Exciting new research showcased at the Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria (September 15-19) and published simultaneously in NEJM indicates that daily treatment with the new once-daily GLP-1 agonist orforglipron leads to significant weight loss in individuals living with obesity who do not have type 2 diabetes. The study, led by Dr. Sean Wharton from McMaster University in Hamilton, Ontario, Canada, and the Wharton Weight Management Clinic in Burlington, was sponsored by Eli Lilly, the manufacturer of orforglipron.
Orforglipron is an oral glucagon-like peptide-1 (GLP-1) receptor agonist. In this phase 3, multinational, randomized, double-blind trial, researchers investigated the safety and effectiveness of once-daily orforglipron at doses of 6 mg, 12 mg, or 36 mg compared to a placebo (distributed in a ratio of 3:3:3:4) over a period of 72 weeks. All participants had obesity but no diabetes. The main goal was to assess the percentage change in body weight from baseline to week 72.
A total of 3,127 patients across 9 countries, including the USA, China, Brazil, India, Japan, South Korea, Spain, Slovakia, and Taiwan, participated in the trial. The average weight change from baseline to week 72 was -7.5% with 6 mg of orforglipron, -8.4% with 12 mg, and -11.2% with 36 mg. In contrast, the placebo group saw only a -2.1% change.
Among those receiving the 36 mg dose of orforglipron, 54.6% experienced a weight reduction of 10% or more, 36.0% lost 15% or more, and 18.4% achieved a loss of 20% or more, compared to just 12.9%, 5.9%, and 2.8% respectively in the placebo group.
Other important outcomes, including waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels, showed significant improvement with orforglipron treatment (see table 3 in the full paper). Adverse events leading to treatment discontinuation occurred in 5.3% to 10.3% of patients in the orforglipron groups, compared to 2.7% in the placebo group. The most common side effects were gastrointestinal, primarily mild to moderate, which aligns with the typical side effects of GLP-1 class medications.
The researchers highlighted that other GLP-1 receptor agonists (like semaglutide) often lead to mean weight reductions of around 15% to above 20%, along with extra health benefits such as reduced cardiovascular risk. However, many existing GLP-1 medications require subcutaneous injections, which can hinder patient adherence to treatment.
The authors stated: “After 72 weeks of treatment, all patients in the three orforglipron groups experienced significant and clinically meaningful reductions in body weight that were dose-dependent. Those receiving the highest dose (36 mg) experienced an average weight loss of 11.2%, with over one third losing at least 15%, and nearly one fifth losing at least 20%. Additionally, all cardiometabolic measures improved compared to the placebo group. A weight reduction of 10% or more is recognized as a therapeutic threshold linked to meaningful health benefits. In this trial, patients receiving orforglipron exhibited an average weight reduction of 11.2%, along with improvements in blood pressure, blood lipid levels, blood sugar profiles, and systemic inflammation markers.”
While the trial had some limitations—like not comparing with currently approved obesity medications and using BMI standards primarily developed for White populations—the strengths included a diverse patient pool from nine countries and jurisdictions, with over 35% men participating.
The conclusion states: “In patients with obesity, orforglipron resulted in statistically and clinically significant weight reductions with an adverse event profile similar to other GLP-1 receptor agonists.”
Dr. Wharton added: “This could expand obesity treatment options for groups currently excluded due to the high cost and limited access to injectable medications.”
As it stands, orforglipron is not yet approved by the US Food and Drug Administration (FDA) or related regulatory bodies worldwide.
Summary: New research indicates that orforglipron, a once-daily GLP-1 agonist, leads to significant weight loss in individuals with obesity without diabetes. In a study involving over 3,000 participants, those taking orforglipron experienced considerable weight reductions compared to a placebo. Improvements were also noted in various health markers, though the drug is yet to receive FDA approval.
