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Vol 73, No 4 (2022)
Review paper
Submitted: 2022-01-09
Accepted: 2022-01-17
Published online: 2022-05-20
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Tirzepatide — a dual GIP/GLP-1 receptor agonist — a new antidiabetic drug with potential metabolic activity in the treatment of type 2 diabetes

Mariusz Nowak1, Wojciech Nowak2, Władysław Grzeszczak3
DOI: 10.5603/EP.a2022.0029
·
Pubmed: 35593668
·
Endokrynol Pol 2022;73(4):745-755.
Affiliations
  1. Pathophysiology Division, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
  2. Science Students’ Association, Pathophysiology Division, Department of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland., Poland
  3. Department of Internal Medicine, Diabetology and Nephrology, FMS in Zabrze, SUM 41-800 Zabrze , Poland.

open access

Vol 73, No 4 (2022)
Review Article
Submitted: 2022-01-09
Accepted: 2022-01-17
Published online: 2022-05-20

Abstract

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for up to 65% of postprandial insulin secretion. Tirzepatide, developed by Eli Lilly, is a dual GIP/GLP-1 receptor agonist in the form of a synthetic linear peptide; its acylation technology allows it to bind to albumin, thus making it possible to dose the drug once a week. This review summarizes the key characteristics and pharmacokinetics of tirzepatide.

The authors present the results of a phase 1, 2, and 3 clinical trial on the effects of tirzepatide on glycaemic and lipid control and the beneficial effects on body weight in a dose-dependent manner in patients with type 2 diabetes mellitus (T2DM). Tirzepatide has the ability to reduce glycaemic levels, improve insulin sensitivity, reduce body weight, and improve lipid metabolism, which is critically important in T2DM.

Tirzepatide administered by weekly subcutaneous injections appears to be a promising drug for the treatment of T2DM as well as cardiometabolic disorders. The mechanism of action and safety profile of tirzepatide potentially fills important gaps in the current treatment of T2DM.

Abstract

The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for up to 65% of postprandial insulin secretion. Tirzepatide, developed by Eli Lilly, is a dual GIP/GLP-1 receptor agonist in the form of a synthetic linear peptide; its acylation technology allows it to bind to albumin, thus making it possible to dose the drug once a week. This review summarizes the key characteristics and pharmacokinetics of tirzepatide.

The authors present the results of a phase 1, 2, and 3 clinical trial on the effects of tirzepatide on glycaemic and lipid control and the beneficial effects on body weight in a dose-dependent manner in patients with type 2 diabetes mellitus (T2DM). Tirzepatide has the ability to reduce glycaemic levels, improve insulin sensitivity, reduce body weight, and improve lipid metabolism, which is critically important in T2DM.

Tirzepatide administered by weekly subcutaneous injections appears to be a promising drug for the treatment of T2DM as well as cardiometabolic disorders. The mechanism of action and safety profile of tirzepatide potentially fills important gaps in the current treatment of T2DM.

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Keywords

type 2 diabetes; glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); tirzepatide

About this article
Title

Tirzepatide — a dual GIP/GLP-1 receptor agonist — a new antidiabetic drug with potential metabolic activity in the treatment of type 2 diabetes

Journal

Endokrynologia Polska

Issue

Vol 73, No 4 (2022)

Article type

Review paper

Pages

745-755

Published online

2022-05-20

Page views

7296

Article views/downloads

1822

DOI

10.5603/EP.a2022.0029

Pubmed

35593668

Bibliographic record

Endokrynol Pol 2022;73(4):745-755.

Keywords

type 2 diabetes
glucagon-like peptide-1 (GLP-1)
glucose-dependent insulinotropic polypeptide (GIP)
tirzepatide

