Diabetologie und Stoffwechsel 2012; 7(4): 290-301
DOI: 10.1055/s-0032-1313120
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Synergien nutzen: Insulin plus GLP-1-Rezeptoragonisten – innovative Therapiestrategie mit Zukunft?

Using Synergies: Insulin plus GLP-1 Receptor Agonists – Emerging Treatment Strategy for the Future?
B. Gallwitz
1   Medizinische Klinik IV, Universität Tübingen
,
A. Hamann
2   Medizinische Klinik IV, Hochtaunus-Kliniken Bad Homburg
,
O. Bachmann
3   Medizinische Abteilung – Diabetes, Lilly Deutschland GmbH, Bad Homburg
,
A. Haupt
3   Medizinische Abteilung – Diabetes, Lilly Deutschland GmbH, Bad Homburg
› Author Affiliations
Further Information

Publication History

Publication Date:
23 August 2012 (online)

Zusammenfassung

Trotz neuer Therapieoptionen und moderner Insuline bleibt die Therapie des Typ-2-Diabetes eine Herausforderung, insbesondere bei Patienten mit Adipositas. Oft ist es schwierig, die strengen HbA1c-Zielwerte zu erreichen, und selbst wenn es gelingt, ist die HbA1c-Senkung nicht selten durch Gewichtszunahme und Häufung von Hypoglykämien erkauft. Neue Therapiestrategien sind deshalb gerade für das problematische Patientensegment mit Adipositas, Insulinresistenz und inadäquat erhöhtem HbA1c erforderlich. Aus pathophysiologischer Sicht ist die Kombinationstherapie mit Insulin und Glukagon-like-Peptide-1(GLP-1)-Rezeptoragonisten sinnvoll, wenngleich harte klinische Daten zur Reduktion mikro- und makrosvaskulärer Komplikationen noch ausstehen. Diese Übersichtsarbeit fasst die verfügbaren Studiendaten zusammen und zeigt, dass die Kombination von Insulin plus GLP-1-Rezeptoragonist häufig mit einer erheblichen Stoffwechselverbesserung einhergeht und zusätzlich zur Gewichtsabnahme führt, bei nur geringem Anstieg des Hypoglykämierisikos, allerdings assoziiert mit dem bekannten gastrointestinalen Nebenwirkungsprofil der GLP-1-Rezeptoragonisten. Außerdem wird dargestellt, warum kurz wirksame GLP-1-Rezeptoragonisten, die mit einer deutlichen Senkung der postprandialen Blutzuckerspiegel assoziiert sind, eventuell besonders geeignet sind für die Kombination mit einem Basalinsulin, lang wirksame GLP-1-Rezeptoragonisten, die auf die Kontrolle des Nüchternblutzuckers abzielen, dagegen wahrscheinlich eher für die Kombination mit komplexeren Regimes wie der intensivierten konventionellen Insulintherapie, wenngleich auch hier klinische Vergleichsdaten fehlen.

Abstract

Treatment of type 2 diabetes remains a challenge in spite of new treatment options and modern types of insulin, in particular for obese subjects. It is frequently difficult to achieve strict HbA1c targets, and even in case of success this frequently happens at the expense of weight gain and an increased risk of hypoglycemia. Therefore, new treatment strategies are needed in particular for the high risk patient population with obesity, insulin resistance and inadequately high HbA1c. From a pathophysiological perspective, it is reasonable to combine insulin and glucagon-like peptide 1 (GLP‑1) receptor agonists, although hard clinical data regarding the reduction of micro- and macrovascular complications are still missing. This review summarizes the clinical data available and illustrates that combined treatment with insulin plus GLP-1 receptor agonist will frequently achieve improved glycemic control and results in weight loss, with only a slightly increased risk of hypoglycemia, but associated with the known gastrointestinal side effect profile of GLP-1 receptor agonists. Additionally, this review explains why short-acting GLP-1 receptor agonists that are associated with a marked decrease of postprandial blood glucose levels may be particularly suitable for a combination with basal insulin, whereas long-acting GLP-1 receptor agonists that primarily aim at fasting blood glucose control may be more suitable for a combination with more complex insulin regimens such as the intensified conventional insulin therapy, although comparative clinical data are also missing here.

