The results of this landmark trial are particularly significant, as oral therapies for obesity could improve both access to and affordability of treatment; moreover, many patients prefer oral medications over injectables.
New findings presented at the Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria (Sept 15-19) and published in the New England Journal of Medicine report that a daily regimen of the once-daily GLP-1 agonist orforglipron leads to meaningful weight loss in people with obesity who do not have type 2 diabetes.
The research was led by Dr. Sean Wharton of McMaster University, Hamilton, ON, Canada, and the Wharton Weight Management Clinic, Burlington, ON, Canada, with a team of collaborators. The trial was funded by Eli Lilly, which manufactures orforglipron.
Orforglipron is a small-molecule, oral glucagon-like peptide-1 (GLP-1) receptor agonist. In this phase 3, multinational, randomized, double-blind trial, the investigators assessed the safety and effectiveness of once-daily orforglipron at 6 mg, 12 mg, or 36 mg against placebo (assigned in a 3:3:3:4 ratio) alongside guidance on healthy diet and physical activity over 72 weeks. All participants had obesity and did not have diabetes. The primary endpoint was the percentage change in body weight from baseline to week 72.
Key Results
Altogether, 3,127 participants from 9 countries/jurisdictions (USA, China, Brazil, India, Japan, South Korea, Spain, Slovakia, and Taiwan) were randomized. By week 72, average weight change from baseline was −7.5% with 6 mg of orforglipron, −8.4% with 12 mg, and −11.2% with 36 mg, compared with −2.1% in the placebo group.
In the 36 mg group, 54.6% of participants reduced their body weight by at least 10%, 36.0% achieved a reduction of at least 15%, and 18.4% reached a reduction of at least 20%. In the placebo group, the corresponding proportions were 12.9%, 5.9%, and 2.8%, respectively.
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.
Comparison with Other GLP-1 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 recognised 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.”
Strengths, Limitations, and Future Implications
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% enrolment 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.”
Reference: “Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment” by Sean Wharton, Louis J. Aronne, Adam Stefanski, Nasreen F. Alfaris, Andreea Ciudin, Koutaro Yokote, Bruno Halpern, Alpana P. Shukla, Chunmei Zhou, Lisa Macpherson, Sheryl E. Allen, Nadia N. Ahmad and Suzanne R. Klise, 15 September 2025, New England Journal of Medicine.
DOI: 10.1056/NEJMoa2511774
Orforglipron is not yet approved by the US Food and Drug Administration (FDA) or other similar agencies worldwide.
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