By Medha Baranwal

Copyright medicaldialogues

Canada: A large international clinical trial has demonstrated that the oral GLP-1 receptor agonist orforglipron can produce substantial and sustained weight loss in adults with obesity who do not have diabetes.Published in The New England Journal of Medicine, the phase 3 study led by Dr. Sean Wharton of McMaster University found that once-daily orforglipron achieved far greater reductions in body weight over 72 weeks than placebo, while maintaining a safety profile similar to other GLP-1–based therapies.The double-blind trial enrolled 3,127 participants from multiple countries, all of whom had obesity and were advised to follow a healthy diet and regular physical activity. Participants were randomly assigned to receive either a placebo or one of three orforglipron doses—6 mg, 12 mg, or 36 mg—taken orally once a day. The primary goal was to measure the percentage change in body weight from the start of the study to week 72. The study revealed the following notable findings:The trial showed a clear dose-dependent effect, with average weight loss at 72 weeks of 7.5% for the 6 mg dose, 8.4% for the 12 mg dose, and 11.2% for the 36 mg dose, compared with only 2.1% in the placebo group, and all orforglipron groups demonstrated statistically significant differences versus placebo.In the highest dose group, 54.6% of participants lost at least 10% of their baseline weight, 36% achieved a loss of 15% or more, and nearly 20% reached a loss of 20% or greater, while in the placebo arm only 12.9% achieved a 10% weight reduction, with far lower percentages reaching higher thresholds.Participants receiving orforglipron also experienced notable improvements in waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol, indicating broader metabolic benefits beyond weight loss.Safety outcomes were in line with those reported for other GLP-1 receptor agonists, with gastrointestinal symptoms such as nausea and diarrhea being the most common side effects, generally mild to moderate in severity.Treatment discontinuation due to adverse events occurred in 5.3% to 10.3% of patients across the orforglipron doses, compared with 2.7% among placebo recipients, and no unexpected safety concerns were identified during the 72-week follow-up period.Orforglipron stands out because it is a small-molecule, nonpeptide GLP-1 receptor agonist that can be taken orally, avoiding the need for injections required by many other drugs in this class. The study’s authors note that these findings support the potential of orforglipron as an effective, convenient option for obesity management when combined with lifestyle changes.”With obesity rates climbing worldwide, an oral medication capable of delivering double-digit weight loss could broaden access to GLP-1–based treatment. While further real-world studies and long-term data will help define its role in clinical practice, the results position orforglipron as a promising new addition to the expanding toolkit for obesity care,” the authors concluded. Reference:DOI: 10.1056/NEJMoa2511774