Switching to the oral small molecule glucagon-like peptide-1 (GLP-1) orforglipron after taking injectable GLP-1s helped patients maintain most - but not all - of their weight loss, according to a clinical trial led by Weill Cornell Medicine and NewYork-Presbyterian investigators.
While injectable GLP-1s work well for weight loss, keeping the weight off after discontinuing the therapies is challenging. The results of the ATTAIN-MAINTAIN trial, published May 12 in Nature Medicine, showed that switching to the once-daily orforglipron pill may address this need and help maintain the cardiometabolic benefits.
Patients in the phase 3b clinical trial maintained about 75%-80% of their weight loss and health benefits, such as reduced waist circumference and improvements in blood pressure, blood sugar, triglycerides and cholesterol levels. Participants also tolerated the oral medication well, with mild to moderate gastrointestinal side effects. The study was sponsored by Eli Lilly and Company, the manufacturer of orforglipron and the injectable GLP-1 tirzepatide.
"Obesity is a chronic condition like high blood pressure, elevated cholesterol or high blood sugar and requires chronic treatment," said lead author Dr. Louis J. Aronne, director of the Comprehensive Weight Control Center and Sanford I. Weill Professor of Metabolic Research at Weill Cornell.
Yet, some patients may not want to stay long term on injectable versions of GLP-1 weight loss drugs, such as semaglutide and tirzepatide. Many want to avoid injections or may prefer the convenience of a daily pill; refrigerating the injectable versions may pose difficulties, as well. Over the long run, the oral version may also be less costly, Aronne said.
"This is the first study of its type looking at longer-term maintenance with an oral GLP-1 after taking an injectable," said Aronne, who is also an internist specializing in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center.
The ATTAIN-MAINTAIN trial
The trial enrolled patients who had achieved substantial weight loss that had plateaued while taking weekly injectable GLP-1s in the SURMOUNT-5 trial. This was a randomized, head-to-head comparison that enrolled 751 individuals and found those who took tirzepatide lost 20% of their body weight, about 50 pounds on average, while those on semaglutide lost 14% of their body weight, or about 33 pounds on average.
In the ATTAIN-MAINTAIN trial, 205 patients taking tirzepatide and 171 patients taking semaglutide were randomized to take orforglipron or placebo (no active drug) daily for a year.
Patients who switched from tirzepatide to orforglipron maintained a mean 74.7% of their body weight reduction from the SURMOUNT-5 trial compared with those in the placebo group, which maintained a mean 49.2% of their weight loss. Patients who switched from semaglutide to orforglipron maintained a mean 79.3% of their body weight reduction compared with the placebo arm, which maintained a mean 37.6% of their weight loss.
Across the 52 weeks of ATTAIN-MAINTAIN, participants treated with orforglipron gained an average of 5 kilograms (11 pounds) in the tirzepatide group and an average of 1 kilogram (2.2 pounds) in the semaglutide group.
These results were not surprising based on how the two drugs work, Aronne said. Tirzepatide acts on two targets in the body, leading to greater initial weight loss, which also may translate to regaining more weight after switching to orforglipron. Semaglutide and orforglipron act on the same single target - so this group may have maintained weight loss better after switching treatments, but they started with a less dramatic weight loss.
The authors suggest that maintaining extremely large weight losses may be harder biologically. Dual-acting oral GLP-1s are not yet available, but they are expected in the future.
"When treating a chronic disease like obesity," Aronne said, "it is key to have options throughout the weight loss journey to health."
Dr. Louis Aronne is a paid consultant and advisory board member for Eli Lilly and Company, the study sponsor and the manufacturer of orforglipron and tirzepatide.
Bridget Kuehn is a freelance writer for Weill Cornell Medicine.
