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ISTANBUL — Patients who lost significant weight with injectable tirzepatide or semaglutide were able to maintain much of that loss after switching to once-daily oral orforglipron, according to findings from the ATTAIN-MAINTAIN trial. The study also found that patients who switched from semaglutide to orforglipron maintained weight loss more consistently than those who switched from tirzepatide.

The results suggest orforglipron could offer an oral continuation option for some patients after injectable obesity therapy.

“A common question we get from patients is, ‘Will I be able to maintain my weight loss in the long run if I change my treatment?’” said Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine, New York City, who presented the findings.

“The key message is that continued treatment matters and that an oral agent may help many patients maintain substantial weight loss and metabolic benefit.”

Aronne presented the findings at the 33rd European Congress on Obesity (ECO) 2026. The study was published simultaneously in Nature Medicine.

From Injectable to Oral: A Different Kind of GLP-1

Orforglipron is a once-daily oral, small-molecule, nonpeptide GLP-1 receptor agonist, distinguishing it from peptide-based GLP-1 therapies.

Aronne said the drug may offer practical advantages. “It is easier to manufacture and is absorbed more readily,” he said. “You don’t need to take it with four ounces of water and wait half an hour before or after a meal.”

However, he noted that switching is not necessarily straightforward because orforglipron can interact with other medications. “There are benefits to using it and there are other things that need to be adjusted,” he said.

The ATTAIN-MAINTAIN trial enrolled adults with obesity or overweight with weight-related complications who had completed SURMOUNT-5 after 72 weeks of treatment with tirzepatide or semaglutide and had lost at least 5% of their body weight. Participants were randomly assigned to once-daily orforglipron or placebo to test whether switching to an oral GLP-1 receptor agonist could help preserve weight loss after injectable incretin therapy. The main analysis focused on participants whose weight had stabilized near the end of SURMOUNT-5, defined as less than 5% weight change between weeks 60 and 72.

Orforglipron was started at a higher dose than is typically used in treatment-naive patients and was increased as tolerated. Aronne said the higher starting dose reflected participants’ prior weight loss and exposure to incretin therapy.

The trial also included a rescue-treatment protocol for participants assigned to placebo. Beginning at week 24, those who regained at least half of the weight they had lost during SURMOUNT-5 could receive orforglipron rescue treatment. “The idea was to prevent people from losing all the benefit they had achieved from weight loss,” Aronne said.

In the tirzepatide cohort, orforglipron maintained 74.7% of prior weight reduction among participants whose weight had plateaued compared with 49.2% with placebo. In a sensitivity analysis of orforglipron-treated participants, those switching from tirzepatide had maintained about 20 kg of weight loss from the start of SURMOUNT-5 to week 52 of the ATTAIN-MAINTAIN trial, despite regaining about 5 kg after the switch.

In the semaglutide cohort, orforglipron maintained 79.3% of prior weight reduction among participants whose weight had plateaued compared with 37.6% with placebo. In the corresponding sensitivity analysis, orforglipron-treated participants had maintained about 17 kg of weight loss overall, with approximately 1 kg regained over 52 weeks.

Aronne said the difference between the two groups made sense. “Tirzepatide is a dual agonist, so it acts on both GLP-1 and GIP [glucose-dependent insulinotropic polypeptide] and has two effects,” he said. “Semaglutide is more similar to orforglipron, which is also GLP-1 active. So going from semaglutide to orforglipron is more similar than going from tirzepatide to orforglipron.”

“In the future, we may have oral dual agonists, perhaps dual agonist small molecules. In that case, I would expect weight to remain stable after tirzepatide treatment.”

Most placebo-treated participants who met the weight-regain threshold received rescue orforglipron: 39 in the tirzepatide cohort and 42 in the semaglutide cohort, corresponding to 65.0% and 64.6%, respectively. Participants already receiving orforglipron at 24 mg could be re-escalated to 36 mg to maintain blinding; this occurred in two participants in the tirzepatide cohort and one participant in the semaglutide cohort.

“The majority of placebo-treated participants ultimately received orforglipron to prevent weight regain,” reported Aronne.

