Abstract
Obesity remains a major global health challenge, driving type 2 diabetes, cardiovascular disease, and other complications. Despite effective lifestyle and surgical interventions, pharmacotherapy uptake has historically been limited. Injectable GLP-1 receptor agonists, including semaglutide and tirzepatide, have redefined expectations for medical obesity therapy, achieving 15–20% weight reductions in clinical trials. However, barriers such as injections, cost, and adherence limit their real-world use. In September 2025, two pivotal phase-3 trials of oral GLP-1 therapies were published. ATTAIN-1 evaluated orforglipron in 3,127 adults with obesity over 72 weeks, demonstrating a mean weight loss of 11.2%, ≥ 10% weight loss in 54.6%, and improvements in cardiometabolic parameters. OASIS-4 studied oral semaglutide 25 mg in 307 adults over 64 weeks, showing a mean weight loss of 13.6%, ≥ 10% weight loss in 63%, and favorable metabolic changes. Both agents exhibited gastrointestinal adverse events consistent with the GLP-1 class; additionally, orforglipron had five mild pancreatitis cases, while oral semaglutide reported mild dysesthesia. These results confirm that oral GLP-1 receptor agonists can produce clinically meaningful weight loss and metabolic benefits, expanding options beyond injectables. Real-world adoption will hinge on adherence, tolerability, long-term safety, patient preference, and payer coverage. Oral GLP-1 therapies represent a transformative step in obesity management, offering a convenient alternative that may broaden access and optimize individualized care.