Download PDF
Diabetologie und Stoffwechsel 2010; 5(5): 287-292
DOI: 10.1055/s-0030-1262593
Übersicht

© Georg Thieme Verlag KG Stuttgart ˙ New York

Blutzuckerkontrolle und Hypoglykämierisiko bei der Behandlung des Typ-2-Diabetes mit dem neuen GLP-1-Rezeptoragonisten Liraglutid

Blood Sugar Control and Risk for Hypoglycemia within Therapy of Type 2 Diabetes with the New GLP-1 Receptor Agonist LiraglutideW. Kern1
  • 1MVZ Endokrinologikum Ulm
Further Information

Publication History

Publication Date:
27 October 2010 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die zwei wichtigsten Aspekte bei der Wahl eines Antidiabetikums sind dessen Kapazität zur Blutzuckereinstellung und das Hypoglykämierisiko. Mit der heutigen großen Auswahl an Antidiabetika wird das Therapieziel (HbA1c < 7 %) aber in 40–50 % der Fälle nicht erreicht. Einer der Gründe dafür ist die Angst vor Hypoglykämien, die häufig bei der klassischen antidiabetischen Therapie mit Sulfonylharnstoffen und Insulinen auftreten können. Die Angst verzögert die Initiierung von effektiven Therapien und deren notwendiger Intensivierung und bewirkt einen konstant schlecht eingestellten Blutzuckerspiegel. Durch die neuartigen Behandlungsansätze mit inkretinbasierten Therapeutika (GLP-1-Rezeptoragonisten und DPP-IV-Hemmer) lassen sich klinisch relevante Hypoglykämien vermeiden. Insbesondere die GLP-1-Rezeptoragonisten bewirken zudem eine effektive glykämische Kontrolle und bieten weiteren zusätzlichen Nutzen durch die Reduktion des Körpergewichtes und die Verbesserung von Surrogatmarkern der β-Zellfunktion. Damit bieten sie möglicherweise eine alternative Therapieop­tion zu den gängigen Therapien. Exenatid war das erste zugelassene inkretinbasierte Medikament, das zu der Klasse der GLP-1-Rezeptoragonisten gehört. Im Juli 2009 wurde mit Liraglutid ein weiterer GLP-1-Rezeptoragonist in den deutschen Markt eingeführt. Ergebnisse aus dem Phase-3-Liraglutid-Studienprogramm (LEAD), v. a. im Hinblick auf Hypoglykämien, sollen hier zusammengefasst werden. 

Abstract

The most important aspect for the optimal choice of diabetes treatment is its capacity for effective glycemic control and a low risk of hypoglycemia. However, approximately 40–50 % of patients do not reach the glycemic control target (HbA1c < 7 %) with the currently available treatment options. One of the reasons for this is the fear of hypoglycemia which often occurs with conventional diabetes medications such as sulfonylurea and insulin. This fear entails a reluctance to initiate or intensify more effective therapies in a timely manner, resulting in prolonged periods of poor glycemic control. The new incretin-based therapy of type 2 diabetes (GLP-1-receptor agonists and DPP-4-inhibitors) avoids clinically relevant hypoglycaemia. Particularly, GLP-1-receptor agonists are advantageous in terms of glycemic control, reduction of body weight and β-cell function, and are therefore a useful alternative treatment option to currently available therapies. Exenatide was the first approved GLP-1mimetic. Since July 2009, another GLP-1 receptor agonist, liraglutide, was launched in Germany. This article reviews results from the phase 3 liraglutide study program (LEAD), with particular emphasis on hypoglycemia. 

