Orforglipron Added to Insulin Glargine Improves Glycemic Control and Reduces Weight in Uncontrolled Type 2 Diabetes: ACHIEVE-5 Trial
Italy: It has been found in a recent study that in people with type 2 diabetes inadequately controlled with insulin glargine, adding oral orforglipron significantly improved glycemic control and reduced body weight compared with placebo. Importantly, these benefits were achieved without increasing the risk of hypoglycemia.
Orforglipron is a novel oral, non-peptide GLP-1 receptor agonist, offering the advantages of GLP-1–based therapy in a convenient tablet form. The findings suggest that orforglipron may become an effective treatment option for patients requiring additional glucose-lowering and weight management despite basal insulin therapy.
The findings are from the ACHIEVE-5 randomized clinical trial, published in JAMA by Francesco Giorgino and colleagues, which assessed the efficacy and safety of once-daily oral orforglipron as an add-on to titrated insulin glargine in adults with inadequately controlled type 2 diabetes.
The phase 3, double-blind study enrolled 546 adults across 72 sites in the United States, Brazil, China, Japan, and Romania between November 2023 and September 2025. Participants receiving insulin glargine, with or without metformin and/or SGLT-2 inhibitors, were randomly assigned to receive oral orforglipron (3 mg, 12 mg, or 36 mg once daily) or placebo alongside their existing treatment.
The primary outcome was the change in HbA1c from baseline to week 40. At study entry, participants had a mean HbA1c of 8.5% and a median diabetes duration of 14.6 years.
The trial revealed the following findings:
- After 40 weeks, mean HbA1c levels decreased by 1.58%, 1.88%, and 1.82% in the orforglipron 3 mg, 12 mg, and 36 mg groups, respectively, compared with a 0.79% reduction in the placebo group.
- All three doses of orforglipron demonstrated statistically significant improvements in glycemic control compared with placebo.
- Mean body weight decreased by 2.6% with the 3 mg dose, 4.8% with the 12 mg dose, and 5.4% with the 36 mg dose, while body weight remained largely unchanged in the placebo group.
- A higher proportion of participants receiving orforglipron achieved recommended HbA1c targets than those receiving placebo.
- Gastrointestinal events, including nausea, vomiting, and diarrhea, were the most commonly reported adverse effects and were generally mild to moderate in severity.
- Orforglipron did not increase the risk of clinically significant hypoglycemia compared with placebo.
The investigators acknowledged several limitations. The standardized insulin titration protocol used in the trial may not fully reflect routine clinical practice, and the relatively short study duration limits assessment of long-term outcomes. Insulin dose adjustments may also have influenced treatment effects, and continuous glucose monitoring was not used.
The researchers concluded that among adults with type 2 diabetes inadequately controlled on basal insulin therapy, daily oral orforglipron significantly improved glycemic control and reduced body weight without increasing hypoglycemia risk, supporting its potential role as an effective add-on treatment option.
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. Published online June 07, 2026. doi:10.1001/jama.2026.9512
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