Switching from injectable incretins to oral orforglipron maintained weight loss in a Phase 3 trial

A new trial called ATTAIN-MAINTAIN found that patients who switched from injectable tirzepatide (Zepbound) or semaglutide (Wegovy) to Eli Lilly's oral orforglipron pill, sold under the brand name Foundayo, kept most of their prior weight loss over one year. The results were published in Nature Medicine and led by researchers including Dr. Louis Aronne of Weill Cornell Medicine, who also led the earlier SURMOUNT-5 trial that supplied the study's patients ^[1][2].

The phase 3b trial enrolled 376 adults with obesity, or a BMI of at least 27 with weight-related health problems, who had already finished 72 weeks of injectable treatment in SURMOUNT-5 and whose weight had leveled off, changing less than 5% in the final weeks ^[1]. Researchers then randomly assigned them to take 36 milligrams of orforglipron once daily or a placebo for another year ^[1].

Among the 205 patients who had been on tirzepatide, those switched to orforglipron kept an average of 74.7% of their earlier weight loss, compared with 49.2% for those given placebo. On average, the orforglipron group in this cohort gained back about 11 pounds over the year ^[1][2]. Among the 171 patients who had been on semaglutide, orforglipron patients held onto 79.3% of their prior loss versus 37.6% on placebo, with an average gain of about 2.2 pounds ^[1][2].

Aronne says the gap between the two groups likely reflects how the drugs work. Tirzepatide activates two hormone receptors, GLP-1 and GIP, and tends to produce larger weight loss than single-receptor drugs. Orforglipron and semaglutide both act only on the GLP-1 receptor, so stepping down from tirzepatide to orforglipron represents a bigger change in mechanism than stepping down from semaglutide, which may explain the larger regain in the tirzepatide group ^[1][2]. The study itself was not designed to prove this explanation ^[2].

Beyond the scale, patients who switched to orforglipron also kept most of their improvements in waist circumference, blood sugar (HbA1c), insulin, fasting glucose, cholesterol markers, and blood pressure ^[1]. Serious side effects occurred in fewer than 2% of patients, and the most common complaints were nausea, constipation, vomiting, and diarrhea, mostly mild to moderate ^[1].

Why it matters for patients

Stopping GLP-1 treatment altogether tends to bring weight back. Earlier research cited by Noom found that people who stopped weekly semaglutide regained about two-thirds of their lost weight within a year, and more than 80% of people who stopped tirzepatide regained at least a quarter of their lost weight in a year ^[2]. This new trial suggests a daily pill could be one way to keep treating obesity without continuing weekly injections, which some patients find costly, inconvenient to store, or otherwise hard to stick with long-term ^[1][2].

The data also show the switch is not seamless. People coming from tirzepatide, the more potent of the two injectables, saw more weight regain on orforglipron than those coming from semaglutide, even while staying on active treatment ^[1][2]. That means the choice of a maintenance pill may depend partly on which injectable someone started with.

Dr. Aronne discloses paid consulting work for Lilly, the study sponsor and maker of orforglipron and tirzepatide, and for Novo Nordisk, which makes semaglutide ^[1]. The trial was funded by Lilly, and the findings, while published in a peer-reviewed journal, come from a single company-backed study ^[1][2].

What happens next

The researchers say more studies are needed comparing GLP-1 treatments and testing how patients maintain weight loss over a lifetime while balancing lifestyle and cost ^[1]. No dates for additional trials or regulatory filings tied to this maintenance use are given in the available coverage.