Schlüsselwörter

GLP-1-Rezeptoragonisten - Hypoglykämie - humanes GLP-1-Analogon - Liraglutid - HbA1c

Key words

GLP-1 receptor agonists - hypoglycemia - human GLP-1 analogue - liraglutide - HbA1c

Literatur

  • 1 Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.  Diabetes Care. 2004;  27 1047-1053
    Google Scholar
  • 2 U.K. Prospective Diabetes Study Group . U.K. prospective diabetes study 16. Overview of 6 Years’ therapy of type II diabetes: a progressive disease.  Diabetes. 1995;  44 1249-1258
    CrossrefGoogle Scholar
  • 3 Deutsche Diabetes Gesellschaft (DDG) .Medikamentöse antihyperglykämische Therapie des Diabetes mellitus Typ 2. Update der evidenzbasierten Leitlinie der Deutschen Diabetes-Gesellschaft. Oktober 2008
    Google Scholar
  • 4 Ford E S, Li C L, Little R R et al. Trends in A1c concentrations among U.S. adults with diagnosed diabetes from 1999 to 2004.  Diabetes Care. 2008;  31 102-104
    CrossrefGoogle Scholar
  • 5 Berthold H K, Gouni-Berthold I, Bestehorn K et al. Kardiovaskuläre Risikofaktoren bei Typ-2-Diabetikern in Deutschland – ein Versorgungs­paradox.  Dtsch Arztebl. 2007;  104 A861-A867
    Google Scholar
  • 6 Turner R C, Cull C A, Frighi V UK Prospektive Diabetes Study (UKPDS) Group et al. for the. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus.  JAMA. 1999;  281 2005-2012
    CrossrefPubMedGoogle Scholar
  • 7 Briscoe V J, Davis S N. Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management.  Clinical Diabetes. 2006;  24 115-120
    CrossrefGoogle Scholar
  • 8 UK Prospective Diabetes Study (UKPDS) Group . Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 837-853
    CrossrefGoogle Scholar
  • 9 ADVANCE Collaborative Group . Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2008;  358 2560-2572
    CrossrefGoogle Scholar
  • 10 The Action to Control Cardiovascular Risk in Diabetes Study Group . Effect of intensive glucose lowering in type 2 diabetes.  N Eng J Med. 2008;  358 2545-2559
    CrossrefGoogle Scholar
  • 11 Korytkowski M. When oral agents fail: practical barriers to starting insulin.  Int J Obes. 2002;  26 (Suppl. 3) S18-S24
    Google Scholar
  • 12 Leslie C A, Satin-Rapaport W, Matheson R N et al. Psychological insulin resistance: a missed diagnosis?.  Diabetes Spectrum. 1994;  7 52
    Google Scholar
  • 13 Alberti K G. The DAWN (Diabetes Attitudes, Wishes and Needs) study.  Pract Diab Int. 2002;  19 22-24
    CrossrefGoogle Scholar
  • 14 Hunt L M, Valenzuela M A, Pugh J A. NIDDM patients’ fears and hopes about insulin therapy. The basis of patient reluctance.  Diabetes Care. 1997;  20 292-298
    CrossrefGoogle Scholar
  • 15 Drucker D J, Nauck M A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.  Lancet. 2006;  368 1696-1705
    CrossrefPubMedGoogle Scholar
  • 16 Farilla L, Bulotta A, Hirshberg B et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.  Endocrinology. 2003;  144 5149-5158
    CrossrefGoogle Scholar
  • 17 Rolin B, Larsen M O, Gotfredsen C F et al. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases β-cell mass in diabetic mice.  Am J Physiol Endocrinol Metab. 2002;  283 E745-E752
    Google Scholar
  • 18 Turton M D, O’Shea D, Gunn I et al. A role for glucagon-like peptide-1 in the central regulation of feeding.  Nature. 1996;  379 69-72
    CrossrefGoogle Scholar
  • 19 MacDonald P E, El-Kholy W, Riedel M J et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion.  Diabetes. 2002;  51 (Suppl. 3) S434-442
    CrossrefGoogle Scholar
  • 20 Edwards C M, Stanley S A, Davis R et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.  Am J Physiol Endocrinol Metab. 2001;  281 E155-E161
    Google Scholar
  • 21 Degn K, Juhl C, Sturis J et al. One week’s treatment with the long-acting glucagon-like peptide-1 derivative Liraglutide (NN2211) markedly improves 24-h glycemia and α- and β-cell function and reduces endogeneous glucose release in patients with type 2 Diabetes.  Diabetes. 2004;  53 1187-1194
    CrossrefGoogle Scholar
