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Randomized Controlled Trial
. 2020 Jun;22(6):938-946.
doi: 10.1111/dom.13979. Epub 2020 Feb 11.

Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens

Juan Pablo Frias  1 , Michael A Nauck  2 , Joanna Van  3 , Charles Benson  4 , Ross Bray  4 , Xuewei Cui  4 , Zvonko Milicevic  5 , Shweta Urva  4 , Axel Haupt  4 , Deborah A Robins  4
Affiliations
Randomized Controlled Trial

Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens

Juan Pablo Frias et al. Diabetes Obes Metab. 2020 Jun.

Abstract

Aim: To assess the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes.

Materials and methods: In this double-blind, placebo-controlled study, patients were randomized (1:1:1:1) to receive either once-weekly subcutaneous tirzepatide or placebo. The tirzepatide dose groups and dose-escalation regimens were: 12 mg (4 mg weeks 0-3; 8 mg weeks 4-7; 12 mg weeks 8-11), 15 mg-1 (2.5 mg weeks 0-1; 5 mg weeks 2-3; 10 mg weeks 4-7; 15 mg weeks 8-11) and 15 mg-2 (2.5 mg weeks 0-3; 7.5 mg weeks 4-7; 15 mg weeks 8-11). The primary objective was to compare tirzepatide with placebo in HbA1c change from baseline at 12 weeks.

Results: Overall, 111 patients were randomized: placebo, 26; tirzepatide 12 mg, 29; tirzepatide 15 mg-1, 28; tirzepatide 15 mg-2, 28. The mean age was 57.4 years, HbA1c 8.4% and body mass index 31.9 kg/m2 . At week 12, absolute HbA1c change from baseline (SE) was greater in the tirzepatide treatment groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19]). The incidence of nausea was: placebo, 7.7%; 12 mg group, 24.1%; 15 mg-1 group, 39.3%; 15 mg-2 group, 35.7%. Three patients discontinued the treatment because of adverse events, one from each of the placebo, 12 mg and 15 mg-1 groups.

Conclusions: Tirzepatide treatment for 12 weeks resulted in clinically significant reductions in HbA1c. This suggests that lower starting doses and smaller dose increments are associated with a more favourable side effect profile.

Keywords: antidiabetic drug; glucagon-like peptide-1 analogue; glucose-dependent insulinotropic peptide; incretin therapy; randomized trial; type 2 diabetes.

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Conflict of interest statement

J.P.F. declares grants from Eli Lilly during the conduct of the study; grants from AbbVie, Akcea, Allergan, AstraZeneca, Boehringer Ingelheim, BMS, Cirius, CymaBay, Enanta, Genentech, Intercept, Janssen, Johnson and Johnson, Lexicon, Ligand, Madrigal, Merck, Mylan, NGM, Novartis, Novo Nordisk, Pfizer, Sanofi and Theracos; advisory board and consulting from Boehringer Ingelheim, Gilead, Johnson and Johnson, Eli Lilly, Merck, Novo Nordisk and Sanofi; and speaker bureau from Merck, Sanofi. M.A.N. has received compensation for lectures or advisory board membership from AstraZeneca, Berlin‐Chemie/Menarini, Medscape, Merck Sharp & Dohme, Novo Nordisk, Sanofi‐Aventis, Takeda and Sun Pharma; and received grant support from Berlin‐Chemie/Menarini, Eli Lilly and Company, Merck Sharp & Dohme and Novo Nordisk. J.V. declares research support from Aptinyx, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Genentech, Lexicon, Melior, Mylan, Novo Nordisk, Regenesis and Sanofi. R.B., X.C., C.B., S.U., Z.M., D.A.R. and A.H. are employees and shareholders of Eli Lilly and Company.

Figures

Figure 1
Figure 1
(A) Study design; (B) patient disposition. mITT, modified intent‐to‐treat; QW, once‐weekly; TZP, tirzepatide
Figure 2
Figure 2
Efficacy outcomes of treatment with tirzepatide at 12 weeks treatment: (A) HbA1c (%); (B) fasting blood glucose (FBG); (C) body weight; (D) waist circumference. CFB, change from baseline; LS, least squares; mITT, modified intent‐to‐treat; MMRM, mixed effect model repeat measurement; SE, standard error; TZP, tirzepatide; mITT population, MMRM on treatment analysis; P‐values versus placebo
See this image and copyright information in PMC

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