New findings published in Nature Medicine demonstrate that orforglipron, a once-daily oral nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, helps patients to maintain a significant and clinically meaningful level of weight loss after discontinuing an injectable GLP-1 therapy.
The study results suggest that switching to an oral GLP-1 could be an effective option for patients with obesity who do not want to continue with injectable therapy. While injectable GLP-1s have demonstrated significant weight loss and generally manageable side effects, cost, storage challenges, and patient preferences can pose barriers to long-term use.
“Obesity is a chronic condition like high blood pressure, elevated cholesterol, or high blood sugar and requires chronic treatment,” says Louis J. Aronne, M.D., an internist specializing in diabetes and obesity at NewYork-Presbyterian and Weill Cornell Medicine and director of the Comprehensive Weight Control Center at Weill Cornell Medicine, who led the ATTAIN-MAINTAIN trial evaluating orforglipron.
In the phase 3b trial, researchers evaluated orforglipron versus placebo for maintenance of body weight reduction among 376 patients with either obesity or a body mass index of at least 27 kilograms per square meter with obesity-related complications, and who had previously received injectable GLP-1 therapy with either tirzepatide or semaglutide as part of the SURMOUNT-5 trial, a head-to-head study of the two injectables. The researchers also assessed the impact on orforglipron on waist circumference and other cardiometabolic risk factors.
“This is the first study of its type looking at longer-term maintenance with an oral GLP-1 after taking an injectable,” says Dr. Aronne, who was also principal investigator of the SURMOUNT-5 trial.
Maintaining weight loss of this magnitude yields the vast majority of the health benefits expected from losing weight.
— Dr. Louis Aronne
Results from the ATTAIN-MAINTAIN Trial
The 205 patients who completed tirzepatide treatment and 171 patients who completed semaglutide treatment were randomized to receive either a placebo or 36 milligrams of orforglipron once daily for one year. These patients had achieved body weight plateau — defined as a less than 5% body weight change from weeks 60 to 72 during the SURMOUNT-5 trial — on an injectable GLP-1.
In the tirzepatide cohort, patients who received orforglipron maintained a mean of 74.7% of their previous body weight reduction, compared with just 49.2% for those who received placebo. On average, tirzepatide-treated patients who received orforglipron gained 11 pounds during the 52-week study.
In the semaglutide cohort, patients who received orforglipron maintained a mean of 79.3% of their previously achieved weight loss, compared with 37.6% for placebo. On average, semaglutide-treated patients who received orforglipron gained 2.2 pounds.
The greater weight gain in the tirzepatide cohort was expected, Dr. Aronne says, because tirzepatide is a dual gastric inhibitory polypeptide (GIP)/GLP-1 receptor agonist, while both semaglutide and orforglipron are single GLP-1 receptor agonists. “Dual-receptor agonists are generally more effective than single-receptor agonists, so switching from dual to single is expected to result in weight regain,” he adds.
Across both cohorts, patients maintained their decreases in waist circumference and maintained or improved glycated hemoglobin (HbA1c) levels, insulin levels, fasting serum glucose, lipid markers, and systolic blood pressure. Serious adverse events occurred in less than 2% of patients. The most common adverse events for patients receiving orforglipron were nausea, constipation, vomiting, and diarrhea, and most were mild to moderate. “Maintaining weight loss of this magnitude yields the vast majority of the health benefits expected from losing weight,” says Dr. Aronne.
Moving forward, more research is needed to compare GLP-1 treatments and assess how they can assist patients in maintaining weight loss for a lifetime in a way that complements their lifestyle and cost considerations. Says Dr. Aronne, “When treating a chronic disease like obesity, 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 manufacturer of orforglipron and Zepbound (tirzepatide). Dr. Aronne also serves as a paid advisory board member for Novo Nordisk, the manufacturer of Wegovy (semaglutide).
A version of this article originally ran on the Weill Cornell Medicine newsroom.
