Novo Nordisk will present new data from the ORION study at the upcoming Obesity Medicine Association (OMA) Annual Conference in San Diego, highlighting the weight-loss efficacy of Wegovy® (semaglutide) 25 mg tablets compared with orforglipron. The findings suggest that oral semaglutide may deliver greater weight reduction and better tolerability, offering valuable insights for clinicians managing obesity.
ORION Study Compares Oral Semaglutide and Orforglipron
As per the Novo Nordisk Press release, the ORION study conducted a population-adjusted indirect treatment comparison (ITC) to evaluate the efficacy and tolerability of oral semaglutide 25 mg versus orforglipron 36 mg. Researchers used clinical trial data from the OASIS 4 and ATTAIN-1 phase 3 studies.
To assess weight loss, investigators applied a simulated treatment comparison measuring the percentage change in body weight from baseline. Meanwhile, they used a two-stage matching-adjusted indirect comparison to evaluate tolerability outcomes, including treatment discontinuation due to adverse events and gastrointestinal (GI) side effects. The analysis adjusted for baseline body weight, glycemic status, and sex.
Greater Weight Loss and Improved Tolerability
Results showed that oral semaglutide 25 mg achieved significantly greater weight loss than orforglipron 36 mg. The mean difference in weight reduction reached –3.2 percentage points when considering treatment regardless of adherence and –3.0 percentage points in an ideal scenario where all patients remained on therapy.
Furthermore, orforglipron showed higher odds of treatment discontinuation due to adverse events. Specifically, patients taking orforglipron had about four times higher odds of stopping treatment because of any adverse event and nearly fourteen times higher odds due to GI-related side effects compared with oral semaglutide.
However, researchers noted that indirect comparisons and differences between clinical trial protocols may influence the results. Therefore, clinicians should interpret the magnitude of tolerability differences cautiously.
Patient Preference Favors Semaglutide-Like Profile
In addition, the OPTIC patient preference study, conducted online between October and November 2025, evaluated treatment priorities among 800 adults with overweight or obesity. Participants compared hypothetical profiles similar to oral semaglutide and orforglipron.
The results showed that 84% of respondents preferred the oral semaglutide–like profile. Moreover, 65% reported that taking medication on an empty stomach and waiting 30 minutes before eating would not disrupt their daily routine.
Safety Considerations and Regulatory Context
The FDA recently approved orforglipron under the brand name Foundayo™, with doses up to 17.2 mg, equivalent to the 36 mg capsules used in Phase 3 trials.
Meanwhile, semaglutide tablets carry a boxed warning for potential thyroid tumors, including cancer, and should not be used in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). Common side effects include nausea, diarrhea, vomiting, constipation, abdominal pain, fatigue, dizziness, and hair loss.
Together, these findings add to the growing evidence supporting semaglutide-based obesity treatments and may help guide shared decision-making between physicians and patients when selecting oral weight-loss therapies.