New research presented at this year's European Congress on Obesity (ECO2026) in Istanbul, Turkey (12-15 May) and published in Nature Medicine shows that most weight loss achieved using the injectable obesity drugs tirzepatide or semaglutide can be maintained by switching to daily oral orforglipron treatment. The study is by Dr Louis J. Aronne, Director of the Comprehensive Weight Control Center at Weill Cornell Medicine, New York, New York, USA, and colleagues, and is sponsored by Eli Lilly and Company, the manufacturer of tirzepatide and orforglipron.
While the efficacy of injectable therapies has been repeatedly proven in clinical trials, how best to maintain weight loss achieved with these therapies remains a key area of research. One of the unanswered questions is if patients can maintain weight loss by switching from injectable therapies to daily oral therapies – and what happens if therapy is stopped altogether. Thus in this trial, the authors followed participants of the previously published SURMOUNT-5 trial, where weight loss was achieved using either injectable tirzepatide or injectable semaglutide. For this new study these patients were switched to either daily oral orforglipron, a new GLP-1 receptor agonist (recently approved by the US Food and Drug Administration), or placebo.
In this double-blind, placebo-controlled trial participants previously treated with tirzepatide (cohort 1: N = 205) or semaglutide (cohort 2: N = 171) during the SURMOUNT-5 study and who had reached a weight plateau were randomised to orforglipron once daily (36 mg or maximum tolerated dose of 24 or 36 mg) or placebo for 1 year after the end of SURMOUNT-5. In cohort 1, 125 participants received orforglipron and 80 received placebo; in cohort 2, 105 received orforglipron and 66 placebo.
In cohort 1, participants maintained a mean 74.7% of body weight reduction from SURMOUNT-5 with orforglipron compared with 49.2% with placebo. A secondary method for analysing weight maintenance looked at the proportion of patients who maintained 80% or more of weight lost in SURMOUNT-5. This was achieved by 43.7% of participants treated with orforglipron compared with 16.4% given placebo.
Participants in cohort 1 randomised only to orforglipron in ATTAIN-MAINTAIN had a mean baseline body weight of 115.8 kg at the start of SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a baseline body weight of 90.9 kg with a reduction of 21.5%. From the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN, these participants in cohort 1 had a mean body weight reduction of 16.8% and absolute bodyweight reduction of 19.6 kg.
In cohort 2, participants maintained a mean 79.3% of body weight reduction from SURMOUNT-5 with orforglipron compared with 37.6% with placebo. And 55.0% of those treated with orforglipron maintained at least 80% of the body weight reduction achieved during SURMOUNT-5, compared with 6.9% with placebo.
Participants in cohort 2 randomised only to orforglipron in ATTAIN-MAINTAIN had a mean baseline body weight of 113.5 kg at the start of SURMOUNT-5. At the start of the ATTAIN-MAINTAIN study, they had a baseline body weight of 95.0 kg with a reduction of 16.5%. From the beginning of SURMOUNT-5 to the end of ATTAIN-MAINTAIN these participants in cohort 2 had a mean body weight reduction of 15.1% and absolute body weight reduction of 17.1 kg.
Across both cohorts, cardiometabolic improvements that had occurred during SURMOUNT-5 were maintained to the end of ATTAIN-MAINTAIN, including improvements in cholesterol profiles, blood pressure and blood sugar control. In terms of safety, the proportion of participants reporting any adverse events (AEs) and the number of reported serious adverse events (SAEs) were similar between arms.
Another key feature of the trial was that, starting at week 24 after randomisation, participants on placebo who regained 50% or more of the weight loss achieved during the SURMOUNT-5 trial were initiated on orforglipron as rescue therapy – only orforglipron was permitted for this purpose. The rescue therapy was instigated to ensure patients did not lose all the benefits of the weight loss they achieved in SURMOUNT-5, including cardiometabolic improvements, by mitigating weight regain in the placebo group.
The authors say a key finding of this trial is that participants were better able to maintain the majority of weight loss originally achieved in SURMOUNT-5 with either injectable therapy when switched to orforglipron compared with placebo.
Across the 52 weeks of ATTAIN-MAINTAIN, participants treated with orforglipron demonstrated average weight regain of approximately 5 kg (5%) in cohort 1 and 1 kg (1%) in cohort 2. The authors explain that, consistent with the orforglipron clinical trial program demonstrating an efficacy and safety profile generally similar to injectable GLP-1RAs, orforglipron maintained nearly all the weight loss achieved on injectable semaglutide. They predicted that patients would experience more weight regain on average when transitioning off high doses of the dual agonist GIP/GLP-1 tirzepatide to a single agonist GLP-1 RA (orforglipron) than when transitioning from one single agonist GLP-1 RA (semaglutide) to another single agonist GLP-1 RA (orforglipron), but further exploration is necessary to explain these findings.
They say: "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 also highlight that a common misconception among individuals living with obesity, as well as some clinicians, is that obesity medications can be discontinued after achieving initial weight loss. The approach of stopping medication after intentional weight loss can lead to weight cycling and loss of improvements in cardiometabolic health such as increased insulin resistance or blood pressure, as is seen when individuals stop therapy in other chronic diseases such as hypertension and abnormal cholesterol.
They conclude: "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."
