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. 2020 Oct;22(10):1886-1891.
doi: 10.1111/dom.14110. Epub 2020 Jul 13.

The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists

Shweta Urva  1 , Tamer Coskun  1 , Corina Loghin  1 , Xuewei Cui  1 , Emily Beebe  1 , Libbey O'Farrell  1 , Daniel A Briere  1 , Charles Benson  1 , Michael A Nauck  2 , Axel Haupt  1
Affiliations

The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists

Shweta Urva et al. Diabetes Obes Metab. 2020 Oct.

Abstract

The effect of dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP-1RAs in non-clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet-induced obese mice versus semaglutide or long-acting GIP analogue alone. Participants [with and without type 2 diabetes (T2DM)] from a phase 1, 4-week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP-1's effect on GE. In participants with and without T2DM, once-weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP-1RAs.

Keywords: GIP; GLP-1 analogue; antidiabetic drug; incretin therapy; type 2 diabetes.

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Conflict of interest statement

S.U., T.C., L.O., E.B., D.B., X.C., A.H., C.B. and C.L. are employees and shareholders of Eli Lilly and Company. M.A.N. has been a member of advisory boards or consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Fractyl, GlaxoSmithKline, Intarcia, Menarini/Berlin Chemie, Merck, Sharp & Dohme and NovoNordisk. His institution has received grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Intarcia, Menarini/Berlin‐Chemie, Merck, Sharp & Dohme, Novartis Pharma and Novo Nordisk A/S. He has served on the speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Menarini/Berlin Chemie, Merck, Sharp & Dohme and Novo Nordisk A/S.

Figures

FIGURE 1
FIGURE 1
Effect of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) on gastric emptying (GE) in mice. Data presented as mean ± SE of five mice per group. A, Effect of semaglutide on GE. B, Effect of tirzepatide on GE. C, Effect of long‐acting GIPRA on GE. D, Impact of ascending doses of long‐acting GIPRA, combined with a fixed dose of semaglutide, on GLP‐1‐induced GE. E, Effect of chronic treatment with semaglutide or tirzepatide on GE. + P <0.05, ++ P ≤0.01, +++ P ≤0.001 and ++++ P ≤0.0001 versus semaglutide; *P <0.05, **P ≤0.01, ***P ≤0.001 and ****P ≤0.0001 versus vehicle (VEH). Sema, semaglutide
FIGURE 2
FIGURE 2
Effect of tirzepatide on gastric emptying in healthy participants (A,B) and participants with type 2 diabetes (C,D). Data presented as geometric least squares mean (SD)
See this image and copyright information in PMC

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