1) to receive daily OFG (3, 12, or 36 mg) or placebo (PBO). The primary endpoint was change from baseline in HbA1c at week 40 (superiority for 12 and/or 36 mg). Results are presented for the efficacy estimand. Results: 546 participants (age 60.2 years; T2D duration 15.0 years; HbA1c 8.5% [69.4 mmol/mol]; BMI 30.8 kg/m2) were randomized. At week 40, all OFG doses were superior to PBO in the primary and all key secondary endpoints (all p <0.001). Mean HbA1c decreased by 1.54 to 2.05% in the OFG groups vs 0.77% with PBO. Bodyweight change ranged from -2.7% to -6.1% with OFG vs 0.6% with PBO. The most frequent adverse events were gastrointestinal and occurred mostly during escalation. Rates of Level 2 hypoglycemia were similar between OFG and PBO. Severe hypoglycemia was reported by 2 participants in the OFG 12 mg group and 1 participant in the OFG 36 mg group. Conclusion: OFG added to titrated basal insulin improved glycemic control and reduced bodyweight without increasing hypoglycemia risk in patients with long-standing T2D. Disclosure F. Giorgino: Advisory Panel; Current; Abbott. Consultant; Current; Lilly, Novo Nordisk. Advisory Panel; Current; AstraZeneca, Medtronic. Research Support; Current; Roche Diabetes Care. Advisory Panel; Current; LifeScan, Sanofi. Advisory Panel; Ended; Merck Sharp & Dohme Corp. Advisory Panel; Current; Boehringer Ingelheim International GmbH. S. Dsouza: Consultant; Current; Eli Lilly and Company. Speaker's Bureau; Current; Eli Lilly and Company. Consultant; Current; Novo Nordisk. Speaker's Bureau; Current; Novo Nordisk. Consultant; Current; Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Current; Madrigal Pharmaceuticals, Inc. L. Ludwig: Employee; Current; Eli Lilly and Company. Stock/Shareholder; Current; Eli Lilly and Company. A. Kiyosue: None. S.M. Ibriga: Employee; Current; Eli Lilly and Company. H. Rha: Employee; Current; Eli Lilly and Company. R. Liu: None. M. Denning: Employee; Current; Eli Lilly and Company. J. Tobian: Employee; Current; Eli Lilly and Company. Funding Eli Lilly and Company (NCT06109311)