Diabetologie und Stoffwechsel 2015; 10(03): 141-147
DOI: 10.1055/s-0035-1553166
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

GLP-1-Rezeptoragonisten in der Therapie des Typ-2-Diabetes

Glykämiekontrolle im direkten VergleichGLP-1 Receptor Agonists in the Treatment of Type 2 DiabetesA Direct Comparison of Glycemic Control
J. Seufert
Further Information

Publication History

Publication Date:
10 July 2015 (online)

Zusammenfassung

Glucagon-like-Peptide-1 (GLP-1)-Rezeptoragonisten sind in der Therapie des Diabetes mellitus Typ 2 zunehmend etabliert. Diese Inkretin-basierten Arzneimittel wirken über die Aktivierung von GLP-1-Rezeptoren. Sie wirken streng Glukose-abhängig insulinotrop und glukagonostatisch und ermöglichen eine effiziente Senkung des HbA1c-Werts bei gleichzeitig geringem Hypoglykämierisiko. Darüber hinaus vermitteln sie über zentralnervöse Mechanismen eine Reduktion des Körpergewichts. Die derzeit zugelassenen sechs GLP-1-Rezeptoragonisten weisen unterschiedliche strukturelle und pharmakokinetische Eigenschaften auf, die eine Unterteilung in kurzwirksame und langwirksame Präparate erlauben. Direkte Vergleichsstudien dieser Substanzen konnten Unterschiede und Gemeinsamkeiten hinsichtlich zentraler therapeutischer Parameter wie der Blutzuckereinstellung, des Hypoglykämierisikos, der Auswirkungen der Therapie auf das Körpergewicht und Substanz-spezifischer Nebenwirkungen herausarbeiten. Diese Ergebnisse können dem Diabetologen dabei helfen, unter sorgfältiger Nutzen-Risiko-Abwägung Präferenzen im Sinne eines individualisierten Therapieansatzes zu definieren.

Abstract

Glucagon-like-peptide-1 (GLP-1) receptor agonists are now established as an integral option for the treatment of type 2 diabetes. These incretin-based substances activate specific GLP-1 receptors, and provide insulinotropic and glucagonostatic actions in a strictly glucose-dependent manner, thus allowing effective control of HbA1c levels with a low risk of hypoglycemia. Moreover, they contribute to weight reduction through actions in the brain. Currently there are six GLP-1 receptor agonists approved in Germany. They demonstrate different structural and pharmacokinetic properties and can be grouped into long-acting and short-acting substances. Several head-to-head trials have revealed differences and similarities regarding key therapeutic parameters such as glycemic control, risk of hypoglycemia, effect on body weight and substance-specific side effects. These results can provide helpful support for the diabetologist in defining preferences for an individualized therapeutic approach, based on a careful risk-benefit-analysis.

