Cardiovascular actions of incretin-based therapies

Circulation Research

Volumn 114, Issue 11, 2014, Pages 1788-1803

  Ussher, John R ^a   Drucker, Daniel J ^a  

^a MOUNT SINAI HOSPITAL   (Canada)

Author keywords

diabetes mellitus; dipeptidyl peptidase 4; glucagon like peptide 1; heart; heart failure; myocardial ischemia

Indexed keywords

DIPEPTIDYL PEPTIDASE IV INHIBITOR; DULAGLUTIDE; EXENDIN 4; G PROTEIN COUPLED RECEPTOR; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; GLUCOSE TRANSPORTER 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN; LIRAGLUTIDE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; MONOCYTE CHEMOTACTIC PROTEIN 1; NITRIC OXIDE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; REACTIVE OXYGEN METABOLITE; TUMOR NECROSIS FACTOR ALPHA; VASCULAR CELL ADHESION MOLECULE 1;

APOPTOSIS; BLOOD PRESSURE REGULATION; CARDIOVASCULAR RESPONSE; CARDIOVASCULAR RISK; CORONARY ARTERY BLOOD FLOW; CYTOKINE RELEASE; DIABETES MELLITUS; DRUG EFFECT; DRUG MECHANISM; DRUG STRUCTURE; DYSLIPIDEMIA; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; GLUCOSE BLOOD LEVEL; GLUCOSE TRANSPORT; HEART FAILURE; HEART MUSCLE; HEART MUSCLE CELL; HEART MUSCLE CONTRACTILITY; HEART MUSCLE ISCHEMIA; HEART PERFORMANCE; HEART PROTECTION; HEART VENTRICLE FUNCTION; HUMAN; HYPERTENSION; ISCHEMIC HEART DISEASE; LIPID METABOLISM; METABOLIC REGULATION; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN STRUCTURE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIUM;

DIABETES MELLITUS; DIPEPTIDYL PEPTIDASE 4; GLUCAGON-LIKE PEPTIDE 1; HEART; HEART FAILURE; MYOCARDIAL ISCHEMIA;

ANIMALS; BLOOD GLUCOSE; CARDIOVASCULAR SYSTEM; DIABETES MELLITUS, TYPE 2; DIABETIC ANGIOPATHIES; DIPEPTIDYL PEPTIDASE 4; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; HUMANS; INCRETINS; LIPID METABOLISM; MICE; RECEPTORS, GLUCAGON; TREATMENT OUTCOME;

EID: 84901462249     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.114.301958     Document Type: Review

References (133)

