Adipositas - Ursachen, Folgeerkrankungen, Therapie 2022; 16(03): 124-131
DOI: 10.1055/a-1904-5552
Review

GLP-1-basierte Polypharmakotherapien als wegweisender neuer Ansatz in der Behandlung von Adipositas und Diabetes

GLP-1-based Polypharmacotherapies as a Pioneering New Approach to the Treatment of Obesity and Diabetes
Timo D. Müller
1   Institut für Diabetes und Adipositas, Helmholtz Diabetes Center am Helmholtz Zentrum München, Deutschland
2   Deutsches Zentrum für Diabetesforschung (DZD), München, Deutschland
› Author Affiliations

Zusammenfassung

Die Prävalenz von Adipositas, Typ-2-Diabetes und dem metabolischen Syndrom nimmt weltweit dramatisch zu. Bestehende Therapieoptionen sind – mit Ausnahme der bariatrischen Chirurgie – nur unzureichend wirksam. Vielversprechende neue Ansätze zur nachhaltigen und effektiven Adipositastherapie basieren besonders auf biochemisch optimierten und langwirksamen Agonisten am Rezeptor für das glukagonähnliche Peptide-1 (GLP-1) sowie auf unimolekularen Ko-Agonisten an den Rezeptoren für GLP-1 und dem glukoseabhängigen insulinotropen Polypeptid (GIP). Jüngste klinische Studien belegen sowohl für den GLP-1R-Agonisten Semaglutid wie auch für den GIPR/GLP-1R-Ko-Agonisten Tirzepatide bei tolerablem Sicherheitsprofil einen Gewichtsverlust>10%.

Abstract

The prevalence of obesity, type 2 diabetes and metabolic syndrome is increasing dramatically worldwide. Existing treatment options – with the exception of bariatric surgery – are insufficiently effective. Promising new approaches to sustainable and effective obesity therapy are based in particular on biochemically optimized and long-acting agonists at the receptor for glucagon-like peptide-1 (GLP-1) and on unimolecular co-agonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Recent clinical studies show a weight loss of>10% for both the GLP-1R agonist semaglutide and the GIPR/GLP-1R co-agonist tyrecepatide with a tolerable safety profile.



Publication History

Article published online:
11 October 2022

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  • Literatur

  • 1 GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, Reitsma MB. et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 2017; 377: 13-27
  • 2 Muller TD, Bluher M, Tschop MH. et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21: 201-223
  • 3 Muller TD, Clemmensen C, Finan B. et al. Anti-Obesity Therapy: from Rainbow Pills to Polyagonists. Pharmacol Rev 2018; 70: 712-746
  • 4 Aberle J, Lautenbach A, Meyhofer S. et al. Obesity and Diabetes. Exp Clin Endocrinol Diabetes 2021; 129: S44-S51
  • 5 Del Prato S, Kahn SE, Pavo I. et al. 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 2021; 1811-1824
  • 6 Frias JP, Davies MJ, Rosenstock J. et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021; 385: 503-515
  • 7 Ludvik B, Giorgino F, Jodar 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: 583-598
  • 8 Rosenstock J, Wysham C, Frias 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: 143-155
  • 9 Davies M, Faerch L, Jeppesen OK. et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021; 397: 971-984
  • 10 Rubino D, Abrahamsson N, Davies M. et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021; 325: 1414-1425
  • 11 Rubino DM, Greenway FL, Khalid U. et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022; 327: 138-150
  • 12 Wadden TA, Bailey TS, Billings LK. et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021; 325: 1403-1413
  • 13 Wilding JPH, Batterham RL, Calanna S. et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021; 384: 989-1002
  • 14 Muller TD, Finan B, Bloom SR. et al. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019; 30: 72-130
  • 15 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728-742
  • 16 Pi-Sunyer X, Astrup A, Fujioka K. et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med 2015; 373: 11-22
  • 17 Tak YJ, Lee SY. Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review. World J Mens Health 2021; 39: 208-221
  • 18 Day JW, Ottaway N, Patterson JT. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 2009; 5: 749-757
  • 19 Finan B, Ma T, Ottaway N. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 2013; 5: 209ra151
  • 20 Finan B, Yang B, Ottaway N. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 2015; 21: 27-36
  • 21 Dahl D, Onishi Y, Norwood P. et al. 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 2022; 327: 534-545
  • 22 Jastreboff AM, Aronne LJ, Ahmad NN. et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022; 387: 205-2016
  • 23 Nauck MA, Heimesaat MM, Orskov C. et al. 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 1993; 91: 301-307
  • 24 Killion EA, Wang J, Yie J. et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci Transl Med 2018; 10: eaat3392
  • 25 Mroz PA, Finan B, Gelfanov V. et al. Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mol Metab 2019; 20: 51-62
  • 26 Zhang Q, Delessa CT, Augustin R. et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 2021; 33: 833-844
  • 27 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
  • 28 Sparre-Ulrich AH, Hansen LS, Svendsen B. et al. Species-specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors. Br J Pharmacol 2016; 173: 27-38
  • 29 Samms RJ, Christe ME, Collins KA. et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest 2021; 131: e146353
  • 30 Borner T, Geisler CE, Fortin SM. et al. GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models. Diabetes 2021; 70: 2545-2553
  • 31 Adriaenssens AE, Biggs EK, Darwish T. et al. Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake. Cell Metab 2019; 30: 987-996
  • 32 Novikoff A, O'Brien SL, Bernecker M. et al. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Mol Metab 2021; 49: 101181