Система инкретинов при сахарном диабете 2-го типа: сердечно-сосудистые эффекты

При сахарном диабете 2-го типа (СД2) сердечно-сосудистые заболевания являются важнейшей причиной высокой смертности пациентов. Кардиоваскулярная безопасность сахароснижающих средств становится определяющей при выборе тактики лечения СД2, что закреплено в отечественных и международных рекомендательных документах. В последнее время стали доступны данные о множественных воздействиях, оказываемых инкретинами на сердечно-сосудистую систему, и потенциальных кардиопротективных свойствах препаратов, механизм действия которых основан на инкретиновом эффекте

сахарный диабет 2-го типа, сердечно-сосудистый риск, инкретин-направленная терапия, ингибиторы ДПП-4

1. Sarwar N., Gao P., Seshasai S.R., Gobin R., Kaptoge S., Di Angelantonio E., Ingelsson E., Lawlor D.A., Selvin E., Stampfer M., Stehouwer C.D., Lewington S., Pennells L., Thompson A., Sattar N., White I.R., Ray K.K., Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease:a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375: 2215—2222.

2. Gardner I.D., Morris A.D. Vascular complications of diabetes. BMJ 2000; 320: 1062—1066.

3. Stamler J., Vaccaro O., Neaton J.D., Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabet Care 1993; 16: 434—444.

4. Haffner S.M., Lehto S., Ronnemaa T., Pyorala K., Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. NEJM 1998; 339: 229—234.

5. Mazzone T., Chait A., Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008; 371: 1800—1809.

6. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837—853.

7. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854—865.

8. Ohkubo Y., Kishikawa H., Araki E., Miyata T., Isami S., Motoyoshi S., Kojima Y., Furuyoshi N., Shichiri M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabet Res Clin Pract 1995; 28: 103—117.

9. Duckworth W., Abraira C., Moritz T., Reda D., Emanuele N., Reaven P.D., Zieve F.J., Marks J., Davis S.N., Hayward R., Warren S.R., Goldman S., McCarren M., Vitek M.E., Henderson W.G., Huang G.D., VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129—139.

10. The ADVANCE Collaborative Group: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560—2572.

11. Gerstein H.C., Miller M.E., Byington R.P., Goff D.C.Jr., Bigger J.T., Buse J.B., Cushman W.C., Genuth S., Ismail-Beigi F., Grimm R.H.Jr., Probstfield J.L., Simons-Morton D.G., Friedewald W.T. 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.

12. International Diabetes Federation. Treatment Algorithm for People with Type 2 Diabetes. Доступно на http://www.idf.org/treatment-algorithm-people-type-2-diabetes

13. Дедов И.И., Шестакова М.В., Аметов А.С., Анциферов М.Б., Галстян Г.Р., Майоров А.Ю., Мкртумян А.М., Петунина Н.А., Сухарева О.Ю. Консенсус совета экспертов Российской ассоциации эндокринологов по инициации и интенсификации сахароснижающей терапии СД 2-го типа. Сахарный диабет 2011; 4: 6—17.

14. Inzucchi S.E., Bergenstal R.M., Buse J.B., Diamant M., Ferrannini E., Nauck M., Peters A.L., Tsapas A., Wender R., Matthews D.R. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577—1596.

15. Deacon C.F., Carr R.D., Holst J.J. DPP-4 inhibitor therapy: new directions in the treatment of type 2 diabetes. Front Biosci 2008; 13: 1780—1794.

16. Baggio L.L., Drucker D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131—2157.

17. Holst J.J. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409—1439.

18. Holst J.J., Vilsboll T., Deacon C.F. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 2009; 297: 127—136.

19. Nauck M., Stöckmann F., Ebert R., Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29: 46—52.

20. Wei Y., Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide 1: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995; 358: 219—224.

21. Ahren B. GLP-1 and extra-islet effects. Horm Metab Res 2004; 36: 842—845.

22. Mayo K.E., Miller L.J., Bataille D., Dalle S., Göke B., Thorens B., Drucker D.J. International Union of Pharmacology. 35-th. The glucagon receptor family. Pharmacol Rev 2003; 55: 167—194.

23. Ravassa S., Zudaire A., Diez J. GLP-1 and cardioprotection. From bench to bedside. Cardiovasc Res 2012; 94: 316—332.

24. Bose A.K., Mocanu M.M., Carr R.D., Brand C.L., Yellon D.M. Glucagon-like peptide 1 can directly protect the heart against ischemia—reperfusion injury. Diabetes 2005; 54: 146—151.