1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007;132:2131-2157.
2. Campbell JE, J. DD. Pharmacology physiology and mechanisms of incretin hormone action. Cell metabolism. 2013;17:819-837.
3. Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA. 1992;89:8641-8645.
4. Hupe-Sodmann K, McGregor GP, Bridenbaugh R, R'diger G, Burkhard G, Thole H, Zimmermann B, Voigt K. Characterisation of the processing by human neutral endopeptidase 24.11 of glp-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept. 1995;58:149-156.
5. Sivertsen J, Rosenmeier J, Holst JJ, Vilsbøll T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nat Rev Cardiol. 2012;9:209-222.
6. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187-215.
7. Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, Brown TJ, Streutker C, Holland D, Cao X, Baggio LL, Drucker DJ. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology 2013;154:127-139.
8. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567-575.
9. Pyke C, Knudsen LB. The glucagon-like peptide-1 receptor-or not? Endocrinology 2013;154:4-8.
10. Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F. Identification and characterisation of glucagonlike peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes. 2014;63:1224-1233.
11. Baggio LL, Huang Q, Brown TJ, Drucker DJ. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 2004;53:2492-2500.
12. Malm-Erjefält M, Bjørnsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, van Lier JJ, Zdravkovic M, Olsen AK. 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.
13. Mayo KE, Miller LJ, Bataille D, Dalle S, Göke B, Thorens B, Drucker DJ. International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev. 2003;55:167-194.
14. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 1996;137:2968-2978.
15. Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: the extrapancreatic effects of glucagon-like peptide-1 and related peptides. J Clin Endocrinol Metab. 2009;94:1843-1852.
16. Wohlfart P, Linz W, Hübschle T, Linz D, Huber J, Hess S, Crowther D, Werner U, Ruetten H. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. J Transl Med. 2013;11:84.
17. Moore-Morris T, Varrault A, Mangoni ME, Le Digarcher A, Negre V, Dantec C, Journot L, Nargeot J, Couette B. Identification of potential pharmacological targets by analysis of the comprehensive G proteincoupled receptor repertoire in the four cardiac chambers. Mol Pharmacol. 2009;75:1108-1116.
18. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, 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.
19. Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995;358:219-224.
20. Ban K, Kim H, Cho J, Diamandis E, Backx PH, Drucker DJ, Husain M. Glp-1(9-36) protects cardiomyocytes and endothelial cells from ischemiareperfusion injury via cytoprotective pathways independent of the glp-1 receptor. Endocrinology 2010;151:1520-1531.
21. Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen YT, Shannon RP. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317:1106-1113.
22. Nikolaidis LA, Elahi D, Shen YT, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005;289:H2401-H2408.
23. Ban K, Hui S, Drucker DJ, Husain M. Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretinbased therapies. J Am Soc Hypertens. 2009;3:245-259.
24. Vila Petroff MG, Egan JM, Wang X, Sollott SJ. Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res. 2001;89:445-452.
25. Ravassa S, Zudaire A, Carr RD, Díez J. Antiapoptotic effects of GLP-1 in murine HL-1 cardiomyocytes. Am J Physiol Heart Circ Physiol. 2011;300:H1361-H1372.
26. Nguyen TD, Shingu Y, Amorim PA, Schwarzer M, Doenst T. Glucagonlike peptide-1 reduces contractile function and fails to boost glucose utilization in normal hearts in the presence of fatty acids. Int J Cardiol. 2013;168:4085-4092.
27. Hattori Y, Jojima T, Tomizawa A, Satoh H, Hattori S, Kasai K, Hayashi T. A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells. Diabetologia 2010;53:2256-2263.
28. Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA-and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010;325:26-35.
29. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun. 2010;391:1405-1408.
30. Tomas E, Stanojevic V, Habener JF. GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept. 2011;167:177-184.
31. Fujita H, Morii T, Fujishima H, Sato T, Shimizu T, Hosoba M, Tsukiyama K, Narita T, Takahashi T, Drucker DJ, Seino Y, Yamada Y. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int. 2014;85:579-589.
32. Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, Arakawa M, Jin WL, Kanazawa A, Kawamori R, Fujitani Y, Hirose T, Watada H. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun. 2011;405:79-84.
33. Hirata Y, Kurobe H, Nishio C, Tanaka K, Fukuda D, Uematsu E, Nishimoto S, Soeki T, Harada N, Sakaue H, Kitagawa T, Shimabukuro M, Nakaya Y, Sata M. Exendin-4, a glucagon-like peptide-1 receptor agonist, attenuates neointimal hyperplasia after vascular injury. Eur J Pharmacol. 2013;699:106-111.
34. Dai Y, Mercanti F, Dai D, Wang X, Ding Z, Pothineni NV, Mehta JL. LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. Biochem Biophys Res Commun. 2013;437:62-66.
35. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005;54:146-151.
36. Younce CW, Burmeister MA, Ayala JE. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol. 2013;304:C508-C518.
37. Chai W, Dong Z, Wang N, Wang W, Tao L, Cao W, Liu Z. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes 2012;61:888-896.
38. Dokken BB, Hilwig WR, Teachey MK, Panchal RA, Hubner K, Allen D, Rogers DC, Kern KB. Glucagon-like peptide-1 (GLP-1) attenuates postresuscitation myocardial microcirculatory dysfunction. Resuscitation 2010;81:755-760.
39. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. 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.
40. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007;293:E1289-E1295.
41. Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, Sjöholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209-E1215.
42. Irace C, De Luca S, Shehaj E, Carallo C, Loprete A, Scavelli F, Gnasso A. Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. Diab Vasc Dis Res. 2013;10:72-77.
43. Tesauro M, Schinzari F, Adamo A, Rovella V, Martini F, Mores N, Barini A, Pitocco D, Ghirlanda G, Lauro D, Campia U, Cardillo C. Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome. Diabetes Care. 2013;36:683-689.
44. Sjøberg KA, Holst JJ, Rattigan S, Richter EA, Kiens B. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am J Physiol Endocrinol Metab. 2014;306:E355-E362.
45. Kelly AS, Bergenstal RM, Gonzalez-Campoy JM, Katz H, Bank AJ. Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial. Cardiovasc Diabetol. 2012;11:64.
46. Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, Yogo M, Ogura M, Takase B, Murakami T, Ikewaki K. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2:e003277.
47. Hsieh J, Longuet C, Baker CL, Qin B, Federico LM, Drucker DJ, Adeli K. The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion. Diabetologia 2010;53:552-561.
48. Parlevliet ET, Schröder-van der Elst JP, Corssmit EP, Picha K, O'Neil K, Stojanovic-Susulic V, Ort T, Havekes LM, Romijn JA, Pijl H. CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice. J Pharmacol Exp Ther. 2009;328:240-248.
49. Parlevliet ET, Wang Y, Geerling JJ, Schröder-Van der Elst JP, Picha K, O'Neil K, Stojanovic-Susulic V, Ort T, Havekes LM, Romijn JA, Pijl H, Rensen PC. GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice. PLoS One. 2012;7:e49152.
50. Burmeister MA, Ferre T, Ayala JE, King EM, Holt RM, Ayala JE. Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice. Am J Physiol Endocrinol Metab. 2012;302:E334-E343.
51. Juntti-Berggren L, Pigon J, Karpe F, Hamsten A, Gutniak M, Vignati L, Efendic S. The antidiabetogenic effect of GLP-1 is maintained during a 7-day treatment period and improves diabetic dyslipoproteinemia in NIDDM patients. Diabetes Care. 1996;19:1200-1206.
52. Meier JJ, Gethmann A, Gotze O, Gallwitz B, Holst JJ, Schmidt WE, Nauck MA. 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.
53. Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001;86:3853-3860.
54. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of 3 months of continuous subcutaneous administration of glucagonlike peptide 1 in elderly patients with type 2 diabetes. Diabetes Care. 2003;26:2835-2841.
55. Schwartz EA, Koska J, Mullin MP, Syoufi I, Schwenke DC, Reaven PD. Exenatide suppresses postprandial elevations in lipids and lipoproteins in individuals with impaired glucose tolerance and recent onset type 2 diabetes mellitus. Atherosclerosis 2010;212:217-222.
56. Xiao C, Bandsma RH, Dash S, Szeto L, Lewis GF. Exenatide, a glucagon-like peptide receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans. Arterioscler Thromb Vasc Biol. 2012;32:1513-1519.
