Pathophysiological background for incretin therapy: is it capable of more than we think?

Czech version

Authors: M. Haluzík ¹; M. Urbanová ¹; D. Haluzíková ^{1, 2}; P. Trachta ¹
Authors‘ workplace: III. interní klinika 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Štěpán Svačina, DrSc., MBA ¹; Ústav tělovýchovného lékařství 1. lékařské fakulty UK a VFN Praha, přednosta doc. MUDr. Zdeněk Vilikus, CSc. ²
Published in: Vnitř Lék 2011; 57(11): 897-902
Category: Birthday

Overview

Incretin-based therapy functions through the increase of endogenous glucagon-like peptide-1 (GLP-1) levels due to inhibition of dipeptidyl peptidase-4 – an enzyme degrading GLP-1 (gliptins) or through the administration of drugs activating GLP-1 receptor (GLP-1 agonists). Both approaches increase insulin and decrease glucagon secretion leading to improved diabetes compensation. The advantages of gliptins include little side effects, body weight neutrality and potential protective effects on pancreatic β cells. GLP-1 agonists on the top of that consistently decrease body weight and blood pressure and their effects on diabetes compensation and likelihood of protective effects on β cells is somewhat higher than those of gliptins. Another advantage of both approaches includes their safety with respect to induction of hypoglycemia. In addition to well-known metabolic effects, other potentially benefitial consequences of incretin based therapy in both type 2 diabetic and non-diabetic patients are anticipated. Direct positive effects of incretin-based therapy on myocardial metabolism and function as well as its positive influence on endothelial dysfunction and neuroprotective effects are intensively studied. The possible indications for GLP-1 agonists could be in future further widened to obese patients with type 1 diabetes and obese patients without diabetes. The aim of this review is to summarize both metabolic and extrapancreatic effects of incretin-based therapies and to outline perspectives of potential wider use of this treatment approach.

Key words:
type 2 diabetes mellitus – incretin-based therapy – cardiovascular complications – hypoglycemia

Sources

1. O‘Rahilly S. Science, medicine, and the future. Non-insulin dependent diabetes mellitus: the gathering storm. BMJ 1997; 314: 955–959.

2. Škrha J et al. Diabetes mellitus 2002 v České republice – epidemiologická studie. DMEV 2005; 8: 5–12.

3. Ravussin E, Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann NY Acad Sci 2002; 967: 363–378.

4. Banegas JR, López-García E, Gutiérrez-Fisac JL et al. A simple estimate of mortality attributable to excess weight in the European Union. Eur J Clin Nutr 2003; 57: 201–208.

5. Bell D. Pathophysiology of type 2 diabetes and its relationship to new therapeutic approaches. Diabetes Educ 2000; 26 (Suppl): 4–7.

6. Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 2004; 59: 207–223.

7. Svačina S, Owen K. Syndrom inzulínové rezistence. Praha: Triton 2003.

8. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234.

9. Škrha J. Diabetologie. Praha: Galén 2009.

10. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004; 287: E199–E206.

11. Nauck MA. Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm Metab Res 2004; 36: 852–858.

12. Gleeson JM, Berenbeim DM, Gilkin RJ. Incretin mimetics: promising new therapeutic options in the treatment of type 2 diabetes. J Manag Care Pharm 2005; 11: (7 Suppl): S2–S13.

13. Doggrell SA. Is liraglutide or exenatide better in type 2 diabetes? Expert Opin Pharmacother 2009; 10: 2769–2772.

14. Stamataros G, Schneider SH. Vildagliptin in the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother 2011; 12: 1967–1973.

15. Madsbad S. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics) – preclinical and clinical results. Best Pract Res Clin Endocrinol Metab 2009; 23: 463–477.

16. Roubicek T, Mraz M, Bartlova M et al. The influence of 6-months treatment with exenatide on type 2 diabetes mellitus compensation, anthropometric and biochemical parameters. Vnitř Lék 2010; 56: 15–20.

17. Haluzík M, Svačina Š. Inkretinová léčba diabetu. Praha: Mladá Fronta 2010.

18. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011; 13: 7–18.

19. Klonoff DC, Buse JB, Nielsen LL 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.

20. Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther 2009; 31: 2472–2488.

21. Buse JB, Rosenstock J, Sesti G et al. LEAD-6 Study Group. 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.

22. Drucker DJ. The biology of incretin hormones. Cell metabolism 2006; 3: 153–165.

23. Abu-Hamdah R, Rabiee A, Meneilly GS et al. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. Journal Clin Endocrinol Metab 2009; 94: 1843–1852.

24. Ahrén B. GLP-1 and extra-islet effects. Horm Metab Res 2004; 36: 842–845.

25. Acuna-Goycolea C, van den Pol A. Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J Neurosci 2004; 24: 8141–8152.

26. Abbas T, Faivre E, Hölscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer‘s disease. Behav Brain Res 2009; 205: 265–271.

27. Wang XH, Li L, Hölscher C et al. Val8--glucagon-like peptide-1 protects against Abeta1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats. Neuroscience 2010; 170: 1239–1248.

28. McClean PL, Gault VA, Harriott P et al. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer’s disease. Eur J Pharmacol 2010; 630: 158–162.

29. Perry T, Holloway HW, Weerasuriya A et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp Neurol 2007; 203: 293–301.

30. Ban K, Noyan-Ashraf MH, Hoefer J et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 2008; 117: 2340–2350.

31. Barragán JM, Rodríguez RE, Blázquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats. Am J Physiol 1994; 266: E459–E466.

32. Gros R, You X, Baggio LL et al. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology 2003; 144: 2242–2252.

33. Timmers L, Henriques JP, de Kleijn DP et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol 2009; 53: 501–510.

34. Noyan-Ashraf MH, Momen MA, Ban K et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58: 975–983.

35. Nikolaidis LA, Elahi D, Hentosz T et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 2004; 110: 955–961.

36. Poornima I, Brown SB, Bhashyam S et al. Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail 2008; 1: 153–160.

37. Sokos GG, Nikolaidis LA, Mankad S et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006; 12: 694–699.

38. Nikolaidis LA, Mankad S, Sokos GG et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004; 109: 962–965.

39. Sokos GG, Bolukoglu H, German J et al. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am J Cardiol 2007; 100: 824–829.

40. Ban K, Kim KH, Cho CK et al. Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. Endocrinology 2010; 151: 1520–1531.

41. Lønborg J, Vejlstrup N, Kelbæk H et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2011. Epub 2011/09/17.

42. Kielgast U, Holst JJ, Madsbad S. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists. Curr Diabetes Rev 2009; 5: 266–275.

43. Ghatak SB, Patel DS, Shanker N et al. Linagliptin: A Novel Xanthine-Based Dipeptidyl Peptidase-4 Inhibitor for Treatment of Type II Diabetes Mellitus. Curr Diabetes Rev 2011. Epub 2011/09/16.

44. Drucker DJ, Buse JB, Taylor K et al. DURATION-1 Study Group. 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.

45. Christensen M, Knop FK, Vilsbøll T et al. Lixisenatide for type 2 diabetes mellitus. Expert Opin Investig Drugs 2011; 20: 549–557.