25. Matsubara M., Kanemoto S., Leshnower B.G., Albone E.F., Hinmon R., Plappert T., Gorman J.H.3rd, Gorman R.C. Single dose GLP-1-Tf ameliorates myocardial ischemia/reperfusion injury. J Surg Res 2011; 165: 38—45.

26. Nikolaidis L.A., Doverspike A., Hentosz T., Zourelias L., Shen Y.T., Elahi D., Shannon R.P. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther 2005; 312: 303—308.

27. Bose A.K., Mocanu M.M., Carr R.D., Yellon D.M. Glucagon like peptide-1 is protective against myocardial ischemia—reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther 2005; 19: 9—11.

28. Kavianipour M., Ehlers M.R., Malmberg K., Ronquist G., Ryden L., Wikström G., Gutniak M. Glucagon-like peptide-1 (9—36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium. Peptides 2003; 24: 569—578.

29. Anagnostis P., Athyros V.G., Adamidou F., Panagiotou A., Kita M., Karagiannis A., Mikhailidis D.P. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabet Obes Metabol 2011; 13: 302—312.

30. Nikolaidis L.A., Mankad S., Sokos G.G., Miske G., Shah A., Elahi D., Shannon R.P. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004; 109: 962—965.

31. Sokos G.G., Bolukoglu H., German J., Hentosz T., Magovern G.J.Jr., Maher T.D., Dean D.A., Bailey S.H., Marrone G., Benckart D.H., Elahi D., Shannon R.P. 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.

32. Read P.A., Khan F.Z., Dutka D.P. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart 2012; 98: 5: 408—413.

33. Lonborg J., Vejlstrup N., Kelbaek H., Botker H.E., Kim W.Y., Mathiasen A.B., Jorgensen E., Helqvist S., Saunamaki K., Clemmensen P., Holmvang L., Thuesen L., Krusell L.R., Jensen J.S., Kober L., Treiman M., Holst J.J., Engstrom T. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J 2011; 33: 12: 1491—1499.

34. Nikolaidis L.A., Elahi D., Hentosz T., Doverspike A., Huerbin R., Zourelias L., Stolarski C., Shen Y.T., Shannon R.P. 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.

35. Poornima I., Brown S., Bhashyam S., Parikh P., Bolukoglu H., Shannon R.P. Chronic Glucagon-like Peptide-1 (GLP-1) Infusion Sustains LV Systolic Function and Prolongs Survival in the Spontaneously Hypertensive-Heart Failure Prone Rat. Circulat Heart Fail 2008; 1: 153—160.

36. Liu Q., Anderson C., Broyde A., Polizzi C., Fernandez R., Baron A., Parkes D.G. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure. Cardiovasc Diabetol 2010; 9: 76.

37. Thrainsdottir I., Malmberg K., Olsson A., Gutniak M., Rydeґ N.L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diabet Vasc Dis Res 2004; 1: 40—43.

38. Sokos G.G., Nikolaidis L.A., Mankad S., Elahi D., Shannon R.P. Glucagonlike peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Cardiol Fail 2006; 12: 694—699.

39. Halbirk M., Nørrelund H., Møller N. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. Am J Physiol Heart Circ Physiol 2010; 298: H1096—H1102.

40. Ussher J.R., Drucker D.J. Cardiovascular biology of the incretin System. Endocrin Rev 2012; 33: 2: 187—215.

41. Bhashyam S., Fields A.V., Patterson B., Testani J.M., Chen L., Shen Y.T., Shannon R.P. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alphaMAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circulat Heart Fail 2010; 3: 512—521.

42. Buteau J., Roduit R., Susini S., Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in b (INS-1)-cells. Diabetologia 1999; 42: 856—864.

43. Hausenloy D.J., Yellon D.M. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 2004; 61: 448—460.

44. Matsui T., Tao J., del Monte F., Lee K.H., Li L., Picard M., Force T.L., Franke T.F., Hajjar R.J., Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001; 104: 330—335.

45. Liu X., Pachori A.S., Ward C.A., Davis J.P., Gnecchi M., Kong D., Zhang L., Murduck J., Yet S.F., Perrella M.A., Pratt R.E., Dzau V.J., Melo L.G. Heme oxygenase-1 (HO-1) inhibits post myocardial infarct remodeling and restores ventricular function. FASEB J 2006; 20: 207—216.

46. Piantadosi C.A., Carraway M.S., Babiker A., Suliman H.B. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circulat Res 2008; 103: 1232—1240.

