Indirect Analysis Suggests Greater Weight Loss With Oral Semaglutide vs Orforglipron

A population-adjusted indirect comparison presented at the Obesity Medicine Association 2026 found greater mean weight loss with oral semaglutide (Wegovy) than with orforglipron (Foundayo) in adults with obesity or overweight and at least 1 weight-related comorbidity, both without diabetes.

The analysis, which comes the day following orforglipron’s FDA approval for obesity, also suggested lower odds of treatment discontinuation due to adverse events, particularly gastrointestinal events, with oral semaglutide.

"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, in a press release from Novo Nordisk. "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."

The ORION analysis used data from 2 phase 3 programs: OASIS 4 for oral semaglutide and ATTAIN-1 for orforglipron. Investigators used a simulated treatment comparison to assess percentage change in body weight and a 2-stage matching-adjusted indirect comparison for tolerability outcomes. Analyses were adjusted for baseline body weight, glycemic status, and sex.

In the efficacy analysis, oral semaglutide 25 mg was associated with a greater reduction in body weight than orforglipron 36 mg, with a mean difference of -3.2 percentage points (95% CI, -5.9 to -0.4) under the treatment-regimen estimand and -3.0 percentage points (95% CI, -5.8 to -0.3) under the efficacy estimand.

For tolerability, orforglipron 36 mg was associated with greater odds of discontinuation due to any adverse event (odds ratio [OR], 4.1; 95% CI, 1.3-13.0) and due to gastrointestinal adverse events (OR, 13.9; 95% CI, 2.0-96.0) relative to oral semaglutide 25 mg. Investigators noted the wide confidence interval for gastrointestinal discontinuation suggests substantial uncertainty around the point estimate.

In their press release, Novo Nordisk noted the comparator in ORION was orforglipron 36 mg used in phase 3 trials and stated the recently FDA-approved orforglipron tablet up to 17.2 mg is considered equivalent to that phase 3 capsule dose. The press release did not provide detailed baseline characteristics, absolute weight-loss rates or adverse-event frequencies from the underlying trials.

Novo Nordisk also presented the OPTIC survey, an online preference study of 800 US adults with obesity or overweight and at least 1 obesity-related complication.

In a predicted-choice comparison between hypothetical treatment profiles resembling oral semaglutide 25 mg and orforglipron, 84% of respondents favored the oral semaglutide-like profile. Of note, this study was observational, used hypothetical profiles, and was conducted before regulatory approval, limiting direct clinical applicability.

"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."

References

1. Novo Nordisk. Wegovy® pill demonstrated greater weight loss than orforglipron and lower odds of stopping medication due to side effects in a new indirect comparison to be presented at Obesity Medicine Association 2026. Novo Nordisk. Published April 2, 2026. Accessed April 2, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916526

2. Lilly. FDA approves Lilly's Foundayo™ (orforglipron), the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions/ April 1, 2026. Accessed April 1, 2026. https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-foundayotm-orforglipron-only-glp-1-pill