Authors

Mariusz Nowak
Wojciech Nowak
Władysław Grzeszczak

References (65)
  1. Johansson K, Sonne D, Knop F, et al. What is on the horizon for type 2 diabetes pharmacotherapy? – An overview of the antidiabetic drug development pipeline. Expert Opin Drug Discov. 2020; 15(11): 1253–1265.
    CrossRef
  2. Nowak M, Grzeszczak W. Imeglimin: a new antidiabetic drug with potential future in the treatment of patients with type 2 diabetes. Endokrynol Pol. 2022; 73(2): 361–370.
    CrossRefPubMed
  3. Elrick H, Stimmler L, Hlad CJ, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24: 1076–1082.
    CrossRefPubMed
  4. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986; 63(2): 492–498.
    CrossRefPubMed
  5. Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016; 4(6): 525–536.
    CrossRefPubMed
  6. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368(9548): 1696–1705.
    CrossRefPubMed
  7. Gasbjerg LS, Helsted MM, Hartmann B, et al. Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals. Diabetes. 2019; 68(5): 906–917.
    CrossRefPubMed
  8. Christensen M, Vedtofte L, Holst JJ, et al. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011; 60(12): 3103–3109.
    CrossRefPubMed
  9. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007; 132(6): 2131–2157.
    CrossRefPubMed
  10. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001; 86(8): 3717–3723.
    CrossRefPubMed
  11. Calanna S, Christensen M, Holst JJ, et al. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013; 56(5): 965–972.
    CrossRefPubMed
  12. Calanna S, Christensen M, Holst JJ, et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes: systematic review and meta-analysis of clinical studies. Diabetes Care. 2013; 36(10): 3346–3352.
    CrossRefPubMed
  13. Vilsbøll T, Krarup T, Madsbad S, et al. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002; 45(8): 1111–1119.
    CrossRefPubMed
  14. Chia CW, Carlson OD, Kim W, et al. Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes. 2009; 58(6): 1342–1349.
    CrossRefPubMed
  15. Frías JP. Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020; 15(6): 379–394.
    CrossRefPubMed
  16. Elahi D, McAloon-Dyke M, Fukagawa NK, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994; 51(1): 63–74.
    CrossRefPubMed
  17. Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013; 5(209): 209ra151.
    CrossRefPubMed
  18. Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021; 12(1): 143–157.
    CrossRefPubMed
  19. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018; 18: 3–14.
    CrossRefPubMed
  20. Willard FS, Douros JD, Gabe MBn, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020; 5(17).
    CrossRefPubMed
  21. Ohwaki K, Furihata K, Oura T, et al. 969-P: Effects of Tirzepatide on Meal Intake and Appetite in Japanese Patients with Type 2 Diabetes. Diabetes. 2020; 69(Suppl 1).
    CrossRef
  22. Furihata K, Mimura H, Urva S, et al. A phase 1 multiple-ascending dose study of tirzepatide in Japanese participants with type 2 diabetes. Diabetes Obes Metab. 2022; 24(2): 239–246.
    CrossRefPubMed
  23. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018; 392(10160): 2180–2193.
    CrossRefPubMed
  24. Frias JP, Nauck MA, Van J, et al. 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. Diabetes Obes Metab. 2020; 22(6): 938–946.
    CrossRefPubMed
  25. Thomas MK, Nikooienejad A, Bray R, et al. Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2021; 106(2): 388–396.
    CrossRefPubMed
  26. Russo GT, Giorda CB, Cercone S, et al. BetaDecline Study Group. Beta cell stress in a 4-year follow-up of patients with type 2 diabetes: A longitudinal analysis of the BetaDecline Study. Diabetes Metab Res Rev. 2018; 34(6): e3016.
    CrossRefPubMed
  27. Lee PDK, Lustig RH, Lenders C, et al. Glaser Pediatric Research Network Obesity Study Group. Insulin-like growth factor binding protein 1 predicts insulin sensitivity and insulin area-under-the-curve in obese, nondiabetic adolescents. Endocr Pract. 2016; 22(2): 136–142.
    CrossRefPubMed
  28. Liew CF, Wise SD, Yeo KP, et al. Insulin-like growth factor binding protein-1 is independently affected by ethnicity, insulin sensitivity, and leptin in healthy, glucose-tolerant young men. J Clin Endocrinol Metab. 2005; 90(3): 1483–1488.
    CrossRefPubMed
  29. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017; 23(7): 804–814.
    CrossRefPubMed
  30. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021; 398(10295): 143–155.
    CrossRefPubMed
  31. Frías JP, Davies MJ, Rosenstock J, et al. SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021; 385(6): 503–515.
    CrossRefPubMed
  32. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021; 398(10300): 583–598.
    CrossRefPubMed
  33. Del Prato S, Kahn SE, Pavo I, et al. SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021; 398(10313): 1811–1824.
    CrossRefPubMed
