Abstract | Importance: Objective: Design, Setting, and Participants: Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin. Interventions: Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. Main Outcomes and Measures: The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. Results: Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%). Conclusions and Relevance: Trial Registration: ClinicalTrials.gov Identifier: NCT04039503.
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Authors | Dominik Dahl, Yukiko Onishi, Paul Norwood, Ruth Huh, Ross Bray, Hiren Patel, Ángel Rodríguez |
Journal | JAMA
(JAMA)
Vol. 327
Issue 6
Pg. 534-545
(02 08 2022)
ISSN: 1538-3598 [Electronic] United States |
PMID | 35133415
(Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
- Blood Glucose
- Glycated Hemoglobin A
- Hypoglycemic Agents
- Insulin Glargine
- Gastric Inhibitory Polypeptide
- Metformin
- tirzepatide
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Topics |
- Blood Glucose
(analysis)
- Diabetes Mellitus, Type 2
(blood, drug therapy)
- Dose-Response Relationship, Drug
- Double-Blind Method
- Drug Therapy, Combination
- Female
- Gastric Inhibitory Polypeptide
(administration & dosage, adverse effects)
- Glycated Hemoglobin
(analysis)
- Glycemic Control
(methods)
- Humans
- Hypoglycemic Agents
(administration & dosage, adverse effects, therapeutic use)
- Injections, Subcutaneous
- Insulin Glargine
(administration & dosage)
- Male
- Metformin
(therapeutic use)
- Middle Aged
- Weight Loss
(drug effects)
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