 
  • Literatur

  • 1 Bretzel RG, Nuber U, Landgraf W et al. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 2008; 371: 1073-1084
  • 2 Rosenstock J, Davies M, Home PD et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51: 408-416
  • 3 Riddle MC, Rosenstock J, Gerich J et al. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: 3080-3086
  • 4 Holman RR, Farmer AJ, Davies MJ et al. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med 2009; 361: 1736-1747
  • 5 U.K. Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853
  • 6 Gerstein HC, Miller ME et al. Action to Control Cardiovascular Risk in Diabetes Study Group Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559
  • 7 Whitlock G, Lewington S et al. Prospective Studies Collaboration Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373: 1083-1096
  • 8 Nauck M, Meier JJ. GLP-1 analogues and insulin: sound the wedding bells?. Nat Rev Endocrinol 2011; 7: 193-195
  • 9 Cusi K, Cunningham GR, Comstock JP. Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 1995; 18: 843-851
  • 10 Pennartz C, Schenker N, Menge BA et al. Chronic reduction of fasting glycemia with insulin glargine improves first- and second-phase insulin secretion in patients with type 2 diabetes. Diabetes Care 2011; 34: 2048-2053
  • 11 Linn T, Fischer B, Soydan N et al. Nocturnal glucose metabolism after bedtime injection of insulin glargine or neutral protamine hagedorn insulin in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 3839-3846
  • 12 Gallwitz B. Glukagon-like Peptide-1 Analogues for Type 2 Diabetes Mellitus: Current and Emerging Agents. Drugs 2011; 71: 1675-1688
  • 13 Portha B, Tourrel-Cuzin C, Movassat J. Activation of the GLP-1 receptor signalling pathway: a relevant strategy to repair a deficient beta-cell mass. Exp Diabetes Res 2011; 376509 . Epub 2011 May 22
  • 14 Kwon DY, Kim YS, Ahn IS et al. Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats. J Pharmacol Sci 2009; 111: 361-371
  • 15 Xu G, Stoffers DA, Habener JF et al. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270-2276
  • 16 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
  • 17 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
  • 18 Amylin Pharmaceuticals, Inc. Byetta Prescribing Information. 2011 Available at: http://pi.lilly.com/us/byetta-pi.pdf Accessed February 20, 2011
  • 19 Christensen M, Knop FK, Vilsbøll T et al. Lixisenatide for type 2 diabetes mellitus. Expert Opin Investig Drugs 2011; 20: 549-557
  • 20 Novo Nordisk A/S. Victoza Prescribing Information. 2010 . Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022341lbl.pdf Accessed February 20, 2011
  • 21 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
  • 22 Nauck MA, Kemmeries G, Holst JJ et al. Rapid tachyphylaxis of the Glukagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 2011; 60: 1561-1565
  • 23 Little TJ, Pilichiewicz AN, Russo A et al. Effects of intravenous Glukagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J Clin Endocrinol Metab 2006; 91: 1916-1923
  • 24 Meier JJ, Kemmeries G, Holst JJ et al. Erythromycin antagonizes the deceleration of gastric emptying by Glukagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 2005; 54: 2212-2218
  • 25 Werner U, Kuhlmann-Gottke JK, Schäfer HW et al. Effect of the once-daily GLP-1R Agonist lixisenatide on gastric emptying and prandial carbohydrate utilization in animal models: a comparison with liraglutide. Abstract. ADA, 24–28 June 2011, San Diego, U.S.A., Abstract 2267-PO.
  • 26 Degn KB, Juhl CB, Sturis J et al. One week‘s treatment with the long-acting Glukagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53: 1187-1194
  • 27 Buse JB, Bergenstal RM, Glass LC et al. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2011; 154: 103-112
  • 28 Arnolds S, Dellweg S, Clair J et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care 2010; 33: 1509-1515
  • 29 ClinicalTrials.Gov. NCT00560417. Comparison of Two Basal Insulins for Patients With Type 2 Diabetes Taking Oral Diabetes Medicines and Exenatide. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00560417?term=NCT00560417&rank=1
  • 30 Nayak UA, Govindan J, Baskar V et al. Exenatide therapy in insulin-treated type 2 diabetes and obesity. QJM 2010; 103: 687-694
  • 31 Levin PA, Mersey JH, Zhou S et al. Clinical Outcomes Using Long-Term Combination Therapy With Insulin Glargine and Exenatide In Patients With Type 2 Diabetes. Endocr Pract 2012; 18: 17-25
  • 32 Yoon NM, Cavaghan MK, Brunelle RL et al. Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology outpatient setting. Clin Ther 2009; 31: 1511-1523
  • 33 Sheffield CA, Kane MP, Busch RS et al. Safety and efficacy of exenatide in combination with insulin in patients with type 2 diabetes mellitus. Endocr Pract 2008; 14: 285-292
  • 34 Viswanathan P, Chaudhuri A, Bhatia R et al. Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract 2007; 13: 444-450