Waist Circumference, Cardiometabolic Benefits Maintained

Despite some weight regain, cardiometabolic benefits were largely preserved.

Waist circumference remained substantially lower than before SURMOUNT-5, even after modest increases during the ATTAIN-MAINTAIN trial. Among participants who switched from tirzepatide to orforglipron, mean waist circumference was 120.8 cm at the start of SURMOUNT-5, 100.3 cm at the start of the ATTAIN-MAINTAIN trial, and 103.4 cm after 52 weeks. In those switching from semaglutide to orforglipron, the corresponding measures were 119.1 cm, 103.4 cm, and 104.5 cm.

Lipid improvements, including triglycerides and cholesterol measures, were also broadly sustained, while blood pressure reductions were generally maintained, particularly after switching from semaglutide.

“The question is: Even though you’ve regained a little bit of body weight, do all of the benefits go away? The answer is no,” Aronne said. “There was very robust maintenance of cardiometabolic improvements.”

Gastrointestinal adverse events, including nausea, vomiting, and diarrhea, were more common with orforglipron than with placebo, although similar side effects were also reported in some placebo-treated participants.

Aronne noted that gastrointestinal adverse events appeared somewhat less frequently when participants switched from semaglutide to orforglipron than when switching from tirzepatide, most likely because orforglipron and semaglutide are both GLP-1-based therapies. Overall, adverse events with orforglipron were consistent with those reported in earlier studies of incretin-based obesity therapies.

Switching Should Be a Shared Decision

Asked by Medscape News Europe how clinicians should approach switching patients, Aronne said decisions should be individualized.

“We talk to the patient and see what they would prefer to do,” he said. “If someone says, ‘I’d like to take a daily oral pill rather than the weekly shot,’ we say, fine, this is what we have available, and we work with them and see how things go.”

However, he said some patients switching from tirzepatide may ultimately switch back because of its greater efficacy.

“In my opinion, the optimal thing to do is to continue the tirzepatide,” he said. “But this is an option for people who want that option.”

Aronne suggested oral agents may be particularly useful for people new to obesity treatment, especially those at the lower end of the weight spectrum rather than those with severe obesity.

“What we need are more options for people, so they don’t feel stuck,” he said. “Different mechanisms, different delivery systems, that is where we are going.”

In the Real World, Injections May Be Easier

Commenting for Medscape News Europe, Nick Finer, MD, trustee of the World Obesity Federation and the International Prader-Willi Syndrome Organisation, and former professor at the UCL Institute of Cardiovascular Science, London, England, said the findings reinforce the chronic nature of obesity treatment.

“I’m not surprised that when you reduce a drug or stop taking it, it no longer works,” Finer said. Reflecting also on the SURMOUNT-MAINTAIN trial presented at ECO 2026, he added, “What these studies clearly showed is that reducing the dose of the drug, or stopping it altogether, leads to weight regain. That’s what happens in almost every area of medicine.”

However, he cautioned that rescue interventions seen in the ATTAIN-MAINTAIN trial complicate interpretation.

“The rescue intervention was clearly pragmatic, probably also ethical, because there are increasing concerns about prolonged placebo exposure in obesity trials,” he said. “But it does complicate interpretation of the data.”

Finer also questioned whether oral therapy would automatically improve adherence.

“We know adherence is poor with many medications, and particularly poor with weight-loss treatment,” he said. “People often forget daily tablets, especially when travelling or routines change. A weekly or monthly injection can actually be easier because it becomes part of a schedule.”

The bigger advantage of oral drugs may ultimately be cost, he said.

The ATTAIN-MAINTAIN trial was funded by Eli Lilly and Company. Aronne reported receiving grants or personal fees from Altimmune, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, ERX, Gelesis, Intellihealth, Jamieson Wellness, Janssen, Novo Nordisk, Optum, Pfizer, Senda Biosciences, and Versanis and being a shareholder of ERX Pharmaceuticals, Gelesis, Intellihealth, and Jamieson Wellness. Finer reported receiving occasional speaking fees for Novo Nordisk.