Switching from injectable GLP-1s to oral orforglipron held most weight loss in phase 3b trial

A daily oral pill kept most of the weight loss people had achieved on injectable tirzepatide or semaglutide, according to a phase 3b trial published May 13 in Nature Medicine ^[1]. The study, called ATTAIN-MAINTAIN, is the first randomized test of switching from an injectable incretin therapy to an oral one during the weight-maintenance phase ^[1].

The trial enrolled 376 people at 29 sites in the United States between September 13, 2024, and November 21, 2025, after screening 400 ^[1]. Everyone had taken part in the SURMOUNT-5 study and had been treated with tirzepatide (sold as Mounjaro and Zepbound) or semaglutide (sold as Ozempic, Wegovy and Rybelsus) for 72 weeks ^[1]. Participants had obesity or a body mass index of at least 27 with obesity-related complications ^[1]. They were placed in one of two cohorts based on which injectable they had used, then randomly assigned to once-daily orforglipron — 36 mg or the highest dose they could tolerate — or placebo ^[1]. The tirzepatide cohort randomized 205 people; the semaglutide cohort randomized 171 ^[1].

The main analysis looked at participants whose weight had leveled off on the injectable, defined as less than 5% body weight change between weeks 60 and 72 of SURMOUNT-5 ^[1]. At week 52 of ATTAIN-MAINTAIN, those in the tirzepatide cohort who took orforglipron maintained a model-based estimate of 74.7% of their earlier weight reduction, compared with 49.2% for placebo — a treatment difference of 25.5 percentage points (95% confidence interval 14.5 to 36.5; P < 0.001) ^[1]. In the semaglutide cohort, orforglipron maintained 79.3% versus 37.6% for placebo, a difference of 41.7 percentage points (95% confidence interval 24.4 to 59.0; P < 0.001) ^[1][2]. All key secondary endpoints were met ^[1].

The most common side effects were gastrointestinal, and they were mostly mild to moderate ^[1][2]. In the tirzepatide cohort, 157 of 205 participants (76.6%) completed study treatment; in the semaglutide cohort, 137 of 171 (80.1%) did ^[1]. Participants were mostly women (62.9% and 68.4%) and mostly white (73.8% and 75.9%), with mean starting weights of 90.1 kg and 94.4 kg ^[1]. The researchers list two limits: the trial had no arm in which people kept taking their injectable medication, so it does not show how switching compares with staying on the shot, and the trial lasted only one year ^[1].

Why it matters for patients

Weight regain after stopping treatment is the practical problem this trial addresses. The placebo groups — people who stopped their injectable and took no active drug — held onto only about half, or a bit more than a third, of the weight they had lost by week 52 ^[1]. Orforglipron is a nonpeptide pill taken once daily, and the authors note it can be taken without food or water restrictions, which may remove barriers such as reluctance to inject, travel difficulties and cold-chain storage that come with injectable medications ^[1].

Several things are not settled. Orforglipron is still under investigation for obesity and type 2 diabetes and is not described in these reports as approved for weight maintenance ^[1]. The trial report does not say whether or when US regulators will review it for this use, and it does not address cost or insurance coverage. The study also does not answer whether people who switch to the pill do as well as people who simply continue their injection, because no such comparison group was included ^[1].

What happens next

The trial is registered on ClinicalTrials.gov as NCT06584916 ^[1]. Orforglipron's phase 3 ATTAIN program has also tested the drug for weight loss in people with and without type 2 diabetes ^[1]. Results beyond one year of maintenance treatment have not been reported, and no timeline for a regulatory decision has been disclosed ^[1].