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Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.

Publication ,  Journal Article
Pirro, V; Roth, KD; Lin, Y; Willency, JA; Milligan, PL; Wilson, JM; Ruotolo, G; Haupt, A; Newgard, CB; Duffin, KL
Published in: J Clin Endocrinol Metab
January 18, 2022

CONTEXT: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. OBJECTIVE: Assess plasma metabolome changes mediated by tirzepatide. DESIGN: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. SETTING: Post hoc analysis. PARTICIPANTS: 259 subjects with T2D. INTERVENTION(S): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. MAIN OUTCOME MEASURE(S): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. RESULTS: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. CONCLUSIONS: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

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Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

January 18, 2022

Volume

107

Issue

2

Start / End Page

363 / 378

Location

United States

Related Subject Headings

  • Young Adult
  • Weight Loss
  • Triglycerides
  • Recombinant Fusion Proteins
  • Receptors, Gastrointestinal Hormone
  • Middle Aged
  • Metabolomics
  • Male
  • Injections, Subcutaneous
  • Immunoglobulin Fc Fragments
 

Citation

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Pirro, V., Roth, K. D., Lin, Y., Willency, J. A., Milligan, P. L., Wilson, J. M., … Duffin, K. L. (2022). Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab, 107(2), 363–378. https://doi.org/10.1210/clinem/dgab722
Pirro, Valentina, Kenneth D. Roth, Yanzhu Lin, Jill A. Willency, Paul L. Milligan, Jonathan M. Wilson, Giacomo Ruotolo, Axel Haupt, Christopher B. Newgard, and Kevin L. Duffin. “Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.J Clin Endocrinol Metab 107, no. 2 (January 18, 2022): 363–78. https://doi.org/10.1210/clinem/dgab722.
Pirro V, Roth KD, Lin Y, Willency JA, Milligan PL, Wilson JM, et al. Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab. 2022 Jan 18;107(2):363–78.
Pirro, Valentina, et al. “Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.J Clin Endocrinol Metab, vol. 107, no. 2, Jan. 2022, pp. 363–78. Pubmed, doi:10.1210/clinem/dgab722.
Pirro V, Roth KD, Lin Y, Willency JA, Milligan PL, Wilson JM, Ruotolo G, Haupt A, Newgard CB, Duffin KL. Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes. J Clin Endocrinol Metab. 2022 Jan 18;107(2):363–378.
Journal cover image

Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

January 18, 2022

Volume

107

Issue

2

Start / End Page

363 / 378

Location

United States

Related Subject Headings

  • Young Adult
  • Weight Loss
  • Triglycerides
  • Recombinant Fusion Proteins
  • Receptors, Gastrointestinal Hormone
  • Middle Aged
  • Metabolomics
  • Male
  • Injections, Subcutaneous
  • Immunoglobulin Fc Fragments