Novo Nordisk presented the ORION study at the Obesity Medicine Association’s annual conference in San Diego showing that Wegovy® (semaglutide) tablets 25 mg was associated with significantly greater mean weight loss than orforglipron 36 mg in a population-adjusted indirect treatment comparison. It is important to note that the FDA recently approved orforglipron under the brand name Foundayo™ at doses ranging up to 17.2 mg. The approved 17.2 mg tablet is the equivalent to the orforglipron 36 mg capsules used in Phase 3 trials, and which served as the study comparator in ORION. Additionally, in a separate patient preference study, adults with overweight or obesity showed greater preference for an oral semaglutide–like profile than an orforglipron-like profile.1,2 These findings suggest potential differentiation and provide valuable insights to inform clinical decision-making.
“These studies add to the growing body of evidence supporting the clinical strength of semaglutide and highlight attributes that patients value when choosing an obesity medicine that fits their lifestyle,” said Jamey Millar, executive vice president, US Operations of Novo Nordisk. “Since its approval, we’ve seen strong interest in Wegovy® pill, from both healthcare professionals and people seeking obesity therapy, underscoring the importance of our continued focus on advancing obesity care through our relentless pursuit of innovation.“
The ORION study was a population-adjusted indirect treatment comparison (ITC) evaluating weight loss efficacy and tolerability between oral semaglutide 25 mg and orforglipron 36 mg using data from the OASIS 4 and ATTAIN-1 phase 3 clinical trials. A simulated treatment comparison was used to assess percentage change from baseline in body weight. A two-stage matching-adjusted indirect comparison was used for tolerability outcomes (treatment discontinuation due to any adverse event and due to gastrointestinal adverse events).1 Analyses were adjusted for baseline body weight, glycemic status, and sex.1
ORION results showed that oral semaglutide 25 mg demonstrated significantly greater weight loss compared with orforglipron 36 mg, with mean differences [95% CI] of -3.2 percentage points [-5.9, -0.4]* regardless of whether patients stayed on treatment and -3.0 percentage points [-5.8, -0.3]** if all patients stayed on treatment.1 In addition, this analysis showed that when compared with oral semaglutide 25 mg, orforglipron 36 mg was associated with ~4 times higher odds of treatment discontinuation due to any adverse event (AEs) (odds ratio [OR] [95% CI]: 4.1 [1.3, 13.0]) and ~14 times higher odds of treatment discontinuation due to AEs related to gastrointestinal (GI) issues (OR [95% CI]: 13.9 [2.0, 96.0]).1
Although researchers adjusted for key baseline characteristics, other unaccounted factors may remain. Additionally, between-trial protocol differences may also influence comparability. While a significant difference was observed for tolerability, the magnitude of these differences should be interpreted with caution due to low adverse event counts.1
“People often ask how one medication compares to another when making obesity treatment management decisions,” said Robert F. Kushner, MD, Northwestern Feinberg School of Medicine. “Since there are no head-to-head trials comparing oral semaglutide for obesity to orforglipron, this indirect treatment comparison from the ORION study provides important information that can be used during the shared decision-making process.”
Additionally, OPTIC was an online patient preference study assessing key factors driving obesity treatment decisions conducted from October to November 2025. The study was conducted among 800 adults with either obesity or overweight and at least one obesity-related complication, with or without prior experience using obesity medicine, and included a predicted choice comparison of hypothetical treatment profiles similar to oral semaglutide 25 mg and orforglipron.2 Results of the predicted choice comparison based on clinical trial results showed that 84% of survey respondents favored the oral semaglutide-like profile option,.2 Additionally, a majority of all respondents (65%) agreed that taking a treatment on an empty stomach and waiting 30 minutes before eating (oral semaglutide-like dosing instructions) would not disrupt their daily lives.2
Key limitations include the study’s observational nature, selection bias, and use of hypothetical profiles.2 Because this survey was conducted prior to regulatory approval, treatment profiles may not exactly match the FDA-approved labeling for products.
It is important to note that semaglutide tablets 25 mg contains a Boxed Warning for possible thyroid tumors, including cancer and should not be used in those with a personal or family
history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). The most common side effects include nausea, diarrhea, vomiting, constipation, stomach (abdomen) pain, changes in skin sensations, headache, tiredness (fatigue), upset stomach, dizziness, feeling bloated, belching, low blood sugar in people with type 2 diabetes, gas, stomach flu, heartburn, and hair loss.3
*Based on the treatment regimen estimand: treatment effect regardless of whether patients stayed on treatment or took other weight loss therapies.
** Based on the efficacy estimand: estimated efficacy in an idealized scenario in which all patients stayed on treatment and took no other weight loss therapies.
Source: Riyadh Daily