  34. Dahl D, Onishi Y, Norwood P, et al. 80-LB: Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist, Is Effective and Safe When Added to Basal Insulin for Treatment of Type 2 Diabetes (SURPASS-5). Diabetes. 2021; 70(Suppl 1).
    CrossRef
  35. A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants with Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) with or without Metformin (SURPASS-6). https://clinicaltrials.gov/ct2/show/NCT04537923 (31 August 2021).
  36. A Study of Tirzepatide (LY3298176) Compared with Duaglutide On Major Cardiovascular Events in Participants with Type 2 Diabetes (SURPASS-CVOT). https://clinicaltrials.gov/ct2/show/NCT04255433 (31 August 2021).
  37. Ganda OmP, Bhatt DL, Mason RP, et al. Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management. J Am Coll Cardiol. 2018; 72(3): 330–343.
    CrossRefPubMed
  38. Wilson JM, Nikooienejad A, Robins DA, et al. The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes Obes Metab. 2020; 22(12): 2451–2459.
    CrossRefPubMed
  39. Gerstein HC, Colhoun HM, Dagenais GR, et al. REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019; 394(10193): 121–130.
    CrossRefPubMed
  40. Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016; 375(4): 311–322.
    CrossRefPubMed
  41. Rizzo M, Nikolic D, Patti AM, et al. GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms. Biochim Biophys Acta Mol Basis Dis. 2018; 1864(9 Pt B): 2814–2821.
    CrossRefPubMed
  42. Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018; 27(4): 740–756.
    CrossRefPubMed
  43. Matikainen N, Söderlund S, Björnson E, et al. Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single-centre randomized controlled study. Diabetes Obes Metab. 2019; 21(1): 84–94.
    CrossRefPubMed
  44. Xiao C, Dash S, Lewis GF. Mechanisms of incretin effects on plasma lipids and implications for the cardiovascular system. Cardiovasc Hematol Agents Med Chem. 2012; 10(4): 289–294.
    CrossRefPubMed
  45. Kim SJ, Nian C, McIntosh CHS. GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J Lipid Res. 2010; 51(11): 3145–3157.
    CrossRefPubMed
  46. Asmar M, Asmar A, Simonsen L, et al. GIP-induced vasodilation in human adipose tissue involves capillary recruitment. Endocr Connect. 2019; 8(6): 806–813.
    CrossRefPubMed
  47. Hartman ML, Sanyal AJ, Loomba R, et al. Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes. Diabetes Care. 2020; 43(6): 1352–1355.
    CrossRefPubMed
  48. White PJ, Newgard CB. Branched-chain amino acids in disease. Science. 2019; 363(6427): 582–583.
    CrossRefPubMed
  49. Rhee EP, Cheng S, Larson MG, et al. Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J Clin Invest. 2011; 121(4): 1402–1411.
    CrossRefPubMed
  50. Flores-Guerrero JL, Osté MCJ, Kieneker LM, et al. Plasma Branched-Chain Amino Acids and Risk of Incident Type 2 Diabetes: Results from the PREVEND Prospective Cohort Study. J Clin Med. 2018; 7(12).
    CrossRefPubMed
  51. Newgard CB. Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab. 2017; 25(1): 43–56.
    CrossRefPubMed
  52. Pirro V, Roth KD, Lin Y, 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; 107(2): 363–378.
    CrossRefPubMed
  53. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64(1): 73–84.
    CrossRefPubMed
  54. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1): 328–357.
    CrossRefPubMed
  55. Loomba R, Abraham M, Unalp A, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012; 56(3): 943–951.
    CrossRefPubMed
  56. Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008; 48(3): 792–798.
    CrossRefPubMed
  57. Cusi K, Sattar N, García-Pérez LE, et al. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018; 35(10): 1434–1439.
    CrossRefPubMed
  58. Retnakaran R, Cull CA, Thorne KI, et al. UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006; 55(6): 1832–1839.
    CrossRefPubMed
  59. Costacou T, Orchard TJ. Cumulative Kidney Complication Risk by 50 Years of Type 1 Diabetes: The Effects of Sex, Age, and Calendar Year at Onset. Diabetes Care. 2018; 41(3): 426–433.
    CrossRefPubMed
  60. Davies M, Chatterjee S, Khunti K. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol. 2016; 8: 61–81.
    CrossRefPubMed
  61. Arnouts P, Bolignano D, Nistor I, et al. Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephrol Dial Transplant. 2014; 29(7): 1284–1300.
    CrossRefPubMed
  62. Urva S, Quinlan T, Landry J, et al. Effects of Renal Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide. Clin Pharmacokinet. 2021; 60(8): 1049–1059.
    CrossRefPubMed
  63. Longato E, Di Camillo B, Sparacino G, et al. Better cardiovascular outcomes of type 2 diabetic patients treated with GLP-1 receptor agonists versus DPP-4 inhibitors in clinical practice. Cardiovasc Diabetol. 2020; 19(1): 74.
    CrossRefPubMed
  64. Husain M, Bain SC, Holst AG, et al. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020; 19(1): 156.
    CrossRefPubMed
  65. Fisman EZ, Tenenbaum A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol. 2021; 20(1): 225.
    CrossRefPubMed

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