Oral Wegovy Is Associated with Greater Early Weight Loss Than Foundayo in Propensity Matched Adult GLP-1 Users

Oral Wegovy was associated with greater early weight loss than Foundayo in a matched cohort at 90 days, but the findings should be interpreted with caution due to small sample sizes.

Summary and findings

This study compared weight loss outcomes between oral semaglutide (Wegovy) and orforglipron (Foundayo) in a matched cohort of adult patients. At 90 days post-initiation, oral Wegovy users experienced a mean weight change of -3.1% (n=26) compared to +0.4% (n=18) for Foundayo. The findings suggest a greater early weight loss with oral Wegovy than Foundayo.

Abstract

<h4>Background: </h4> /Objectives: Oral semaglutide (Wegovy pill) and orforglipron (Foundayo) were recently approved for chronic weight management. Their safety and effectiveness have not been evaluated in real-world practice, particularly during the first few months when dose escalation, early treatment response, and tolerability may shape adherence. <h4>Methods:</h4> We retrospectively analyzed de-identified electronic health records through September 2026, including 16,220 oral Wegovy and 1,106 Foundayo recipients. Propensity matching on demographics, baseline characteristics including cardiometabolic burden, incretin history, the date of treatment initiation, and clinical visit frequency yielded 756 adult patients per drug. Clinical notes were curated with large language models (LLM), validated by physician adjudication. <h4>Results:</h4> In the unmatched cohorts, prior incretin exposure was recorded in 56.0% of oral Wegovy users versus 63.8% of Foundayo users (P&lt;0.001). Prior injectable Wegovy use predominated among subsequent oral Wegovy users, whereas prior Zepbound use predominated among subsequent Foundayo users (both P&lt;0.001). Dose escalation by day-90 lagged the recommended schedules for both agents. In matched cohorts, despite similar pre-treatment weight trajectories, mean weight change by 90 days after GLP-1 pill initiation was −3.1% with oral Wegovy (n=26) versus +0.4% with Foundayo (n=18), corresponding to a 3.55-percentage-point difference (95% CI, 1.02-6.08; P=0.007). Post-treatment initiation, LLM-curated clinical notes with physician adjudication confirmed weight-gain in a higher percentage of Foundayo users (5.3%) than oral Wegovy users (2.4%) (RR 2.20; P=0.016). Higher documentation of abnormal lipids was also evident from the LLM-curated notes among Foundayo users (1.7%) versus oral Wegovy users (&lt;1.4%) (RR&gt;5; P=0.009). Serial diagnostic lab testing showed a decrease in triglycerides during oral Wegovy use (−31.6 mg/dL; P=0.011, n=19) and a decrease in non-HDL cholesterol during Foundayo use (−30.5 mg/dL; P=0.04, n=11). Statins use did not meaningfully change upon Foundayo initiation, whereas significant statin-record frequency decrease was observed upon oral Wegovy prescribing (4.8% to 1.8%; P=0.020). Among Foundayo users, those with post-index statin co-prescriptions had numerically higher documented prevalence of abnormal lipids as expected, but also dizziness, and elevated liver enzymes than those without post-index statin co-prescriptions. Furthermore, adverse liver events and elevated liver enzymes were also numerically more frequent among Foundayo users than matched oral Wegovy users, presenting an emerging hypothesis that warrants prospective validation considering the FDA's postmarketing requirement to evaluate Foundayo liver safety and a subsequent FDA adverse-event report of hepatic failure. <h4>Conclusions:</h4> In a small subset of patients with follow-up weight measurements approximately 90 days after treatment initiation, oral Wegovy was associated with greater weight loss than Foundayo in routine care. Larger-scale and prospective follow-up analyses are warranted to more robustly compare the safety and effectiveness of these agents.

Limitations

Not reported in abstract.

Elsewhere in the Orforglipron (LY-3502970) corpus