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Rezeptoragonisten des „glucagon-like peptide 1”

Gemeinsame Eigenschaften und Unterschiede verschiedener Präparate

Receptor agonists of glucagon-like peptide 1

Common characteristics and differentiation between various compounds

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Der Diabetologe Aims and scope

Zusammenfassung

Hintergrund

Seit ihrer Einführung im Jahr 2006 etablierten sich die injizierbaren GLP-1-Rezeptor-Agonisten (GLP-1-RA, GLP: „glucagon-like peptide“) zur Behandlung des Diabetes mellitus Typ 2. Dies liegt zum einen an ihrer streng glukoseabhängigen Wirkung sowohl auf die Insulin- als auch die Glukagonsekretion und ihrem deswegen sehr geringen Hypoglykämierisiko. Zum anderen bewirken sie einen Gewichtsverlust und senken den Blutdruck.

Anwendung und verfügbare Wirkstoffe

GLP-1-RA werden in einfachen Standarddosierungen verabreicht. Prinzipiell stehen derzeit Moleküle auf Basis des in seiner Struktur dem GLP-1 ähnlichen Exendin-4 (Exenatid und Lixisenatid, in klinischer Prüfung: Efpeglenatid) sowie humane GLP-1-Analoga (Albiglutid, Dulaglutid, Liraglutid, in klinischer Prüfung: Semaglutid) zur Verfügung. Kurz wirksame Substanzen zur 1‑ oder 2‑mal täglichen Injektion wurden aus Exendin-4 entwickelt, die gegenwärtig verfügbaren humanen GLP-1-Analoga sind den lang wirksamen GLP-1-RA zuzuordnen und überwiegend für die 1‑mal wöchentliche Injektion konzipiert und zugelassen (Ausnahme: Liraglutid – 1‑mal tägliche Anwendung). Für eine Kombination mit einem Basalinsulin sind Mischpräparate verfügbar, zum einen Lösungen mit Liraglutid und Insulin Degludec, zum anderen Kombinationspräparate aus Lixisenatid und Insulin Glargin.

Pharmakologie

Die verschiedenen GLP-1-RA weisen Unterschiede bezüglich ihrer spezifischen pharmakologischen Effekte auf Glykämieparameter und Gewichtsabnahme sowie ihren organspezifischen Wirkungen auf, wie in diesem Beitrag dargestellt wird.

Abstract

Background

Since their introduction in the 2006, the injectable glucagon-like peptide-1 receptor agonists (GLP-1 RA) have become established in the therapy of type 2 diabetes because of their strictly glucose-dependent action on both insulin and glucagon secretion with a very low risk of hypoglycemia. They also lead to body weight loss and lower blood pressure.

Administration and active ingredients

GLP-1 RA are given in standard doses. In principle, two molecule classes are currently available: one class is based on the structurally similar exendin-4 (exenatide and lixisenatide, in clinical development: efpeglenatide), while the other class comprises human GLP-1 analogues (albiglutide, dulaglutide, liraglutide, in clinical development: semaglutide). Short-acting substances for once or twice daily injections were developed from the exendin-4 molecule; the presently available human GLP-1 analogues have been designed and approved as long-acting compounds for once weekly injections (with the exception of liraglutide for the once daily application). For a combination therapy with basal insulin, fixed combination solutions exist for liraglutide and insulin degludec as well as a combination of lixisentide and insulin glargine.

Pharmacology

The various GLP-1 RA have differences regarding their effects on glycemic parameters, on body weight, and in specific organ effects. The common characteristics and differences on the various GLP-1 RA are highlighted in this review.

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Literatur

  1. Bain SC (2014) The clinical development program of lixisenatide: a once-daily glucagon-like peptide-1 receptor agonist. Diabetes Ther 5(2):367–383. https://doi.org/10.1007/s13300-014-0073-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Blevins T, Pullman J, Malloy J et al (2011) DURATION-5: Eexenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 96(5):1301–1310. https://doi.org/10.1210/jc.2010-2081

    Article  CAS  PubMed  Google Scholar 

  3. Buse JB, Rosenstock J, Sesti G et al (2009) Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374(9683):39–47. https://doi.org/10.1016/S0140-6736(09)60659-0

    Article  CAS  PubMed  Google Scholar 

  4. Buse JB, Nauck M, Forst T et al (2013) Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open label study. Lancet 381(9861):117–124. https://doi.org/10.1016/S0140-6736(12)61267-7

    Article  CAS  PubMed  Google Scholar 

  5. Bush MA, Matthews JE, De Boever EH et al (2009) Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes Metab 11(5):498–505. https://doi.org/10.1111/j.1463-1326.2008.00992.x

    Article  CAS  PubMed  Google Scholar 

  6. Davies MJ, Bergenstal R, Bode B et al (2015) Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 314(7):687–699. https://doi.org/10.1001/jama.2015.9676

    Article  CAS  PubMed  Google Scholar 

  7. DeYoung MB, MacConell L, Sarin V et al (2011) Encapsulation of exenatide in poly-(D,L-lactide-co-glycolide) microspheres produced an investigational longacting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther 13(11):1145–1154. https://doi.org/10.1089/dia.2011.0050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dungan KM, Povedano ST, Forst T et al (2014) Once-weekly dulaglutide versus oncedaily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 384(9951):1349–1357. https://doi.org/10.1016/S0140-6736(14)60976-4

