New research presented at the Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria (Sept 15–19) and simultaneously published in NEJM shows that daily treatment with the new once-daily GLP-1 agonist orforglipron results in substantial weight loss in people living with obesity that do not have type 2 diabetes.
The study is by Dr. Sean Wharton, McMaster University, Hamilton, ON, Canada and Wharton Weight Management Clinic, Burlington, ON, Canada, and colleagues. The study is sponsored by Eli Lilly, the manufacturer of orforglipron.
Orforglipron is a small-molecule, oral glucagon-like peptide-1 (GLP-1) receptor agonist. In this Phase III, multinational, randomized, double-blind trial, the authors examined the safety and efficacy of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg, as compared with placebo (assigned in a 3:3:3:4 ratio) as an adjunct to healthy diet and physical activity for 72 weeks. All the patients had obesity but not diabetes. The primary end point was the percent change in body weight from baseline to week 72.
A total of 3,127 patients in nine countries / jurisdictions (U.S., China, Brazil, India, Japan, South Korea, Spain, Slovakia and Taiwan) underwent randomization. The mean relative change in body weight from baseline to week 72 was ?7.5% with 6 mg of orforglipron, ?8.4% with 12 mg of orforglipron, and ?11.2% with 36 mg of orforglipron, as compared with ?2.1% with placebo.
Among the patients in the orforglipron 36 mg group, 54.6% had reduction of 10% or more of body weight, 36.0% had a reduction of 15% or more, and 18.4% had a reduction of 20% or more, as compared with 12.9%, 5.9%, and 2.8% of the patients, respectively, in the placebo group.
Other outcomes such as waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels significantly improved with orforglipron treatment.
Adverse events resulted in treatment discontinuation in 5.3% to 10.3% of the patients in the orforglipron groups and in 2.7% of those in the placebo group. The most common adverse events with orforglipron were gastrointestinal effects, which were mostly mild to moderate, consistent with the GLP-1 class of medications.
The authors note that the use of medications such as GLP-1 receptor agonists (such as semaglutide) are reported to result in mean weight reductions of approximately 15% to above 20% and have shown additional health benefits, including decreased cardiovascular risk. However, most available GLP-1 based medications are administered as a subcutaneous injection, which may limit treatment initiation and adherence.
The authors say, “After 72 weeks of treatment, all the patients in the three orforglipron groups had a significant and clinically meaningful dose-dependent reduction in body weight.
The patients who received the highest dose of orforglipron had an average 11.2% weight reduction; more than one third had a reduction of at least 15%, and nearly one fifth had a reduction of at least 20%. All measured cardiometabolic levels improved with orforglipron treatment as compared with placebo … A weight reduction of 10% or more is a recognized therapeutic threshold, one that has been linked to meaningful cardiometabolic benefits.
“In our current trial, patients who received orforglipron had a mean weight reduction of as much as 11.2%, and such reductions were associated with improvements in levels of systolic and diastolic blood pressure, as well as blood fats, blood sugar profiles, and high-sensitivity C-reactive protein—a marker of systemic inflammation.”
The authors note the trial’s limitations include the lack of comparison with currently approved obesity-management medications, the use of cutoffs for BMI inclusion criteria that have been developed in White populations and that exclude patients with lower BMI values who may also have adiposity-related risks, and the increasing availability of obesity-management medications, which could have an effect on treatment adherence and efficacy results.
The strengths of the trial include a highly diverse, large population from nine countries and jurisdictions on four continents—including more than 35% enrollment of men.
They conclude, “In patients with obesity, the use of orforglipron resulted in statistically and clinically significant weight reductions and an adverse-event profile that was consistent with findings regarding other GLP-1 receptor agonists.”
Dr. Wharton adds, “This could mean an expansion of obesity interventions to groups who are currently excluded due to the cost of and lack of access to injectable medications.”
Orforglipron is not yet approved by the US Food and Drug Administration (FDA) or other similar agencies worldwide.
More information:
Sean Wharton et al, Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment, New England Journal of Medicine (2025). DOI: 10.1056/nejmoa2511774
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European Association for the Study of Diabetes
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