47. Burkart E.M., Sambandam N., Han X., Gross R.W., Courtois M., Gierasch C.M., Shoghi K., Welch M.J., Kelly D.P. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest 2007; 117: 3930—3939.

48. Ban K., Kim K.H., Cho C.K., Sauve M., Diamandis E.P., Backx P.H., Drucker D.J., Husain M. GLP-1(9—36) protects cardiomyocytes and endothelial cells from ischemia-reperfusion injury via cytoprotective pathways independent of the GLP-1 receptor. Endocrinology 2010; 151: 1520—1531.

49. Nikolaidis L.A., Elahi D., Shen Y.T., Shannon R.P. Active metabolite of GLP- 1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.Am J Physiol Heart Circulat Phys 2005; 289: 2401—2408.

50. Ban K., Noyan-Ashraf M.H., Hoefer J., Bolz S.S., Drucker D.J., Husain M. 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.

51. Barragan J.M., Rodriguez R.E., Blazquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7—36 amide) in rats. Am J Physiol 1994; 266:459—466.

52. Yamamoto H., Lee C.E., Marcus J.N., Williams T.D., Overton J.M., Lopez M.E., Hollenberg A.N., Baggio L., Saper C.B., Drucker D.J., Elmquist J.K. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest 2002; 110: 43—52.

53. Edwards C.M., Edwards A.V., Bloom S.R. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7—36) amide in the conscious calf. Exp Physiol 1997; 82: 709—716.

54. Moreno C., Mistry M., Roman R.J. Renal effects of glucagon-like peptide in rats. Eur J Pharmacol 2002; 434: 163—167.

55. Hirata K., Kume S., Araki S., Sakaguchi M., Chin-Kanasaki M., Isshiki K., Sugimoto T., Nishiyama A., Koya D., Haneda M., Kashiwagi A., Uzu T. Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem Biophys Res Commun 2009; 380: 44—49.

56. Okerson T., Yan P., Stonehouse A., Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens 2010; 23: 334—339.

57. Gros R., You X., Baggio L.L., Kabir M.G., Sadi A.M., Mungrue I.N., Parker T.G., Huang Q., Drucker D.J., Husain M. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology 2003; 144: 2242—2252.

58. Green B.D., Hand K.V., Dougan J.E., McDonnell B.M., Cassidy R.S., Grieve D.J. GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP. Arch Biochem Biophys 2008; 478: 136—142.

59. Qin X., Shen H., Liu M., Yang Q., Zheng S., Sabo M., D’Alessio D.A., Tso P. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastroint Liver Physiol 2005; 288: 943—949.

60. Ruiz-Grande C., Alarcon C., Merida E., Valverde I. Lipolytic action of glucagon-like peptides in isolated rat adipocytes. Peptides 1992; 13: 13—16.

61. Villanueva-Penacarrillo M.L., Marquez L., Gonzalez N., Díaz-Miguel M., Valverde I. Effect of GLP-1 on lipid metabolism in human adipocytes. Horm Metab Res 2001; 33: 73—77.

62. Meier J.J., Gethmann A., Götze O., Gallwitz B., Holst J.J., Schmidt W.E., Nauck M.A. Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans. Diabetologia 2006; 49: 452—458.

63. Ansar S., Koska J., Reaven P.D. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol 2011; 10: 61.

64. Arakawa M., Mita T., Azuma K., Ebato C., Goto H., Nomiyama T., Fujitani Y., Hirose T., Kawamori R., Watada H. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010; 59: 1030—1037.

65. Chen J., Song M., Yu S., Gao P., Yu Y., Wang H., Huang L. Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overexpression of cell oxidant stress. Mol Cell Biochem 2010; 335: 137—146.

66. Ishibashi Y., Matsui T., Takeuchi M., Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced upregulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun 2010; 391: 1405—1408.

67. DeFronzo R.A., Ratner R.E., Han J., Kim D.D., Fineman M.S., Baron A.D. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin treated patients with type 2. Diabet Care 2005; 28: 1092—1110.

68. Drucker D.J. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes. Preclinical biology and mechanisms of action. Diabet Care 2007; 30: 1335—1343.

69. Kos K., Baker A.R., Jernas M., Harte A.L., Clapham J.C., O’Hare J.P., Carlsson L., Kumar S., McTernan P.G. DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue. Diabet Obes Metab 2009; 11: 285—292.

70. Brandt I., Lambeir A.M., Ketelslegers J.M., Vanderheyden M., Scharpé S., De Meester I. Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form. Clin Chem 2006; 52: 1: 82—87.

