Long-term obesity management increasingly raises a practical question for clinicians and patients alike: Can weight loss achieved with injectable therapies be maintained after transition to an oral agent? Findings from the ATTAIN-MAINTAIN trial presented at the European Congress on Obesity 2026 and simultaneously published in Nature Medicine showed sustained weight-loss maintenance after transition from injectable tirzepatide or semaglutide to daily oral orforglipron.
The double-blind, placebo-controlled randomized trial enrolled participants who had completed the SURMOUNT-5 study and reached a weight plateau after treatment with injectable tirzepatide or semaglutide. Participants were randomized to once-daily oral orforglipron at 36 mg or the maximum tolerated dose of 24 mg or 36 mg, or placebo, for an additional 52 weeks.
Cohort 1 included 205 participants previously treated with tirzepatide, including 125 randomized to orforglipron and 80 to placebo. Cohort 2 included 171 participants previously treated with semaglutide, including 105 randomized to orforglipron and 66 to placebo.
Among participants previously treated with tirzepatide, mean maintenance of weight reduction achieved during SURMOUNT-5 reached 74.7% with orforglipron compared with 49.2% with placebo. Maintenance of at least 80% of prior weight loss occurred in 43.7% and 16.4% of participants, respectively. Across the combined SURMOUNT-5 and ATTAIN-MAINTAIN periods, mean body weight reduction reached 16.8%, corresponding to an absolute reduction of 19.6 kg.
Among participants previously treated with semaglutide, mean maintenance of weight reduction achieved during SURMOUNT-5 reached 79.3% with orforglipron compared with 37.6% with placebo. Maintenance of at least 80% of prior weight loss occurred in 55.0% and 6.9% of participants, respectively. Across the combined study periods, mean body weight reduction reached 15.1%, corresponding to an absolute reduction of 17.1 kg.
Across both cohorts, cardiometabolic improvements achieved during SURMOUNT-5, including changes in cholesterol profiles, blood pressure, and blood sugar control, were maintained through follow-up. Rates of adverse events and serious adverse events were similar between treatment groups.
The study also incorporated rescue therapy beginning at week 24. Participants in the placebo group who regained at least 50% of previously lost weight were initiated on orforglipron to mitigate additional weight regain.
Across 52 weeks of follow-up, participants receiving orforglipron demonstrated average weight regain of approximately 5 kg (5%) in the tirzepatide cohort and 1 kg (1%) in the semaglutide cohort.
“A head-to-head clinical trial of injectable tirzepatide versus injectable semaglutide has already demonstrated superior weight loss with tirzepatide. Even so, most participants transitioning from tirzepatide maintained the majority of their weight loss with orforglipron, particularly compared with placebo…For some patients, a small degree of weight regain while maintaining the majority of weight loss achieved with injectable therapy may be clinically acceptable, particularly if switching to a different therapy that has attributes that facilitate long-term persistence on therapy, such as taking an oral pill daily instead of receiving injections. The individual differences highlight the need for shared decision-making conversations across the entire obesity management journey.”
The authors noted that discontinuation of obesity therapy after initial weight loss may lead to weight regain and loss of cardiometabolic improvements.
They concluded: “So far, injectable obesity medications have proven to be highly efficacious and safe for use, but persistence on therapy remains challenging. This trial provides evidence of how to switch to oral therapy and its ability to improve weight loss maintenance compared with stopping therapy, and could serve as a potential solution for persistence on therapy for those who wish to stop injectable therapy owing to patient preference, convenience, cost, or cold storage requirements.”
