• Sean Wharton, Thomas Blevins, Lisa Connery, Julio Rosenstock, Sohini Raha, Rong Liu, Xiaosu Ma, Kieren J Mather, Axel Haupt, Deborah Robins, Edward Pratt, Christof Kazda, Manige Konig, and GZGI Investigators.
• From McMaster University, York University, and Wharton Weight Management Clinic - all in Toronto (S.W.); Texas Diabetes and Endocrinology, Austin (T.B.), and Velocity Clinical Research at Medical City, Dallas (J.R.) - both in Texas; Alliance for Multispecialty Research, Norman, OK (L.C.); and Eli Lilly, Indianapolis (S.R., R.L., X.M., K.J.M., A.H., D.R., E.P., C.K., M.K.).
• N. Engl. J. Med. 2023 Sep 7; 389 (10): 877888877-888.

BackgroundObesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.MethodsIn this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).ResultsA total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.ConclusionsDaily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).Copyright © 2023 Massachusetts Medical Society.

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