This phase 3 randomized clinical trial evaluated oral orforglipron, a nonpeptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), when added to titrated insulin glargine in adults with type 2 diabetes whose glycemic control remained inadequate on basal insulin. The study addressed the clinical question of whether an oral GLP-1 RA can provide incremental glycemic and weight benefits without increasing hypoglycemia when combined with basal insulin.
ACHIEVE-5 was a randomized, double-blind, phase 3 study conducted at 72 sites across the United States, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025. The trial enrolled adults with type 2 diabetes receiving titrated insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors. A total of 546 participants were randomized; baseline characteristics included a median age of 61.0 years, mean HbA1c of 8.50% (SD 0.95%), mean body mass index of 30.8 (SD 6.1), and median diabetes duration of 14.6 years. Of the randomized participants, 507 (92.9%) completed the 40-week treatment period.
Participants were randomized 1:1:1:1 to receive once-daily oral orforglipron at doses of 3 mg (n = 137), 12 mg (n = 132), or 36 mg (n = 136), or placebo (n = 141). All study arms continued titrated insulin glargine according to the trial protocol. The primary analysis focused on the 12-mg and 36-mg dosages for the primary outcome; the 3-mg dose was evaluated as a key secondary outcome.
The primary outcome was the mean change in hemoglobin A1c (HbA1c) from baseline to week 40 for the 12-mg and 36-mg doses of orforglipron. Key secondary outcomes included the mean HbA1c change for the 3-mg dose, the proportion of participants achieving HbA1c targets of less than 7.0% and 6.5% or lower, and mean change and percentage change in body weight from baseline to week 40.
At week 40, orforglipron produced clinically and statistically significant reductions in HbA1c compared with placebo. Mean changes from baseline in HbA1c were:
Each orforglipron dose was superior to placebo. Estimated treatment differences versus placebo were -0.78% (95% CI, -1.02% to -0.55%) for 3 mg, -1.08% (95% CI, -1.33% to -0.83%) for 12 mg, and -1.03% (95% CI, -1.28% to -0.77%) for 36 mg; P < .001 for all comparisons. All key secondary outcome measures, including achievement of HbA1c targets, demonstrated statistically significant differences in favor of orforglipron compared with placebo.
Addition of orforglipron to titrated insulin glargine resulted in dose-related weight reductions by week 40. Mean percentage body weight changes from baseline were:
These findings indicate that orforglipron produced meaningful weight loss in participants already receiving basal insulin, with larger reductions at higher doses.
The most frequently reported adverse events with orforglipron were gastrointestinal in nature and described as mild to moderate. Importantly, the addition of orforglipron did not increase the risk of clinically significant hypoglycemia compared with placebo in this trial. The abstract reports safety findings at a high level; detailed adverse event rates, serious adverse event counts, and specific gastrointestinal event rates beyond being the most common were not provided in the abstract.
Conflict of interest disclosures reported multiple relationships between authors and industry, including employment and stock ownership by Eli Lilly and Company for several authors and personal fees or grants to others.
In adults with type 2 diabetes inadequately controlled on titrated basal insulin, addition of oral orforglipron significantly improved glycemic control (larger reductions in HbA1c) and produced weight loss at 40 weeks compared with placebo, without increasing the risk of clinically significant hypoglycemia. The trial is registered at ClinicalTrials.gov (Identifier NCT06109311). The abstract does not provide longer-term outcomes beyond 40 weeks or granular subgroup and safety data; those details would require consultation of the full text.
Overall, ACHIEVE-5 supports the efficacy of oral orforglipron as an add-on to titrated insulin glargine for improved glycemic and weight outcomes in type 2 diabetes, with a tolerability profile characterized mainly by gastrointestinal events and no observed excess of clinically significant hypoglycemia in the reported period.