• Juan P Frías, Melanie J Davies, Julio Rosenstock, Federico C Pérez Manghi, Fernández LandóLauraLFrom the National Research Institute, Los Angeles (J.P.F.); the Diabetes Research Centre, University of Leicester, and the National Institute of Health Research Leicester Biomedical Research Centre - both in Leicester, United Kingdom , Brandon K Bergman, Bing Liu, Xuewei Cui, Katelyn Brown, and SURPASS-2 Investigators.
• From the National Research Institute, Los Angeles (J.P.F.); the Diabetes Research Centre, University of Leicester, and the National Institute of Health Research Leicester Biomedical Research Centre - both in Leicester, United Kingdom (M.J.D.); the Dallas Diabetes Research Center at Medical City, Dallas (J.R.); Centro de Investigaciones Metabólicas, Buenos Aires (F.C.P.M.); and Eli Lilly, Indianapolis (L.F.L., B.K.B., B.L., X.C., K.B.).
• N. Engl. J. Med. 2021 Aug 5; 385 (6): 503-515.

BackgroundTirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown.MethodsIn an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks.ResultsThe estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide.ConclusionsIn patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).Copyright © 2021 Massachusetts Medical Society.

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