Lilly trial finds oral orforglipron helped maintain weight loss after injectable GLP-1s

People who lost weight on a weekly injectable GLP-1 and then switched to a once-daily pill kept much more of that weight loss than people who stopped treatment, according to results from a Phase 3b trial called ATTAIN-MAINTAIN ^[1][2]. The pill was oral orforglipron, sold under the brand name Foundayo ^[2].

The trial followed 376 adults with obesity, or a body mass index of at least 27 with obesity-related complications, who had already completed 72 weeks of injectable therapy in the earlier SURMOUNT-5 study ^[1]. Of those, 205 had finished treatment with tirzepatide (sold as Zepbound and Mounjaro) and 171 had finished semaglutide (sold as Wegovy and Ozempic) ^[1]. All had reached a weight plateau, defined in the study as a change of less than 5% in body weight between weeks 60 and 72 ^[1]. They were then randomly assigned to take either 36 milligrams of orforglipron once daily or a placebo for one year ^[1].

Among people who had taken tirzepatide, those who switched to orforglipron maintained an average of 74.7% of their earlier weight loss, compared with 49.2% for those who took a placebo ^[1]. On average, the orforglipron group regained 11 pounds over the 52-week study ^[1], or about 5% of body weight ^[2].

Among people who had taken semaglutide, those who switched to orforglipron maintained an average of 79.3% of their prior weight loss, versus 37.6% for placebo ^[1]. That group regained an average of 2.2 pounds, or about 1% of body weight ^[1][2].

The lead investigator, Dr. Louis J. Aronne of NewYork-Presbyterian and Weill Cornell Medicine, said the larger regain in the tirzepatide group was expected because tirzepatide activates both the GIP and GLP-1 receptors, while semaglutide and orforglipron act on GLP-1 alone ^[1]. An account of the trial from the company Noom noted that the study was not designed to test why the two groups differed, and described that explanation as a theory rather than a finding ^[2].

Across both groups, patients maintained their reductions in waist circumference and stayed steady or improved on HbA1c, insulin, fasting glucose, lipid markers and systolic blood pressure ^[1]. Serious side effects occurred in fewer than 2% of patients. The most common side effects among those taking orforglipron were nausea, constipation, vomiting and diarrhea, and most were mild to moderate ^[1][2].

The trial was sponsored by Eli Lilly, which makes orforglipron and Zepbound ^[1]. Dr. Aronne disclosed that he is a paid consultant and advisory board member for Lilly and a paid advisory board member for Novo Nordisk, which makes Wegovy ^[1]. The findings were described as published in Nature Medicine ^[1][2].

Noom also cited earlier studies in which people who stopped weekly semaglutide regained about two-thirds of their lost weight within a year, and in which more than 80% of people who stopped tirzepatide had regained at least a quarter of their lost weight within a year ^[2]. In a separate Phase 3 trial in adults with obesity or overweight but without diabetes, the highest orforglipron dose produced average weight loss of about 12% of starting weight after 72 weeks, less than the most effective injectables ^[2].

Why it matters for patients

The results speak to a practical question for people already taking injectable GLP-1s: what happens if they want to stop weekly shots but not stop treatment ^[1][2]. Both accounts frame orforglipron as an option that may address barriers to long-term injectable use, including cost, storage and patient preference ^[1][2]. Orforglipron is a nonpeptide, small-molecule GLP-1 drug that is taken once a day with no food or water restrictions, which is not true of every oral option ^[2].

Maintenance was not perfect. People switching from tirzepatide, a dual-receptor drug, regained more on average than those switching from semaglutide, a single-receptor drug ^[1]. Digestive side effects were common, and the trial lasted one year, so longer-term safety and durability of the effect have not been reported ^[1][2]. Specific pricing for maintenance use and whether insurers will cover the pill for that purpose have also not been reported.

One limit of the design: everyone in the trial had first lost weight on an injectable and reached a plateau, so the results describe switching rather than starting treatment ^[1].

What happens next

Dr. Aronne said more research is needed to compare GLP-1 treatments and to understand how patients can maintain weight loss for a lifetime ^[1]. No timeline or specific follow-up studies are described in the accounts of the trial ^[1][2].