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June 9, 2026

Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes

FGFrancesco GiorginoUniversity of Bari Aldo Moro SDSHERWIN DʼSOUZASt. Luke's Clinic LLLisa LudwigEli Lilly (United States)

Key Points

To evaluate the efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control.
Randomized, double-blind, phase 3 study at 72 sites across multiple countries.
Participants received once-daily doses of orforglipron (3-mg, 12-mg, 36-mg) or placebo alongside titrated insulin glargine.
Primary outcome assessed was mean HbA1c change from baseline to week 40.
At week 40, mean HbA1c changes were -1.58%, -1.88%, and -1.82% for orforglipron doses vs -0.79% for placebo (P<0.001 for all).
Mean percentage body weight changes were -2.6%, -4.8%, and -5.4% for orforglipron groups vs 0.2% for placebo.
Orforglipron was associated with mild to moderate gastrointestinal adverse events without increased risk of significant hypoglycemia.

Abstract

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 A 1c (HbA 1c ) 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 HbA 1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA 1c 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 HbA 1c , 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 HbA 1c 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 lt; .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

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