Lilly says orforglipron helped maintain weight loss after switching off Wegovy or Zepbound

Eli Lilly said on December 18, 2025 that people who switched from the weekly injections Wegovy or Zepbound to its experimental once-daily pill orforglipron kept most of the weight they had lost over the following year ^[1]. In the Phase 3 ATTAIN-MAINTAIN trial, people who switched from Wegovy (semaglutide) kept all but 0.9 kg of their earlier weight loss on average, and those who switched from Zepbound (tirzepatide) kept all but 5.0 kg ^[1].

How the trial worked

ATTAIN-MAINTAIN enrolled 376 people at 29 sites in the United States between September 13, 2024 and November 21, 2025 ^[2]. All had finished the 72-week SURMOUNT-5 trial comparing Zepbound with Wegovy and had reached a plateau, defined as less than 5% body weight change between weeks 60 and 72 ^[1]. Of those, 205 had taken Zepbound and 171 had taken Wegovy ^[2].

Participants were assigned in a 3:2 ratio to orforglipron at the highest dose they could tolerate (24 mg or 36 mg) or to placebo, along with a healthy diet and physical activity ^[1]. Dosing started at 12 mg and increased every four weeks until the assigned dose was reached, and anyone who regained 50% or more of their body weight was offered rescue orforglipron ^[1]. Orforglipron is an investigational once-daily oral GLP-1 receptor agonist that can be taken at any time of day without food or water restrictions ^[1].

What the numbers showed

At 52 weeks, the trial met its primary endpoint and all key secondary endpoints versus placebo ^[1]. In the report published in Nature Medicine, people who had taken Zepbound maintained a model-based estimate of 74.7% of their body weight reduction with orforglipron, compared with 49.2% with placebo, a treatment difference of 25.5 percentage points (95% confidence interval 14.5 to 36.5; P < 0.001) ^[2]. Among those who had taken Wegovy, the figures were 79.3% against 37.6%, a difference of 41.7 points (95% confidence interval 24.4 to 59.0; P < 0.001) ^[2].

Lilly also reported average weights. In the Wegovy group, the average starting weight in SURMOUNT-5 was 113.5 kg (250.2 lb), the weight at the switch was 95.0 kg (209.4 lb) and the weight after 52 weeks of oral maintenance was 95.9 kg (211.4 lb). In the Zepbound group, the same three figures were 115.8 kg (255.3 lb), 90.9 kg (200.4 lb) and 95.9 kg (211.4 lb) ^[1].

At 24 weeks, the last point before placebo participants could receive rescue therapy, people who had taken Wegovy changed by -0.1 kg on orforglipron versus a gain of 9.4 kg on placebo. For those who had taken Zepbound, the change was a gain of 2.6 kg on orforglipron versus 9.1 kg on placebo ^[1].

Safety and regulatory status

The most common side effects were gastrointestinal and generally mild to moderate, Lilly said, and no hepatic safety signal was observed ^[1]. Discontinuations due to adverse events were 4.8% for orforglipron after Wegovy, 7.6% for placebo after Wegovy, 7.2% for orforglipron after Zepbound and 6.3% for placebo after Zepbound ^[1]. The Nature Medicine report describes the same pattern of mostly mild-to-moderate gastrointestinal effects ^[2].

Lilly said it has submitted a new drug application to the FDA for orforglipron for adults with obesity or overweight, and that the drug received a Commissioner's National Priority Voucher ^[1]. A decision date has not been disclosed.

Why it matters for patients

Obesity is a chronic disease, and weight regain after stopping treatment is common, which makes long-term options important for people who have already lost weight ^[2]. Until now, patients and doctors choosing between an injectable and an oral GLP-1 had no trial data on switching directly from one to the other; this is described as the first clinical trial of a switch from injectable incretin therapy to an oral obesity medication for maintaining weight reduction ^[2].

Two limits matter. The trial did not include a group that stayed on Wegovy or Zepbound, so it does not show whether switching preserves weight as well as continuing the injections ^[2]. And it ran for one year, so longer-term results are not yet known ^[2].

Orforglipron is not approved for obesity. Availability, price and insurance coverage have not been disclosed.

What happens next

Lilly said detailed results will be presented at a future medical meeting and published in a peer-reviewed journal next year ^[1]. The ATTAIN Phase 3 program has enrolled more than 4,500 people with obesity or overweight ^[1]. The FDA review of the obesity application is pending, with no timeline disclosed ^[1].