Oral orforglipron improves glycemic control in insulin-treated type 2 diabetes

Clinical Takeaway: For patients with type 2 diabetes inadequately controlled on basal insulin, adding oral orforglipron may offer an alternative to further insulin intensification. The drug improved glycemic control and body weight without increasing clinically significant hypoglycemia.

Many patients with type 2 diabetes remain above glycemic targets despite basal insulin therapy, and further insulin intensification is often limited by concerns about weight gain and hypoglycemia. GLP-1 receptor agonists are commonly added in this setting, but most available agents require injection.

Orforglipron, marketed as Foundayo for chronic weight management, is an oral, nonpeptide GLP-1 receptor agonist designed for once-daily administration without food or water restrictions. The phase 3 ACHIEVE-5 trial evaluated whether adding orforglipron to titrated insulin glargine could improve glycemic control in adults with inadequately controlled type 2 diabetes.

At 40 weeks, hemoglobin A1c (HbA1c) decreased by 1.6% to 1.9% across the three orforglipron dose groups compared with 0.8% with placebo. Between 57% and 71% of participants receiving orforglipron achieved an HbA1c below 7%, compared with 25% of those receiving placebo.

Orforglipron also produced clinically meaningful weight loss. Mean body weight decreased by 2.6% to 5.4% across dose groups, while weight remained essentially unchanged with placebo. Up to 48% of participants receiving orforglipron achieved at least 5% weight loss.

Importantly, glycemic improvements occurred despite less insulin escalation. Participants receiving orforglipron required substantially smaller increases in insulin glargine doses than those receiving placebo, suggesting that addition of a GLP-1 receptor agonist may reduce the need for ongoing insulin intensification.

The most common adverse events were gastrointestinal and were generally mild to moderate, occurring primarily during dose escalation. Treatment discontinuation due to gastrointestinal adverse events ranged from 1.5% to 6.7% with orforglipron versus 0.7% with placebo. No cases of pancreatitis or medullary thyroid cancer were reported during the study.

“In adults with type 2 diabetes inadequately controlled despite treatment with basal insulin with or without metformin and/or SGLT-2 inhibitors, daily oral orforglipron added to titrated insulin glargine significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo,” the study authors concluded.

Source: Giorgino F, et al. 2026 June 7. JAMA. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes (ACHIEVE-5 Randomized Clinical Trial)