Patients receiving oral orforglipron may have achieved larger reductions in their hemoglobin A1c levels and body weight compared with those receiving placebo, without increased clinically significant hypoglycemia in a recent clinical trial.
In the randomized phase 3 ACHIEVE-5 clinical trial, researchers enrolled 546 patients with inadequately controlled type 2 diabetes at 72 sites across the United States, Brazil, China, Japan, and Romania. The patients were receiving insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 (SGLT2) inhibitors and were randomly assigned to receive once-daily oral orforglipron at doses of 3 mg, 12 mg, or 36 mg, or placebo, for 40 weeks. The primary outcome was the change in hemoglobin A1c (HbA1c) from baseline to week 40.
At the follow-up period, mean HbA1c reductions were 1.58, 1.88, and 1.82 percentage points with 3, 12, and 36 mg of orforglipron compared with 0.79 percentage points with placebo. The researchers reported that all three doses were superior to placebo for glycemic control.
Higher proportions of patients receiving orforglipron also achieved prespecified glycemic targets. HbA1c levels below 7% were achieved by 57% of patients receiving 3 mg, 70% receiving 12 mg, and 65% receiving 36 mg compared with 25% of patients receiving placebo. HbA1c levels of 6.5% or lower were achieved by 43%, 60%, and 55% of the patients in the respective orforglipron groups compared with 12% in the placebo group.
The researchers also reported reductions in body weight across all orforglipron groups. Mean body weight decreased by about 3% with the 3-mg dose and about 5% with both the 12-mg and 36-mg doses, whereas body weight remained essentially unchanged with placebo. Insulin dose requirements increased less among the patients receiving orforglipron compared with among those receiving placebo.
The most common adverse events were gastrointestinal and included nausea, vomiting, diarrhea, decreased appetite, constipation, and dyspepsia. These events were generally mild to moderate in severity and occurred primarily during dose escalation. Treatment discontinuation as a result of adverse events occurred in 4% of the patients receiving 3 mg of orforglipron, 8% receiving 12 mg, and 10% receiving 36 mg compared with 4% of those receiving placebo.
The rates of clinically significant hypoglycemia were comparable across the treatment groups, and the researchers reported that orforglipron did not increase the risk of level 2 hypoglycemia compared with placebo. No adjudicated cases of pancreatitis or medullary thyroid cancer were reported during the study.
Subgroup analyses showed larger HbA1c reductions among patients with baseline HbA1c levels greater than 8%, although the researchers reported no treatment-by-subgroup interaction. The treatment effects were also consistent regardless of SGLT2 inhibitor use at baseline.
The researchers noted several limitations. The trial duration was limited to 40 weeks, preventing assessment of longer-term safety and efficacy. The standardized insulin-titration algorithm and glycemic targets may not reflect routine clinical practice, background insulin adjustments may have influenced outcomes, and continuous glucose monitoring was not used.
In an accompanying editorial, Kishore M. Gadde, MD, and colleagues wrote that the findings add to a growing body of evidence supporting incretin-based therapies for obesity and type 2 diabetes. The editorial authors also noted that gastrointestinal adverse effects, treatment cost, and weight regain following treatment discontinuation remain important considerations for this class of drugs.
"[D]aily oral orforglipron added to titrated insulin glargine significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo," wrote lead study author Francesco Giorgino, MD, of the Department of Regenerative and Precision Medicine and Ionian Area in the Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases at the University of Bari Aldo Moro in Italy, and colleagues.
The study was sponsored by Eli Lilly and Company. Full disclosures of the study authors can be found in the study.