    Article  CAS  PubMed  Google Scholar 

  9. Eng J, Kleinman WA, Singh L et al (1992) Isolation and characterization of exendin-4, an exendin-3 analogue, from heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 267(11):7402–74055

    CAS  PubMed  Google Scholar 

  10. Ferrer-Garcia JC, Martinez-Chanza N, Tolosa-Torrens M et al (2010) Exenatide and renal failure. Diabet Med 27(6):728–729. https://doi.org/10.1111/j.1464-5491.2010.03009.x

    Article  CAS  PubMed  Google Scholar 

  11. Fineman MS, Bicsak TA, Shen LZ et al (2003) Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 26(8):2370–2377. https://doi.org/10.2337/diacare.26.8.2370

    Article  CAS  PubMed  Google Scholar 

  12. Glaesner W, Vick AM, Millican R et al (2010) Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev 26(4):287–296. https://doi.org/10.1002/dmrr.1080

    Article  CAS  PubMed  Google Scholar 

  13. Grimm M, Han J, Weaver C et al (2013) Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials. Postgrad Med 125(3):47–57. https://doi.org/10.3810/pgm.2013.05.2660

    Article  PubMed  Google Scholar 

  14. Jendle J, Grunberger G, Blevins T et al (2016) Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev 32(8):776–779. https://doi.org/10.1002/dmrr.2810

    Article  CAS  PubMed  Google Scholar 

  15. Kendall DM, Riddle MC, Rosenstock J et al (2005) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28(5):1083–1091. https://doi.org/10.2337/diacare.28.5.1083

    Article  CAS  PubMed  Google Scholar 

  16. Knop FK, BrØnden A, VilsbØll T (2017) Exenatide: pharmacokinetics, clinical use, and future directions. Expert Opin Pharmacother 18(6):555–571. https://doi.org/10.1080/14656566.2017.1282463

    Article  CAS  PubMed  Google Scholar 

  17. Knudsen LB, Nielsen PF, Huusfeldt PO et al (2000) Potent derivatives of glucagonlike peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 43(9):1664–1669. https://doi.org/10.1021/jm9909645

    Article  CAS  PubMed  Google Scholar 

  18. Lau J, Bloch P, Schaffer L et al (2015) Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem 58(18):7370–7380. https://doi.org/10.1021/acs.jmedchem.5b00726

    Article  CAS  PubMed  Google Scholar 

  19. Lovshin JA (2017) Glucagon-like peptide-1 receptor agonists: a class update for treating type 2 diabetes. Can J Diabetes. https://doi.org/10.1016/j.jcjd.2017.02.003

    Google Scholar 

  20. Madsbad S (2016) Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 18(4):317–332. https://doi.org/10.1111/dom.12596

    Article  CAS  PubMed  Google Scholar 

  21. Marso SP, Daniels GH, Brown-Frandsen K et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375(4):311–322. https://doi.org/10.1056/NEJMoa1603827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 75(19):1834–1844. https://doi.org/10.1056/NEJMoa1607141

    Article  Google Scholar 

  23. Meier JJ (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 8(12):728–742. https://doi.org/10.1038/nrendo.2012.140

    Article  CAS  PubMed  Google Scholar 

  24. Nauck MA (2012) The design of the liraglutide clinical trial programme. Diabetes Obes Metab 14(Suppl. 2):4–12. https://doi.org/10.1111/j.1463-1326.2012.01573.x

    Article  CAS  PubMed  Google Scholar 

  25. Nauck M, Rizzo M, Johnson A et al (2016) Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care 39(9):1501–1509. https://doi.org/10.2337/dc15-2479

    Article  PubMed  Google Scholar 

  26. Pratley RE, Nauck MA, Barnett AH et al (2014) Once-weekly albiglutide versus oncedaily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, noninferiority phase 3 study. Lancet Diabetes Endocrinol 2(4):289–297. https://doi.org/10.1016/S2213-8587(13)70214-6

    Article  CAS  PubMed  Google Scholar 

  27. Rosenstock J, Raccah D, Koranyi L et al (2013) Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (getgoal-X). Diabetes Care 36(10):2945–2951. https://doi.org/10.2337/dc12-2709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Steinert RE, Poller B, Castelli MC et al (2009) Orally administered glucagon-like peptide-1 affects glucose homeostasis following an oral glucose tolerance test in healthy male subjects. Clin Pharmacol Ther 86(6):644–650. https://doi.org/10.1038/clpt.2009.159

    Article  CAS  PubMed  Google Scholar 

  29. Wysham C, Blevins T, Arakaki R et al (2014) Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 37(8):2159–2167. https://doi.org/10.2337/dc13-2760

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Medizinische Klinik IV, Universitätsklinikum Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Deutschland

    B. Gallwitz

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Interessenkonflikt

B. Gallwitz erhielt im Zeitraum 2014–2017 Honorare für die Mitarbeit in Advisory-Boards von den Firmen Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, MSD, Novartis und Novo Nordisk. Vortragshonorare erhielt er von Amgen, Abbott, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Menarini/Berlin-Chemie, Lilly, MSD, Novo Nordisk und Sanofi.

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Gallwitz, B. Rezeptoragonisten des „glucagon-like peptide 1”. Diabetologe 13, 487–497 (2017). https://doi.org/10.1007/s11428-017-0266-y

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