57. Xiao C, Dash S, Morgantini C, Patterson BW, Lewis GF. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, acutely inhibits intestinal lipoprotein particle secretion in healthy humans [published online ahead of print February 28, 2014]. Diabetes doi:10.2337/db13-1654. http://diabetes. diabetesjournals. org/content/early/2014/02/27/db13-1654.long. Accessed May 9, 2014.
58. 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.
59. Pyke C, Heller RS, Kirk RK, Orskov C, Reedtz-Runge S, Kaastrup P, Hvelplund A, Bardram L, Calatayud D, Knudsen LB. Glp-1 receptor localization in monkey and human tissue; novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014:en20131934.
60. Gill A, Hoogwerf BJ, Burger J, Bruce S, Macconell L, Yan P, Braun D, Giaconia J, Malone J. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebocontrolled, randomized pilot study. Cardiovasc Diabetol. 2010;9:6.
61. Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, Wilhelm K, Trautmann M, Shen LZ, Porter LE; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 2010;33:1255-1261.
62. Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD, Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006;8:436-447.
63. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rössner S, Savolainen MJ, Van Gaal L; NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843-854.
64. Yang W, Chen L, Ji Q, Liu X, Ma J, Tandon N, Bhattacharyya A, Kumar A, Kim KW, Yoon KH, Bech OM, Zychma M. Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, double-blind, active control trial. Diabetes Obes Metab. 2011;13:81-88.
65. Gallwitz B, Vaag A, Falahati A, Madsbad S. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64:267-276.
66. Li CJ, Yu Q, Yu P, Yu TL, Zhang QM, Lu S, Yu DM. Changes in liraglutideinduced body composition are related to modifications in plasma cardiac natriuretic peptides levels in obese type 2 diabetic patients. Cardiovasc Diabetol. 2014;13:36.
67. Skov J, Holst JJ, Gøtze JP, Frøkiær J, Christiansen JS. Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males. Endocr Connect. 2014;3:11-16.
68. Bao W, Aravindhan K, Alsaid H, Chendrimada T, Szapacs M, Citerone DR, Harpel MR, Willette RN, Lepore JJ, Jucker BM. Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving cardiac metabolic efficiency. PLoS One 2011;6:e23570.
69. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-258.
70. Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA, Pasterkamp G, Hoefer IE. 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.
71. Kristensen J, Mortensen UM, Schmidt M, Nielsen PH, Nielsen TT, Maeng M. Lack of cardioprotection from subcutaneously and preischemic administered liraglutide in a closed chest porcine ischemia reperfusion model. BMC Cardiovasc Disord. 2009;9:31.
72. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009;58:975-983.
73. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 2004;109:962-965.
74. Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart 2012;98:408-413.
75. Read PA, Hoole SP, White PA, Khan FZ, O'Sullivan M, West NE, Dutka DP. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv. 2011;4:266-272.
76. Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33:1491-1499.
77. Lønborg J, Kelbæk H, Vejlstrup N, Bøtker HE, Kim WY, Holmvang L, Jørgensen E, Helqvist S, Saunamäki K, Terkelsen CJ, Schoos MM, Køber L, Clemmensen P, Treiman M, Engstrøm T. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5:288-295.
78. Lønborg J, Vejlstrup N, Kelbæk H, Nepper-Christensen L, Jørgensen E, Helqvist S, Holmvang L, Saunamäki K, Bøtker HE, Kim WY, Clemmensen P, Treiman M, Engstrøm T. Impact of acute hyperglycemia on myocardial infarct size, area at risk and salvage in patients with st elevation myocardial infarction and the association with exenatide treatment-results from a randomized study [published online ahead of print February 28, 2014]. Diabetes doi:10.2337/db13-1849. http://diabetes. diabetesjournals.org/content/early/2014/02/27/db13-1849.abstract?sid= 3f46d8bf-42d9-468e-9c24-dec96654121c. Accessed May 9, 2014.
79. Woo JS, Kim W, Ha SJ, Kim JB, Kim SJ, Kim WS, Seon HJ, Kim KS. Cardioprotective effects of exenatide in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of exenatide myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol. 2013;33:2252-2260.
80. Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen YT, Shannon RP. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail. 2010;3:512-521.
81. Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP. 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.
82. Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, Volchuk A, Robinson LA, Billia F, Drucker DJ, Husain M. A glucagonlike peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation 2013;127:74-85.
83. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagonlike peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12:694-699.
84. Halbirk M, Norrelund H, Moller N, Holst JJ, Schmitz O, Nielsen R, Nielsen-Kudsk JE, Nielsen SS, Toftegard T, Eiskjaer H, Botker HE, Wiggers H. Cardiovascular and metabolic effects of 48-hour glucagonlike peptide 1 infusion in compensated chronic heart failure patients. Am J Physiol Heart Circ Physiol. 2010;298:H1096-1102.
85. Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 2007;30:1335-1343.
86. 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.
87. Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, Cheng XW, Okumura T, Hirashiki A, Nagata K, Murohara T. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and-independent actions. Circulation 2012;126:1838-1851.
88. Sauve M, Ban K, Momen A, Zhou Y-Q, Henkelman RM, Husain M, Drucker DJ. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes following myocardial infarction in mice. Diabetes 2010;59:1063-1073.
89. Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol. 2010;298:H1454-H1465.
90. 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 Drugs Ther. 2011;25:13-20.
91. Theiss HD, Gross L, Vallaster M, David R, Brunner S, Brenner C, Nathan P, Assmann G, Mueller-Hoecker J, Vogeser M, Steinbeck G, Franz WM. Antidiabetic gliptins in combination with G-CSF enhances myocardial function and survival after acute myocardial infarction. Int J Cardiol. 2013;168:3359-3369.
92. Petit I, Jin D, Rafii S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 2007;28:299-307.
93. Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair. Gene Ther. 2012;19:583-587.
94. Takahashi M. Role of the SDF-1/CXCR4 system in myocardial infarction. Circ J. 2010;74:418-423.
95. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev. 2013;65:967-986.
96. Chang LT, Yuen CM, Sun CK, Wu CJ, Sheu JJ, Chua S, Yeh KH, Yang CH, Youssef AA, Yip HK. Role of stromal cell-derived factor-1alpha, level and value of circulating interleukin-10 and endothelial progenitor cells in patients with acute myocardial infarction undergoing primary coronary angioplasty. Circ J. 2009;73:1097-1104.
97. Tillmanns J, Rota M, Hosoda T, et al. Formation of large coronary arteries by cardiac progenitor cells. Proc Natl Acad Sci USA. 2008;105:1668-1673.
98. Saxena A, Fish JE, White MD, Yu S, Smyth JW, Shaw RM, DiMaio JM, Srivastava D. Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction. Circulation 2008;117:2224-2231.
99. Fadini GP, Avogaro A. Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis 2013;229:23-29.
100. Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC. Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest. 2007;117:1249-1259.
101. Fadini GP, 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: possible role of stromal-derived factor-1alpha. Diabetes Care 2010;33:1607-1609.
102. Theiss HD, Vallaster M, Rischpler C, Krieg L, Zaruba MM, Brunner S, Vanchev Y, Fischer R, Gröbner M, Huber B, Wollenweber T, Assmann G, Mueller-Hoecker J, Hacker M, Franz WM. Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res. 2011;7:244-255.
103. Zaruba MM, Theiss HD, Vallaster M, et al. Synergy between CD26/DPPIV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 2009;4:313-323.
104. Hansotia T, Baggio LL, Delmeire D, Hinke SA, Yamada Y, Tsukiyama K, Seino Y, Holst JJ, Schuit F, Drucker DJ. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 2004;53:1326-1335.
105. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 1993;133:2861-2870.
106. Kim SJ, Nian C, McIntosh CH. Resistin is a key mediator of glucosedependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in adipocytes. J Biol Chem. 2007;282:34139-34147.
107. Kim SJ, Nian C, McIntosh CH. GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J Lipid Res. 2010;51:3145-3157.
108. Miyawaki K, Yamada Y, Ban N, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8:738-742.
109. Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, Drucker DJ. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117:143-152.