  • 22 Jonker D, Toft A D, Kristensen P et al. Diabetes. 2007;  56 (Suppl. 1) A160
  • 23 Mest H J. Dipeptidyl peptidase-IV inhibitors can restore Glucose homeostasis in type 2 diabetes via incretin enhancement.  Curr Opin Invest. 2006;  7 338-343
    Google Scholar
  • 24 Edwards C M, Stanley S A, Davis R et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.  Am J Physiol Endocrinol Metab. 2001;  281 E155-E161
    Google Scholar
  • 25 Jonker D, Toft A D, Kristensen P et al. Diabetes. 2007;  56 (Suppl. 1) A160
  • 26 Fachinformation Victoza®. Stand September 2009
    Google Scholar
  • 27 DeFronzo R A, Ratner R E, Han J et al. Effects of Exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2005;  25 1092-1100
    Google Scholar
  • 28 Kendall D M, Riddle M C, Rosenstock J et al. 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. 2005;  28 1083-1091
    CrossrefPubMedGoogle Scholar
  • 29 Zinman B, Hoogwerf B J, Garcia S D et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes.  Ann Intern Med. 2007;  146 477-485
    Google Scholar
  • 30 Nauck M A, Duran S, Kim D et al. A comparison of twice daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study.  Diabetologia. 2007;  50 259-267
    CrossrefGoogle Scholar
  • 31 Klonoff D C, Buse J B, Nielsen L L et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.  Curr Med Res Opin. 2008;  24 275-286
    CrossrefGoogle Scholar
  • 32 Madsbad S. Liraglutide effect and action in diabetes (LEAD™) trial.  Exp Rev Endocrino Metab. 2009;  4 119-129
    Google Scholar
  • 33 Garber A, Henry R, Ratner R (LEAD-3 (Mono) Study Group et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial.  Lancet. 2009;  373 473-481
    CrossrefPubMedGoogle Scholar
  • 34 Marre M, Shaw J, Brändle M et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater im-provements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU).  Diabet Med. 2009;  26 268-278
    CrossrefGoogle Scholar
  • 35 Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study.  Diabetes Care. 2009;  32 84-90
    CrossrefGoogle Scholar
  • 36 Zinman B, Gerich J, Buse J B et al. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met + TZD).  Diabetes Care. 2009;  32 1224-1230 Epub 2009 Mar 6. Erratum in: Diabetes Care. 2010 Mar; 33 (3): 692
    CrossrefGoogle Scholar
  • 37 Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs. insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met + SU): a randomised controlled trial.  Diabetologia. 2009;  52 2046-2055
    CrossrefGoogle Scholar
  • 38 Buse J B, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6).  Lancet. 2009;  374 39-47
    CrossrefGoogle Scholar
  • 39 Gallwitz B. Liraglutide.  Drugs of the future. 2008;  33 13-20
    CrossrefGoogle Scholar
  • 40 Vilsbøll T, Zdravkovic M, Le-Thi T et al. Liraglutide, a long-acting human GLP-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes mellitus.  Diabetes Care. 2007;  30 1608-1610
    CrossrefGoogle Scholar
  • 41 Vilsbøll T. Liraglutide: A once daily GLP-1 analogue for the treatment of type 2 diabetes mellitus.  Expert Opin Investig Drugs. 2007;  16 231-237
    CrossrefGoogle Scholar
  • 42 Kahn S E, Haffner S M, Heise M A et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.  NEJM. 2006;  355 2427-2443
    CrossrefGoogle Scholar
  • 43 Riddle M C, 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
    CrossrefPubMedGoogle Scholar
  • 44 Mikhail N. Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes.  Expert Opin Investig Drugs. 2008;  17 845-853
    CrossrefGoogle Scholar
  • 45 Nauck M A, Meininger G, Sheng D et al. Efficacy and safety of the dipep­tidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonyl­urea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.  Diabetes Obes Metab. 2007;  9 194-205
    CrossrefGoogle Scholar

Professor Dr. W. Kern

MVZ Endokrinologikum Ulm

Hafenbad 33

89073 Ulm

Phone: 07 31 / 9 38 08 80

Fax: 07 21 / 93 80 88 19

Email: werner.kern@endokrinologikum.com