Skip to main content
SpringerLink
Log in

Gastrointestinale Hormone – zunehmende arzneitherapeutische Bedeutung bei Stoffwechselerkrankungen

Gastrointestinal hormones: their increasing pharmacotherapeutic relevance in metabolic diseases

  • Arzneimitteltherapie
  • Published:
Die Innere Medizin Aims and scope Submit manuscript

Zusammenfassung

Gastrointestinale Hormone nehmen eine wichtige Rolle in der endokrinen Kommunikation zwischen Darm, Pankreas, Leber und Gehirn ein. Glucagon-like-peptide-1-Rezeptor-Agonisten (GLP-1RA) sind als Therapeutika bei Diabetes mellitus Typ 2 mittlerweile fest etabliert. Eine pharmakologische Weiterentwicklung sind die multiplen Agonisten, die als Liganden an mehreren Darmhormonrezeptoren fungieren. Zielstrukturen für die Wirkung sind hier neben „glucagon-like peptide 1“ (GLP-1) die Rezeptoren von „glucose-dependent insulinotropic polypeptide“ (GIP) und Glukagon. Durch die multiple Agonistenwirkung sollen glykämische Wirkungen und Effekte auf das Körpergewicht verstärkt werden. Der vorliegende Beitrag gibt eine Übersicht über GLP-1RA und die multiplen Agonisten. Unter den dualen Agonisten hat der GIP/GLP-1-Agonist Tirzepatid mittlerweile eine Zulassung zur Behandlung des Typ-2-Diabetes. Klinische Zulassungsstudien zum Einsatz von Tirzepatid bei Adipositas werden derzeit durchgeführt. Die aktuellen Daten aus Studien zu GLP-1/Glukagon-Agonisten und Dreifachagonisten werden hier ebenfalls zusammengefasst.

Abstract

Gastrointestinal hormones play an important role in the endocrine communication between the intestine, the pancreas, the liver and the brain. Glucagon-like peptide‑1 receptor agonists (GLP-1RA) are established therapeutic agents in the treatment of type‑2 diabetes. Multiple agonists acting as ligands on various gastrointestinal hormone receptors are a novel pharmacological development. In addition to glucagon-like peptide 1 (GLP-1), these multiple agonists also have glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptors as target structures for their pharmacological action. The multiple agonist action is designed to increase glycaemic effects as well as the effects on body weight. This article provides an overview of GLP-1RA and the multiple agonists. Among the dual agonists, the GIP/GLP-1-agonist tirzeptide has been approved for the treatment of type‑2 diabetes, and clinical studies with tirzepatide as a treatment for obesity are ongoing. The currently available data on studies with GLP-1/glucagon agonists and triple agonists are also summarized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. Asano M, Sekikawa A, Kim H et al (2021) Pharmacokinetics, safety, tolerability and efficacy of cotadutide, a glucagon-like peptide‑1 and glucagon receptor dual agonist, in phase 1 and 2 trials in overweight or obese participants of Asian descent with or without type 2 diabetes. Diabetes Obes Metab 23(1):1859–1867

    Article  CAS  Google Scholar 

  2. Baggio LL, Drucker DJ (2007) Biology of incretins: GLP‑1 and GIP. Gastroenterology 132:2131–2157

    Article  CAS  Google Scholar 

  3. Clemmensen C, Finan B, Müller TD et al (2019) Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. Nat Rev Endocrinol 15:90–104

    Article  Google Scholar 

  4. Creutzfeldt W (1979) The incretin concept today. Diabetologia 16:75–85

    Article  CAS  Google Scholar 

  5. Dahl D, Onishi Y, Norwood P et al (2022) Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS‑5 randomized clinical trial. JAMA 327:534–545

    Article  CAS  Google Scholar 

  6. Del Prato S, Gallwitz B, Holst JJ et al (2022) The incretin/glucagon system as a target for pharmacotherapy of obesity. Obes Rev 23:e13372. https://doi.org/10.1111/obr.13372

