The impact of current and novel anti-diabetic therapies on cardiovascular risk

Future Cardiology

Volumn 8, Issue 6, 2012, Pages 895-912

  Ussher, John R ^a   Sutendra, Gopinath ^b   Jaswal, Jagdip S ^b  

^a MOUNT SINAI HOSPITAL   (Canada)

^b UNIVERSITY OF ALBERTA   (Canada)

Author keywords

cardiovascular disease; energetics; heart failure; insulin resistance; ischemia reperfusion; myocardial infarction; obesity; type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACARBOSE; ALOGLIPTIN; ALPHA GLUCOSIDASE INHIBITOR; ANTIDIABETIC AGENT; BIGUANIDE; BROMOCRIPTINE; CANAGLIFLOZIN; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EXENDIN 4; GLIBENCLAMIDE; GLIMEPIRIDE; GLIPIZIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INSULIN; LIRAGLUTIDE; METFORMIN; MIGLITOL; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; SITAGLIPTIN; SULFONYLUREA; SULFONYLUREA DERIVATIVE; TOLBUTAMIDE; TROGLITAZONE; UNINDEXED DRUG; VOGLIBOSE;

ACUTE HEART INFARCTION; BLADDER CANCER; CANCER RISK; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; DRUG DESIGN; EDEMA; FLUID RETENTION; GLUCOSE BLOOD LEVEL; HEART FAILURE; HEART INFARCTION; HUMAN; HYPERGLYCEMIA; HYPOGLYCEMIA; ISCHEMIC PRECONDITIONING; LACTIC ACIDOSIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OUTCOME ASSESSMENT; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; PERIPARTUM CARDIOMYOPATHY; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; UNSPECIFIED SIDE EFFECT; WEIGHT GAIN;

ANIMALS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; METFORMIN;

EID: 84870205804     PISSN: 14796678     EISSN: 17448298     Source Type: Journal    
DOI: 10.2217/fca.12.68     Document Type: Review

References (144)

