Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial.

Importance: The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described. Objective: To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control. Design, Setting, and Participants: Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors over 40 weeks. Interventions: Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n = 137), 12-mg (n = 132), or 36-mg (n = 136) dosages of orforglipron or placebo (n = 141), in addition to titrated insulin glargine. Main Outcomes and Measures: The primary outcome was mean hemoglobin A1c (HbA1c) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA1c targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40. Results: Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA1c, 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo. Each dosage of orforglipron was superior to placebo (estimated treatment differences: 3 mg once daily, -0.78% [95% CI, -1.02% to -0.55%]; 12 mg once daily, -1.08% [95% CI, -1.33% to -0.83%]; 36 mg once daily, -1.03% [95% CI, -1.28% to -0.77%]; P < .001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was -2.6%, -4.8%, and -5.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo. Conclusions and Relevance: In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT06109311.