 
  • Literatur

  • 1 Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 17: 819-837
  • 2 Seufert J, Gallwitz B. The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab 2014; 16: 673-688
  • 3 Lund A, Knop FK, Vilsboll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med 2014; 25: 407-414
  • 4 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: 1696-1705
  • 5 Lyxumia® (Lixisenatid) in Deutschland außer Vertrieb. , Pressemitteilung der Sanofi Aventis Deutschland GmbH vom 15.03.2014
  • 6 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728-742
  • 7 Bush MA, Matthews JE, De Boever EH et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes Metab 2009; 11: 498-505
  • 8 Kuritzky L, Umpierrez G, Ekoe JM et al. Safety and efficacy of dulaglutide, a once weekly GLP-1 receptor agonist, for the management of type 2 diabetes. Postgrad Med 2014; 126: 60-72
  • 9 Christensen M, Knop FK, Holst JJ et al. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. IDrugs 2009; 12: 503-513
  • 10 Gallwitz B. Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data. Int J Clin Pract 2006; 60: 1654-1661
  • 11 Barnett AH. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evid 2011; 6: 67-79
  • 12 Christensen M, Knop FK. Once-weekly GLP-1 agonists: How do they differ from exenatide and liraglutide?. Curr Diab Rep 2010; 10: 124-132
  • 13 European public assessment report (EPAR) Byetta® (Exenatide). http://www.ema.europa.eu
  • 14 European public assessment report (EPAR) Victoza® (Liraglutid). http://www.ema.europa.eu
  • 15 Agerso H, Jensen LB, Elbrond B et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 2002; 45: 195-202
  • 16 Fineman M, Flanagan S, Taylor K et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet 2011; 50: 65-74
  • 17 Matthews JE, Stewart MW, De Boever EH et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 4810-4817
  • 18 Barrington P, Chien JY, Tibaldi F et al. LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects. Diabetes Obes Metab 2011; 13: 434-438
  • 19 Malm-Erjefalt M, Bjornsdottir I, Vanggaard J et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos 2010; 38: 1944-1953
  • 20 Leiter LA, Carr MC, Stewart M et al. Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study. Diabetes Care 2014; 37: 2723-2730
  • 21 Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 2006; 49: 706-712
  • 22 Buse JB, Nauck M, Forst T et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381: 117-124
  • 23 Buse JB, Rosenstock J, Sesti G et al. 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 2009; 374: 39-47
  • 24 Kapitza C, Forst T, Coester HV et al. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab 2013; 15: 642-649
  • 25 Pratley RE, Nauck MA, Barnett AH et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol 2014; 2: 289-297
  • 26 Fineman MS, Cirincione BB, Maggs D et al. GLP-1 based therapies: differential effects on fasting and postprandial glucose. Diabetes Obes Metab 2012; 14: 675-688
  • 27 Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 2003; 26: 881-885
  • 28 Parkin CG, Brooks N. Is postprandial glucose control important? Is it practical in primary care settings?. Clinical Diabetes 2002; 20: 71-76
  • 29 Relimpio F, Guerrero R, Martinez-Brocca MA. HbA1c levels are better predicted by prebreakfast than postbreakfast blood glucose self-analyses in type 2 diabetes. Influence of duration of diabetes and mode of treatment. Acta Diabetol 2007; 44: 55-59
  • 30 Schrot RJ. Targeting plasma glucose: preprandial versus postprandial. Clinical Diabetes 2004; 22: 169-172
  • 31 Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Therapie des Typ-2-Diabetes – Langfassung, 1. Auflage. Version 4. 2013, zuletzt geändert: November 2014. Available from: DOI: 10.6101/AZQ/000213 www.dm-therapie.versorgungsleitlinien.de [cited: 22.12.2014]
  • 32 Buse JB, Sesti G, Schmidt WE et al. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care 2010; 33: 1300-1303
  • 33 Dungan KM, Povedano ST, Forst T et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet 2014; 384: 1349-1357
  • 34 Jonker D, Toft AD, Kristensen P et al. Pharmacokinetic Modelling of the Once-Daily Human GLP-1 Analogue Liraglutide in Healthy Volunteers and Comparison to Exenatide. Diabetes 2007; 56
  • 35 Watson E, Jonker DM, Jacobsen LV et al. Population pharmacokinetics of liraglutide, a once-daily human glucagon-like peptide-1 analog, in healthy volunteers and subjects with type 2 diabetes, and comparison to twice-daily exenatide. J Clin Pharmacol 2010; 50: 886-894
  • 36 Rosenstock J, Raccah D, Koranyi L et al. 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 2013; 36: 2945-2951
  • 37 Blevins T, Pullman J, Malloy J et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 1301-1310
  • 38 Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008; 372: 1240-1250
  • 39 DeYoung MB, MacConell L, Sarin V et al. Encapsulation of exenatide in poly-(D, L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther 2011; 13: 1145-1154
  • 40 Rosenstock J, Rodbard HW, Bain SC et al. One-year sustained glycemic control and weight reduction in type 2 diabetes after addition of liraglutide to metformin followed by insulin detemir according to HbA1c target. J Diabetes Complications 2013; 27: 492-500
  • 41 Buse JB, Henry RR, Han J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628-2635
  • 42 Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann Pharmacother 2009; 43: 1433-1444
  • 43 Ratner RE, Rosenstock J, Boka G et al. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med 2010; 27: 1024-1032
  • 44 Wang B, Zhong J, Lin H et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab 2013; 15: 737-749
  • 45 Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375: 1447-1456
  • 46 Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429-442
  • 47 DeVries JH, Bain SC, Rodbard HW et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care 2012; 35: 1446-1454