  • 35 Thong KY, Jose B, Sukumar N et al. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit. Diabetes Obes Metab 2011; 13: 703-710
  • 36 Pawaskar MD, Blickensderfer AL, Hoogwerf BJ et al. Hypoglycemia in patients with type 2 diabetes using concomitant exenatide BID and long-acting insulin therapy. J Med Econ 2011; 14: 705-708
  • 37 John LE, Kane MP, Busch RS et al. Expanded use of exenatide in the management of type 2 diabetes. Diabetes Spectrum 2007; 20: 59-63
  • 38 Devries JH, Bain SC, Rodbard HW et al. on behalf of the Liraglutide-Detemir Study Group. 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
  • 39 Bain SC, deVries JH, Seufert J et al. Adding insulin detemir (IDet) to liraglutide and metformin improves glycaemic control with sustained weight reduction and low hypoglycaemia rate: 52 week results. Abstract. EASD, 12–16 September 2011, Lisbon, Portugal, Presentation 73.
  • 40 ClinicalTrials.Gov . Available at: NCT00856986. The Effect of Insulin Detemir in Combination With Liraglutide and Metformin Compared to Liraglutide and Metformin in Subjects With Type 2 Diabetes. http://www.clinicaltrials.gov/ct2/show/NCT00856986?term=NCT00856986&rank=1
  • 41 Lane W, Weinrib S, Rappaport J. The effect of liraglutide added to U-500 insulin in patients with type 2 diabetes and high insulin requirements. Diabetes Technol Ther 2011; 13: 592-595
  • 42 Anholm C, Frandsen H, Højgaard-Hansen EC et al. Use of once daily liraglutide in type 2 diabetes: clinical practice and experiences from combination with oral antidiabetic drugs or insulin. Abstract. Diabetes 2011; 60: A314
  • 43 Ghosal S. Using liraglutide in combination with insulin therapy for type 2 diabetic patients: an early clinical experience. Abstract. ADA, 24–28 June 2011, San Diego, U.S.A., Abstract 1144-P.
  • 44 Lind M, Jendle J, Torffvit O et al. Glukagon-like peptide 1 (GLP-1) analogue combined with insulin reduces HbA1c and weight with low risk of hypoglycemia and high treatment satisfaction. Prim Care Diabetes 2011; Oct 17 [Epub ahead of print]
  • 45 Seino Y, Min K, Niemoeller E et al. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab 2012; May 8 [Epub ahead of print]
  • 46 ClinicalTrials.Gov. NCT00866658. GLP-1 Agonist AVE0010 in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Basal Insulin ± Sulfonylurea (GETGOAL-L-ASIA). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00866658?term=NCT00866658&rank=1
  • 47 ClinicalTrials.Gov. NCT00960661. A Trial Comparing Two Therapies: Basal Insulin/Glargine, Exenatide and Metformin Therapy (BET) or Basal Insulin/Glargine, Bolus Insulin Lispro and Metformin Therapy (BBT) in Subjects With Type 2 Diabetes. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00960661?term=Insulin+and+Exenatide&recr=Open&rslt=Without&type=Intr&rank=1
  • 48 ClinicalTrials.Gov. NCT01006889. A New Treatment Strategy of Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes (t2DM) and Non-Alcoholic Fatty Liver Disease (NAFLD). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01006889?term=NCT01006889&rank=1
  • 49 ClinicalTrials.Gov. NCT01154933. Exenatide in Type 2 Diabetes on Insulin. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01154933?term=NCT01154933&rank=1
  • 50 ClinicalTrials.Gov. NCT01076842. Efficacy Evaluation of Different Medication Combination in Type 2 Diabetes Treatment. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01076842?term=NCT01076842&rank=1
  • 51 ClinicalTrials.Gov. NCT01336023. Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes: A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec and Liraglutide in Subjects With Type 2 Diabetes (DUAL™ I). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01336023?term=NCT01336023&rank=1
  • 52 ClinicalTrials.Gov. NCT01392573. A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec in Subjects With Type 2 Diabetes (DUAL™ II). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01392573?term=NCT01392573&rank=1
  • 53 ClinicalTrials.Gov. NCT01388361. Comparison of the Efficacy and Safety of Two Intensification Strategies in Subjects With Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin (BEGIN™). Available at: http://www.clinicaltrials.gov/ct2/show/NCT01388361?term=NCT01388361&rank=1
  • 54 ClinicalTrials.Gov. NCT01392898. Liraglutide and Insulin Therapy in Patients With Type 2 Diabetes. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01392898?term=NCT01392898&rank=1
  • 55 ClinicalTrials.Gov. NCT 00975286. 24-week Treatment With Lixisenatide in Type 2 Diabetes Insufficiently Controlled With Metformin and Insulin Glargine. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00975286?term=NCT+00975286&rank=1
  • 56 Hirsch IB, Xu Y, Davis KL et al. Patient Factors Associated with Glukagon like Peptide 1 Receptor Agonist use with and without Insulin. Endocr Pract 2011; 17: 707-716