Patients taking an experimental oral GLP-1 drug lost significant weight and improved their heart and metabolic risk factors in a large, international, phase III clinical trial led by investigators at Weill Cornell Medicine, McMaster University, York University and other institutions.
The results from the ATTAIN-1 trial were published Sept. 17 in the New England Journal of Medicine. The trial included 3,127 non-diabetic patients with obesity or overweight with obesity-related complications such as hypertension. Each was randomized to receive a placebo or one of three daily doses (6mg, 12mg, 36mg) of the new oral GLP-1 drug named orforglipron, in addition to a healthy diet and physical activity. Over 72 weeks, patients in the low-, medium- and high-dose orforglipron groups lost an average of 7.8%, 9.3% and 12.4% of their initial body weight, respectively, compared to 2.1% for the placebo group. Side effects were similar to other GLP-1 drugs: mild to moderate gastrointestinal symptoms such as nausea, vomiting and diarrhea.
The findings suggest that orforglipron could offer an important new option for people with obesity, especially those reluctant to use injections or who live in places where cold storage for injectable medications is limited. ATTAIN-1 represents another milestone in developing effective treatments for obesity. In addition, the distribution and storage of a small molecule is less expensive, and scalability is simpler. Given the worldwide demand, these are important factors in making treatment available to those in need."
Dr. Louis Aronne, director of the Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine and lead investigator of the ATTAIN-1 trial
Dr. Aronne is also an internist specializing in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center.
While the average weight loss was somewhat less than that seen with injectable GLP-1 therapies such as semaglutide or tirzepatide, the improvements in heart and metabolic risk factors were substantial. Individuals treated with the drug had greater reductions in waist circumference, systolic blood pressure, non-HDL cholesterol and triglyceride levels, glycated hemoglobin and other measures, compared to the placebo group.
In recent years, injectable GLP-1 drugs have transformed the treatment of obesity and obesity-related type 2 diabetes. Patients who take these drugs long-term can lose more than 15% of their body weight and experience major improvements in blood-sugar control, with reduced risks of heart attacks, strokes, chronic kidney disease, sleep apnea and other obesity-related complications.
However, injectable GLP-1 drugs cannot be taken orally because they are made of peptides—short proteins that are destroyed by the enzymes and acids of the stomach. Orforglipron, by contrast, is a "small molecule" drug that is in pill form and designed to be taken orally. Both forms of the drugs mimic the natural appetite- and digestion-regulating peptide hormone GLP-1.
The trial was sponsored by Eli Lilly, which produces orforglipron and also makes the injectable GLP-1 drug tirzepatide under the brand names Mounjaro for type 2 diabetes and Zepbound for chronic weight loss. There were 137 sites in nine countries, including the United States, Canada, Japan, Brazil, Spain and Saudi Arabia.
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