On 15 May, at the 33rd European Congress on Obesity in Istanbul, Türkiye, findings from a post-hoc indirect treatment comparison of Wegovy (oral semaglutide 25mg) versus Foundayo (orforglipron 36mg capsule; orforglipron 17.2mg tablet equivalent), both oral glucagon-like peptide-1 receptor agonists (GLP-1RA) recently approved in the US for chronic weight management, in adults with overweight or obesity, were presented. In the absence of a head-to-head clinical trial, this analysis aimed to evaluate the relative weight loss efficacy and tolerability of these two orally administered glucagon-like peptide-1 receptor agonists (GLP-1RAs) using data from their respective Phase III registration trials.
The analysis compared outcomes from the Phase III OASIS-4 trial (oral semaglutide; NCT05564117) and ATTAIN-1 (orforglipron; NCT05869903) in adults with overweight or obesity without diabetes. To address cross-trial differences, including body weight, sex distribution and glycaemic status, a simulated treatment comparison (STC) was used for treatment regimen and efficacy, while a two-stage matching-adjusted indirect comparison (2SMAIC) was applied to tolerability outcomes, aligning individual patient data from OASIS 4 to the ATTAIN-1 population.
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In results presented by Martin Bøg, statistical director at Novo Nordisk, Denmark, oral semaglutide was favoured across both efficacy estimands; mean weight reduction was greater by −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. Tolerability differences were more pronounced: orforglipron was associated with a significantly higher risk of discontinuation due to adverse events (odds ratio [OR] 4.1; 95% CI: 1.3 to 13.0) and gastrointestinal adverse events (OR 13.9; 95% CI: 2.0 to 96.0).
Key opinion leaders interviewed by GlobalData recognised oral semaglutide as a meaningful addition to the obesity armamentarium as a practical vehicle for long-term weight maintenance, though its administration requirements were broadly viewed as a competitive disadvantage relative to orforglipron.
In a market where two newly approved oral GLP-1RAs are competing for the same patient population, these findings, albeit from an indirect comparison with inherent methodological limitations, provide the only available head-to-head comparison. The apparent advantages of Wegovy Pill in both efficacy and tolerability are likely to inform clinical positioning and health technology assessment (HTA) considerations as competition in the oral GLP-1RA class intensifies. Direct comparative trials and longer-term cardiometabolic outcomes data will remain the critical next step. According to GlobalData’s Pharma Intelligence Center, there are currently 48 Phase III candidates, 112 Phase II candidates, and 158 Phase I candidates for overweight and obesity in development globally.
