Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison.
Oral semaglutide just edged out orforglipron in a new heavyweight comparison for obesity research. Researchers crunched the numbers from two big studies—OASIS 4 (semaglutide) and ATTAIN-1 (orforglipron)—using a population-adjusted indirect treatment comparison. The goal: see which oral research peptide moves the needle more on body weight and how subjects tolerate them, all in adults without diabetes but with BMI in the overweight or obese range.
Diabetes Obes Metab
by Michalak W, Bøg M, Bendixen T et al.
“Oral Semaglutide 25 mg Versus Orforglipron 36 mg in Obesity: A Population-Adjusted Indirect Treatment Comparison. Michalak W(1), Bøg M(2), Bendixen T(2), Chowdhury R(3), Cowley P(3), Laugesen C(2), Rathor N(2), Kushner RF(4). Author information: (1)Novo Nordisk Inc., Plainsboro, New Jersey, USA. (2)Novo Nordisk A/S, Søborg, Denmark. (3)Petauri Evidence, Bicester, UK. (4)Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. AIMS: This study aimed to indirectly compare the effects of oral semaglutide 25 mg versus orforglipron 36 mg on body weight loss, other cardiometabolic biomarkers, and tolerability in adults with overweight (body mass index [BMI] ≥ 27 kg/m2 and at least one obesity-related complication) or obesity (BMI ≥ 30 kg/m2), without diabetes, using data from OASIS 4 and ATTAIN-1. MATERIALS AND METHODS: Individual patient data from OASIS 4 and aggregate data from ATTAIN-1 informed anchored indirect treatment comparisons (ITCs). Baseline differences in sex, body weight and normoglycaemic status were adjusted for using population-adjustment methods. Efficacy (percentage body weight change, categorical body weight loss thresholds, other cardiometabolic biomarkers) and tolerability outcomes (treatment discontinuation due to any adverse event [AE] and due to gastrointestinal [GI] AEs) were analysed. RESULTS: Population-adjusted analyses showed a significantly greater percentage change from baseline in body weight with oral semaglutide 25 mg than with orforglipron 36 mg, with mean differences (MDs) of -3.2%-points (95% confidence intervals [CIs]: -5.9, -0.4; treatment-regimen estimand) and -3.0%-points (95% CI: -5.8, -0.3; efficacy estimand). Discontinuation was higher with orforglipron (due to any AE: odds ratio [OR]: 4.1 [95% CI: 1.3, 13.0] and due to GI AEs: OR: 13.9 [95% CI: 2.0, 96.0]). CONCLUSIONS: In this ITC, oral semaglutide 25 mg was associated with greater body weight loss and fewer discontinuations due to any AEs and due to GI AEs compared with orforglipron 36 mg. These findings provide insight into the comparative effectiveness and tolerability in the absence of head-to-head clinical trials. © 2026 Novo Nordisk Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.”
Key takeaway: Oral semaglutide 25 mg led to greater average weight loss than orforglipron 36 mg. The difference was clear—about 3% more body weight lost with semaglutide. That’s not just statistical noise, it’s a real margin researchers can work with.
Here’s how it broke down:
Semaglutide 25 mg outperformed orforglipron 36 mg by around 3 percentage points in mean body weight reduction.
Discontinuation rates were higher with orforglipron. Odds of dropping out due to any adverse event were four times higher, and the odds of quitting due to gastrointestinal issues were nearly fourteen times higher versus semaglutide.
This kind of indirect comparison isn’t as airtight as a head-to-head clinical trial, but it’s still valuable for guiding future research. Semaglutide’s edge in both effectiveness and tolerability helps set priorities for anyone investigating oral GLP-1 research compounds.
If you’re tracking oral GLP-1 receptor agonists, this puts semaglutide at the top of the conversation for obesity-related projects. For sourcing, check the vendor directory to find research-grade compounds.
Oral semaglutide keeps proving its value in obesity research, and this latest data only builds its case.
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