    Article  CAS  Google Scholar 

  7. Del Prato S, Kahn SE, Pavo I et al (2021) 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 398:1811–1824

    Article  Google Scholar 

  8. Exenatide: AC 2993, AC002993, AC2993A, exendin 4, LY2148568 (2004) Drugs R D. 5:35–40

  9. Finan B, Clemmensen C, Müller TD (2015) Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide‑1 based multi-agonists. Mol Cell Endocrinol 418:42–54

    Article  CAS  Google Scholar 

  10. Frías JP, Davies MJ, Rosenstock J et al (2021) Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 385:503–515

    Article  Google Scholar 

  11. Gallwitz B (2022) Clinical perspectives on the use of the GIP/GLP‑1 receptor agonist tirzepatide for the treatment of type‑2 diabetes and obesity. Front Endocrinol. https://doi.org/10.3389/fendo.2022.1004044

    Article  Google Scholar 

  12. Inagaki N, Takeuchi M, Oura T et al (2022) Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J‑mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol 10:623–633

    Article  CAS  Google Scholar 

  13. Kadowaki T, Chin R, Ozeki A et al (2022) Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J‑combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol 10:634–644

    Article  CAS  Google Scholar 

  14. Ludvik B, Giorgino F, Jódar E et al (2021) 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 398:583–598

    Article  CAS  Google Scholar 

  15. Müller TD, Blüher M, Tschöp MH et al (2021) Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2021:1–23

    Google Scholar 

  16. Nahra R, Wang T, Gadde KM et al (2021) Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44:1433–1442

    Article  CAS  Google Scholar 

  17. Nauck MA, Heimesaat MM, Orskov C et al (1993) Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type‑2 diabetes mellitus. J Clin Invest 91:301–307

    Article  CAS  Google Scholar 

  18. Nauck MA, Kleine N, Orskov C et al (1993) Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:741–744

    Article  CAS  Google Scholar 

  19. Nauck MA, Quast DR, Wefers J et al (2021) GLP‑1 receptor agonists in the treatment of type 2 diabetes—state-of-the-art. Mol Metab. https://doi.org/10.1016/j.molmet.2020.101102

    Article  Google Scholar 

  20. Nauck MA, Quast DR, Wefers J et al (2021) The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab 23(Suppl 3):5–29

    Article  CAS  Google Scholar 

  21. Parker VER, Hoang T, Schlichthaar H (2022) Efficacy and safety of cotadutide, a dual glucagon-like peptide‑1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 24:1360–1369

    Article  CAS  Google Scholar 

  22. Rosenstock J, Wysham C, Frías JP et al (2021) 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 398:143–155

    Article  CAS  Google Scholar 

  23. Sattar N, Lee MMY, Kristensen SL et al (2021) Cardiovascular, mortality, and kidney outcomes with GLP‑1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9:653–662

    Article  CAS  Google Scholar 

  24. Sattar N, McGuire DK, Pavo I et al (2022) Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med 28:591–598

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department Innere Medizin, Abt. IV – Diabetologie, Endokrinologie, Nephrologie, Universitätsklinikum Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Deutschland

    Baptist Gallwitz

Authors
  1. Baptist Gallwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baptist Gallwitz.

Ethics declarations

Interessenkonflikt

B. Gallwitz ist in wissenschaftlichen Beiräten von AstraZeneca, Bayer Vital, Boehringer Ingelheim, Fractyl, Lilly, MSD und Novo Nordisk tätig gewesen und hat von diesen Firmen sowie von Bristol Myers Squibb und Novartis Vortragshonorare erhalten.

Für diesen Beitrag wurden vom Autor keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

M. Wehling, Mannheim

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gallwitz, B. Gastrointestinale Hormone – zunehmende arzneitherapeutische Bedeutung bei Stoffwechselerkrankungen. Innere Medizin 64, 205–210 (2023). https://doi.org/10.1007/s00108-022-01447-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00108-022-01447-0

Schlüsselwörter

Keywords

Search

Navigation