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Orforglipron oral pill shows substantial weight loss in phase 3 trial
Orforglipron, an oral GLP-1 agonist, helped patients with obesity lose up to 11% of their body weight in a major trial, offering a promising alternative to injectable therapies. (Artist’s concept). Credit: Stock
New phase 3 data presented at the European Association for the Study of Diabetes annual meeting in Vienna (Sept 15–19, 2025) and published in the New England Journal of Medicine report that once-daily orforglipron produces clinically meaningful weight reductions in people with obesity who do not have type 2 diabetes. Because it is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, orforglipron could expand access to pharmacologic obesity care where injectable formulations limit uptake.
Study design and methods
The multinational, randomized, double-blind phase 3 trial enrolled 3,127 adults with obesity (without type 2 diabetes) across nine countries and jurisdictions (United States, China, Brazil, India, Japan, South Korea, Spain, Slovakia, and Taiwan). Participants were randomized in a 3:3:3:4 ratio to receive once-daily oral orforglipron at 6 mg, 12 mg, or 36 mg, or placebo, alongside standardized lifestyle counseling on diet and physical activity. The treatment period lasted 72 weeks, and the primary endpoint was percentage change in body weight from baseline to week 72.
Key results
By week 72, mean weight change from baseline was −7.5% for the 6 mg group, −8.4% for the 12 mg group, and −11.2% for the 36 mg group, compared with −2.1% in the placebo arm. In the highest-dose cohort (36 mg), 54.6% of participants lost at least 10% of their baseline weight, 36.0% lost at least 15%, and 18.4% lost 20% or more. Corresponding proportions in the placebo group were 12.9%, 5.9%, and 2.8%.
Secondary cardiometabolic outcomes improved with orforglipron versus placebo: reductions were observed in waist circumference, systolic blood pressure, triglycerides, and non–HDL cholesterol. Treatment discontinuation due to adverse events occurred in 5.3%–10.3% of participants across the orforglipron dose groups versus 2.7% in placebo. The most frequently reported adverse events were gastrointestinal and were generally mild to moderate, aligning with the known class profile of GLP-1 receptor agonists.
How orforglipron compares with existing GLP-1 therapies
Injectable GLP-1 receptor agonists such as semaglutide and tirzepatide have produced mean weight losses often in the mid-teens to >20% range in clinical trials, with additional benefits for cardiovascular risk reduction in some studies. The orforglipron trial produced lower average weight loss than the most potent injectable regimens but demonstrated meaningful, dose-dependent results for an oral small-molecule agent — a significant development because the oral route can improve patient preference, reduce barriers related to injections, and potentially lower costs and increase treatment uptake.
Strengths, limitations, and clinical implications
Strengths of this trial include its large sample size, geographic diversity across four continents, and inclusion of more than 35% men — addressing a common gender imbalance in obesity research. Limitations noted by the investigators include the absence of a head-to-head comparison with currently approved injectable obesity medications and the use of body mass index cutoffs developed primarily in White populations, which may not capture adiposity-related risk thresholds for all ethnic groups. The increasing real-world availability of obesity medications could also influence future adherence and comparative effectiveness.
Investigators conclude that orforglipron produced statistically significant and clinically meaningful, dose-dependent reductions in body weight with a tolerability profile consistent with other GLP-1 receptor agonists. Lead investigator Dr. Sean Wharton (McMaster University and Wharton Weight Management Clinic) and collaborators highlighted that an effective oral GLP-1 could broaden therapeutic access for patients who are unable or unwilling to use injectable formulations due to cost, logistics, or preference.
Expert Insight
Dr. Elena Moreno, a fictional clinical pharmacologist and science communicator with experience in metabolic therapeutics, comments: "Orforglipron represents an important pharmacologic advance because oral delivery changes the patient and health-system calculus. While injectable GLP-1 agents have produced very large mean weight losses, oral agents can lower barriers to initiation and may improve long-term adherence for many people. Safety monitoring and direct comparative trials will be essential to place orforglipron in therapeutic practice."
Scientific context and future prospects
GLP-1 receptor agonists act on central appetite pathways and slow gastric emptying, which together reduce energy intake and improve glycemic and cardiometabolic parameters. Orforglipron is a small molecule designed to activate the GLP-1 receptor when taken orally, overcoming the peptide stability and absorption issues that have historically required injectable formulations. Future priorities include longer-term safety monitoring, head-to-head trials versus established injectable agents, and assessment of cost-effectiveness and real-world effectiveness across diverse populations.
If confirmed in further research and approved by regulators, an effective oral GLP-1 receptor agonist could reshape obesity treatment landscapes, increasing options for primary care and community settings and allowing broader integration with lifestyle and behavioral interventions.
Conclusion
In a large, international phase 3 trial, once-daily oral orforglipron produced dose-dependent weight reductions up to an average of 11.2% at 36 mg over 72 weeks in adults with obesity without diabetes, with improvements in multiple cardiometabolic markers and a gastrointestinal-predominant adverse-event profile. While injectable GLP-1 agents continue to show larger mean weight losses in other trials, orforglipron’s oral formulation offers a potentially transformative option for expanding access to pharmacologic obesity care. Additional comparative studies and long-term data will determine how this therapy fits into clinical practice.
Source: scitechdaily
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