71. Fadini G.P., Boscaro E., Albiero M., Menegazzo L., Frison V., de Kreutzenberg S., Agostini C., Tiengo A., Avogaro A. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes mellitus. Possible role of stromal derived factor-1 alpha. Diabet Care 2010; 33: 1607—1609.

72. Ta N.N., Li Y., Schuylera C.A., Lopes-Virella M.F., Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 2010; 213: 429—435.

73. Dobrian A.D., Ma Q., Lindsay J.W., Leone K.A., Ma K., Coben J., Galkina E.V., Nadler J.L. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol Endocrinol Metab 2011; 300: 410—421.

74. Shirakawa J., Fujii H., Ohnuma K., Sato K., Ito Y., Kaji M., Sakamoto E., Koganei M., Sasaki H., Nagashima Y., Amo K., Aoki K., Morimoto C., Takeda E., Terauchi Y. Diet-Induced Adipose Tissue Inflammation and Liver Steatosis Are Prevented by DPP-4 Inhibition in Diabetic Mice. Diabetes 2011; 60: 1246—1257.

75. Matheeussen V., Baerts L., De Meyer G., De Keulenaer G., Van der Veken P., Augustyns K., Dubois V., Scharpé S., De Meester I. Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries. Biol Chem 2011; 392: 189—198.

76. Pala L., Pezzatini A., Dicembrini I., Ciani S., Gelmini S., Vannelli B.G., Cresci B., Mannucci E., Rotella C.M. Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells. Acta Diabetol 2010 (Electronic publication ahead of print). doi:10.1007/s00592-010-0195-3.

77. Takasawa W., Ohnuma K., Hatano R., Endo Y., Dang N.H., Morimoto C. Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. Biochem Biophys Res Commun 2010; 401: 7—12.

78. Fadini G.P., Avogaro A. Potential manipulation of endothelial progenitor cells in diabetes and its complications. Diabetes Obes Metab 2010; 12: 570—583.

79. Fadini G.P., Agostini C., Sartore S., Avogaro A. Endothelial progenitor cells in the natural history of atherosclerosis. Atherosclerosis 2007; 194: 46—54.

80. De La Luz Sierra M., Yang F., Narazaki M., Salvucci O., Davis D., Yarchoan R., Zhang H.H., Fales H., Tosato G. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood 2004; 103: 2452—2459.

81. Christopherson II K.W., Cooper S., Broxmeyer H.E. Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood 2003; 101: 4680—4686.

82. Zaruba M.M., Theiss H.D., Vallaster M., Mehl U., Brunner S., David R., Fischer R., Krieg L., Hirsch E., Huber B., Nathan P., Israel L., Imhof A., Herbach N., Assmann G., Wanke R., Mueller-Hoecker J., Steinbeck G., Franz W.M. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 2009; 4: 313—323.

83. Shah Z., Pineda C., Kampfrath T., Maiseyeu A., Ying Z., Racoma I., Deiuliis J., Xu X., Sun Q., Moffatt-Bruce S., Villamena F., Rajagopalan S. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol 2011; 55: 1—3: 2—9.

84. Mason R.P., Jacob R.F., Kubant R., Walter M.F., Bellamine A., Jacoby A., Mizuno Y., Malinski T. Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats. J Atheroscler Thromb 2011; 18: 9: 774—783.

85. Sauve M., Ban K., Momen M.A., Zhou Y.Q., Henkelman R.M., Husain M., Drucker D.J. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 2010; 59: 1063—1073.

86. Huisamen B., Genis A., Marais E., Lochner A. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drug Ther 2010; 25: 13—20.

87. Zhang D., Huang W., Dai B., Zhao T., Ashraf A., Millard R.W., Ashraf M., Wang Y. Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts. Am J Physiol Heart Circ Physiol 2010; 299: 1339—1347.

88. Food and Drug Administration: Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

89. Hirshberg B., Raz I. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabet Care 2011; 34: Suppl 2: S101—S106.

90. Frederich R., Alexander J.H., Fiedorek F.T., Donovan M., Berglind N., Harris S., Chen R., Wolf R., Mahaffey K.W. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 2010; 122: 3: 16—27.

91. Bristol-Myers Squibb, AstraZeneca. Bristol-Myers Squibb, AstraZeneca commence SAVOR-TIMI 53 trial of ONGLYZA for type 2 diabetes. March 2010 (press release) http://www.news-medical.net/news/20100310/Bristol-Myers-Squibb-AstraZeneca-commence-SAVOR-TIMI-53-trial-of-ONGLYZA-for-type-2-diabetes.aspx