110. Zhong Q, Bollag RJ, Dransfield DT, Gasalla-Herraiz J, Ding KH, Min L, Isales CM. Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides. 2000;21:1427-1432.
111. Nagashima M, Watanabe T, Terasaki M, Tomoyasu M, Nohtomi K, Kim-Kaneyama J, Miyazaki A, Hirano T. Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice. Diabetologia 2011;54:2649-2659.
112. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging. 2010;3:195-201.
113. McCormick LM, Kydd AC, Read PA, Ring LS, Bond SJ, Hoole SP, Dutka DP. Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease. Circ Cardiovasc Imaging. 2014;7:274-281.
114. Theiss HD, Brenner C, Engelmann MG, Zaruba MM, Huber B, Henschel V, Mansmann U, Wintersperger B, Reiser M, Steinbeck G, Franz WM. Safety and efficacy of sitagliptin plus granulocyte-colony-stimulating factor in patients suffering from acute myocardial infarction (sitagrami-trial)-rationale, design and first interim analysis. Int J Cardiol. 2010;145:282-284.
115. Franz WM, Theiss H, Brenner C, Adrion C, Grabmaier U, Theisen D, Becker A, Ziegler F, Sohn H, Mansmann U, Steinbeck G. Safety and efficacy of sitagliptin plus granulocyte-colony stimulating factor in patients suffering from acute myocardial infarction-sitagrami trial. Presentation abstract. American Heart Association, November 18, 2013.
116. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.
117. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.
118. Gomez N, Touihri K, Matheeussen V, Mendes Da Costa A, Mahmoudabady M, Mathieu M, Baerts L, Peace A, Lybaert P, Scharpé S, De Meester I, Bartunek J, Vanderheyden M, Mc Entee K. Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur J Heart Fail. 2012;14:14-21.
119. dos Santos L, Salles TA, Arruda-Junior DF, Campos LC, Pereira AC, Barreto AL, Antonio EL, Mansur AJ, Tucci PJ, Krieger JE, Girardi AC. Circulating dipeptidyl peptidase IV activity correlates with cardiac dysfunction in human and experimental heart failure. Circ Heart Fail. 2013;6:1029-1038.
120. Ku HC, Su MJ. DPP4 deficiency preserved cardiac function in abdominal aortic banding rats. PLoS One 2014;9:e85634.
121. Lenski M, Kazakov A, Marx N, Böhm M, Laufs U. Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J Mol Cell Cardiol. 2011;51:906-918.
122. Takahashi A, Asakura M, Ito S, et al. Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice. Am J Physiol Heart Circ Physiol. 2013;304:H1361-H1369.
123. Yin M, Silljé HH, Meissner M, van Gilst WH, de Boer RA. Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of postmyocardial infarction heart failure. Cardiovasc Diabetol. 2011;10:85.
124. McMurray J. The vildagliptin in ventricular dysfunction diabetes trial (VIVIDD). European Society of Cardiology Annual Meeting, August 31, 2013, to September 4, 2013, Amsterdam, the Netherlands.
125. Devin JK, Pretorius M, Nian H, Yu C, Billings FT IV, Brown NJ. Substance p increases sympathetic activity during combined Angiotensinconverting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension 2014;63:951-957.
126. Ku HC, Chen WP, Su MJ. DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion. Naunyn Schmiedebergs Arch Pharmacol. 2011;384:197-207.
127. Patterson JT, Ottaway N, Gelfanov VM, Smiley DL, Perez-Tilve D, Pfluger PT, Tschöp MH, Dimarchi RD. A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1. ACS Chem Biol. 2011;6:135-145.
128. Wheeler MB, Lu M, Dillon JS, Leng XH, Chen C, Boyd AE III. Functional expression of the rat glucagon-like peptide-I receptor, evidence for coupling to both adenylyl cyclase and phospholipase-C. Endocrinology 1993;133:57-62.
129. Serre V, Dolci W, Scrocchi LA, Drucker DJ, Efrat S, Thorens B. Exendin-(9-39) as an inverse agonist of the murine glp-1 receptor. Implications for basal intracellular camp levels and β cell glucose competence. Endocrinology 1998;139:4448-4454.
130. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB, Drucker DJ, Elmquist JK. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest. 2002;110:43-52.
131. Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771.
132. Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J. 2013;166:983-989.e7.
133. Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, Pocock S, Steinberg WM, Bergenstal RM, Mann JF, Ravn LS, Frandsen KB, Moses AC, Buse JB. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J. 2013;166:823-30.e5.