Oral Orforglipron Improves Blood Sugar Control and Weight in Type 2 Diabetes on Basal Insulin: ACHIEVE-5 Trial
Italy: Adults with inadequately controlled type 2 diabetes receiving basal insulin may benefit from the addition of once-daily oral orforglipron, findings from the phase 3 ACHIEVE-5 randomized clinical trial published in JAMA have shown. The study showed that adding the oral glucagon-like peptide-1 (GLP-1) receptor agonist to titrated insulin glargine significantly improved blood sugar control and reduced body weight without increasing the risk of clinically significant hypoglycemia.
The study was led by Francesco Giorgino from the Department of Regenerative and Precision Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, Italy, along with an international team of researchers.
Orforglipron is an oral, nonpeptide GLP-1 receptor agonist being investigated as a treatment for type 2 diabetes. While injectable GLP-1 receptor agonists are well established, evidence for oral orforglipron in patients already receiving basal insulin has been limited.
To evaluate its efficacy and safety, researchers conducted a randomized, double-blind, placebo-controlled phase 3 trial across 72 centers in the United States, Brazil, China, Japan, and Romania between November 2023 and September 2025. The study enrolled 546 adults with inadequately controlled type 2 diabetes who were receiving insulin glargine, with or without metformin and/or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Participants were randomly assigned to receive once-daily oral orforglipron at doses of 3 mg, 12 mg, or 36 mg, or placebo, in addition to titrated insulin glargine, for 40 weeks.
The study population had a median age of 61 years, a median diabetes duration of 14.6 years, a mean HbA1c of 8.5%, and a mean body mass index of 30.8 kg/m². Overall, 92.9% of participants completed the trial.
Key findings:
- At 40 weeks, HbA1c decreased by 1.58%, 1.88%, and 1.82% with 3 mg, 12 mg, and 36 mg of orforglipron, respectively, compared with 0.79% with placebo.
- All three doses produced significantly greater HbA1c reductions than placebo.
- Participants receiving orforglipron were significantly more likely to achieve recommended HbA1c targets than those receiving placebo.
- Mean body weight decreased by 2.6%, 4.8%, and 5.4% with the 3 mg, 12 mg, and 36 mg doses, respectively, while body weight increased slightly (0.2%) in the placebo group.
- Gastrointestinal adverse events, primarily mild to moderate in severity, were the most commonly reported side effects.
- Orforglipron did not increase the risk of clinically significant hypoglycemia compared with placebo.
The investigators acknowledged several limitations. The standardized insulin titration protocol may not reflect routine clinical practice or other insulin regimens. The trial duration was relatively short, background insulin adjustments may have influenced outcomes, and continuous glucose monitoring was not used.
The researchers concluded that adding once-daily oral orforglipron to titrated insulin glargine significantly improved glycemic control and body weight in adults with inadequately controlled type 2 diabetes without increasing hypoglycemia risk, supporting its potential as an effective oral treatment option alongside basal insulin.
Reference:
Giorgino F, D’Souza S, Ludwig L, et al. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial. JAMA. 2026;336(5):389–399. doi:10.1001/jama.2026.9512
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