Lilly’s Obesity Pill Orforglipron Helps Maintain Weight Loss After Switch from Injectable GLP-1s

Eli Lilly’s investigational oral GLP-1 therapy, orforglipron, has shown promising Phase III trial results in helping patients maintain weight loss after switching from injectable incretin GLP-1 treatments such as Novo Nordisk’s Wegovy (semaglutide) and Lilly’s Zepbound (tirzepatide).

Data from the Phase III Attain-Maintain trial, which Lilly describes as a first-of-its-kind trial, shows that orfoglipron led to weight maintenance over 52 weeks after initial treatment for 72 weeks with injectable GLP-1s.

The findings are significant in obesity management by offering an oral alternative for long-term weight maintenance following initial success with injectable medications.

Obesity is widely recognized as a chronic disease, and sustaining weight loss over time remains a challenge in clinical care.

Injectable GLP-1 receptor agonists have transformed the therapeutic landscape by delivering substantial and sustained reductions in body weight, but their injectable nature and long-term use raise practical barriers for patients.

Related: Retatrutide, Eli Lilly’s Next-Gen Obesity Drug, Beats Out Zepbound in Late-Stage Trial

The Attain-Maintain trial is the first large-scale Phase III study specifically designed to evaluate whether an oral GLP-1 therapy can preserve weight loss gains after patients stop injectable treatments.

In the trial, adults with obesity or overweight who had previously completed the Surmount-5 study on the highest tolerated doses of Wegovy or Zepbound were re-randomized to receive once-daily oral orforglipron or placebo for 52 weeks, alongside lifestyle support.

Orforglipron met its primary endpoint of maintaining a greater proportion of prior weight loss compared with placebo. It also met all key secondary endpoints.

Among participants who transitioned from injectable therapy, those switching from Wegovy maintained their weight loss with only about a 0.9 kg average difference after 52 weeks on orforglipron compared with their weight at the start of oral therapy.

For those coming off Zepbound, the average difference was about 5.0 kg, reflecting a sustained benefit relative to placebo.

In post-hoc analyses at the 24-week mark (before placebo participants were offered rescue therapy), patients on orforglipron showed minimal weight regain, while those on placebo regained substantially more weight. This highlights the drug’s ability to support weight stabilization during a period when many people relapse after stopping injectables.

“Obesity is a chronic, progressive disease, and sustaining weight loss remains a significant challenge for many,” said Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health.

“Attain-Maintain showed that orforglipron, a once-daily oral GLP-1, helped people maintain the weight they worked hard to lose. Participants in this study were able to switch directly from the highest tolerated doses of available injectable therapies onto oral doses of orforglipron. If approved for the treatment of obesity, orforglipron could provide a convenient alternative for the millions of individuals living with obesity around the globe to continue their long-term health journey.”

Orforglipron is a once-daily oral small-molecule GLP-1 receptor agonist that can be taken without restrictions on food or water, a convenience advantage over injectable therapies that may support broader patient uptake and adherence.

Based on the Attain-Maintain results and other Phase III data, Lilly has submitted a New Drug Application (NDA) to the FDA for approval of orforglipron in adults with obesity or overweight.

In Clarivate’s newly released “Drugs to Watch 2026” report, orforglipron, along with Lilly’s other promising GLP-1 candidate retatrutide, were named as among the most important upcoming cardiometabolic therapies poised to shape the obesity and diabetes drug market over the next decade.

Recent trial results showed that retatrutide, a triple agonist targeting the GLP-1, GIP and glucagon receptors, produced significantly greater weight loss and superior knee pain reduction in a late-stage Phase III trial, outperforming the company’s current obesity blockbuster Zepbound.