Lilly’s orforglipron has helped people maintain weight loss after switching from injectable incretins to oral GLP-1 therapy in first-of-its-kind Phase III trial. 

The ATTAIN-MAINTAIN trial evaluated orforglipron, a once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, for weight maintenance over 52 weeks after initial treatment for 72 weeks with the highest tolerated doses of Wegovy (semaglutide) or Zepbound (tirzepatide). 

The study analysed participants from SURMOUNT-5 who were offered the opportunity to be re-randomised to receive orforglipron or placebo.  

At one year, orforglipron met the primary and all key secondary endpoints compared to placebo, delivering superior weight maintenance as an adjunct to a healthy diet and physical activity, using the efficacy estimand and modified treatment-regimen estimand. 

“Obesity is a chronic, progressive disease, and sustaining weight loss remains a significant challenge for many,” said Kenneth Custer, 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.” 

Superior maintenance of weight reduction compared to placebo

In the study, orforglipron met the primary endpoint of superior percent maintenance of body weight reduction compared to placebo, among SURMOUNT-5 participants who previously reached a body weight plateau.  

In pre-specified analyses at 52 weeks, participants who switched to orforglipron from Wegovy maintained their previously achieved weight loss with an average difference of 0.9kg, while those who switched to orforglipron from Zepbound maintained their previously achieved weight loss with an average difference of 5kg, using the efficacy estimand.  

In post-hoc analyses at 24 weeks, the last time point before placebo participants were eligible for orforglipron as rescue therapy, the change in body weight from ATTAIN-MAINTAIN baseline for patients switching to orforglipron from Wegovy was -0.1kg vs. 9.4kg for placebo. Likewise, for patients switching to orforglipron from Zepbound, the change from baseline was 2.6kg vs. 9.1kg for placebo. 

The most common adverse events were gastrointestinal-related and generally mild-to-moderate in severity. 

Lilly has submitted a new drug application to the US Food and Drug Administration (FDA) for orforglipron for the treatment of adults with obesity or overweight. 

Diana Turner, Deputy Editor, DDW