1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352(9131), 837-853 (1998).
2. Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358(24), 2545-2559 (2008) •• The ACCORD large-scale and multicenter clinical trial demonstrated increased mortality and no benefit to cardiovascular risk following intensive glucose-lowering therapy in high-risk patients with type 2 diabetes mellitus (T2DM). (Pubitemid 351831356)
3. Zoungas S, Patel A, Chalmers J et al. Severe hypoglycemia and risks of vascular events and death. N. Engl. J. Med. 363(15), 1410-1418 (2010) •• The ADVANCE large-scale and multicenter clinical trial demonstrated a strong positive association between severe hypoglycemia and increased risk for major macrovascular events, major microvascular events and death by cardiovascular disease.
4. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356(24), 2457-2471 (2007) •• This meta-analysis demonstrated an increased risk for myocardial infarction in patients treated with rosiglitazone and resulted in extreme caution with regards to the use of rosiglitazone to control glycemia in patients with T2DM. (Pubitemid 46919772)
5. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 156(3), 218-231 (2012).
6. Smith SA. Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochem. Soc. Trans. 30(Pt 6), 1086-1090 (2002). (Pubitemid 36002413)
7. Yue TL, Bao W, Gu JL et al. Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes 54(2), 554-562 (2005).
8. Yue TL, Bao W, Jucker BM et al. Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury. Circulation 108(19), 2393-2399 (2003). (Pubitemid 37413548)
9. How OJ, Larsen TS, Hafstad AD et al. Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Arch. Physiol. Biochem. 113(4-5), 211-220 (2007).
10. Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD. Targeting fatty acid and carbohydrate oxidation - a novel therapeutic intervention in the ischemic and failing heart. Biochim. Biophys. Acta 1813(7), 1333-1350 (2011).
11. Jaswal JS, Ussher JR, Lopaschuk GD. Myocardial fatty acid utilization as a determinant of cardiac efficiency and function. Clin. Lipidol. 4(3), 379-389 (2009).
12. Akiyama TE, Sakai S, Lambert G et al. Conditional disruption of the peroxisome proliferator-activated receptor gamma gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Mol. Cell. Biol. 22(8), 2607-2619 (2002). (Pubitemid 34262983)
13. Babaev VR, Yancey PG, Ryzhov SV et al. Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 25(8), 1647-1653 (2005). (Pubitemid 41098935)
14. Zamanian RT, Hansmann G, Snook S et al. Insulin resistance in pulmonary arterial hypertension. Eur. Respir. J. 33(2), 318-324 (2009).
15. Dromparis P, Sutendra G, Michelakis ED. The role of mitochondria in pulmonary vascular remodeling. J. Mol. Med. 88(10), 1003-1010 (2010).
16. Hansmann G, Wagner RA, Schellong S et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator- activated receptor-gamma activation. Circulation 115(10), 1275-1284 (2007). (Pubitemid 46594772)
17. Son NH, Park TS, Yamashita H et al. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. J. Clin. Invest. 117(10), 2791-2801 (2007). (Pubitemid 47529610)
18. Duan SZ, Ivashchenko CY, Russell MW, Milstone DS, Mortensen RM. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice. Circ. Res. 97(4), 372-379 (2005). (Pubitemid 41216142)
19. Guan Y, Hao C, Cha DR et al. Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat. Med. 11(8), 861-866 (2005). (Pubitemid 41161118)
20. Lindenfeld J, Masoudi FA. Fluid retention with thiazolidinediones: does the mechanism influence the outcome? J. Am. Coll. Cardiol. 49(16), 1705-1707 (2007).
21. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111(5), 583-590 (2005). (Pubitemid 40216485)
22. Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglit Azone Clinical Trial In macro Vascular Events): a randomised controlled trial. Lancet 366(9493), 1279-1289 (2005). (Pubitemid 41416583)
23. Nissen SE, Wolski K. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch. Intern. Med. 170(14), 1191-1201 (2010).
24. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298(10), 1180-1188 (2007). (Pubitemid 47403104)
25. Goldberg RB, Kendall DM, Deeg MA et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28(7), 1547-1554 (2005). (Pubitemid 40923063)
26. Nicholls SJ, Tuzcu EM, Wolski K et al. Lowering the triglyceride/high- density lipoprotein cholesterol ratio is associated with the beneficial impact of pioglitazone on progression of coronary atherosclerosis in diabetic patients: insights from the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study. J. Am. Coll. Cardiol. 57(2), 153-159 (2011).
27. Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 342, d1309 (2011).
28. Young PW, Buckle DR, Cantello BC et al. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther. 284(2), 751-759 (1998). (Pubitemid 28086668)
29. Graham DJ, Ouellet-Hellstrom R, Macurdy TE et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304(4), 411-418 (2010).
30. Azoulay L, Yin H, Filion KB et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 344, e3645 (2012).
31. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 19, 789-830 (1970).
32. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74(5), 1124-1136 (1986). (Pubitemid 17174962)
33. Kirsch GE, Codina J, Birnbaumer L, Brown AM. Coupling of ATP-sensitive K+ channels to A1 receptors by G proteins in rat ventricular myocytes. Am. J. Physiol. 259(3 Pt 2), H820-H826 (1990). (Pubitemid 20310486)
34. Gross GJ, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ. Res. 70(2), 223-233 (1992).
35. Toombs CF, Moore TL, Shebuski RJ. Limitation of infarct size in the rabbit by ischaemic preconditioning is reversible with glibenclamide. Cardiovasc. Res. 27(4), 617-622 (1993). (Pubitemid 23144586)
36. Horimoto H, Nakai Y, Mieno S, Nomura Y, Nakahara K, Sasaki S. Oral hypoglycemic sulfonylurea glimepiride preserves the myoprotective effects of ischemic preconditioning. J. Surg. Res. 105(2), 181-188 (2002). (Pubitemid 34765325)
37. Nishida H, Sato T, Nomura M, Miyazaki M, Nakaya H. Glimepiride treatment upon reperfusion limits infarct size via the phosphatidylinositol 3-kinase/Akt pathway in rabbit hearts. J. Pharmacol. Sci. 109(2), 251-256 (2009).
38. Song DK, Ashcroft FM. Glimepiride block of cloned beta-cell, cardiac and smooth muscle K (ATP) channels. Br. J. Pharmacol. 133(1), 193-199 (2001). (Pubitemid 32500467)
39. Cribier A, Korsatz L, Koning R et al. Improved myocardial ischemic response and enhanced collateral circulation with long repetitive coronary occlusion during angioplasty: a prospective study. J. Am. Coll. Cardiol. 20(3), 578-586 (1992).
40. Tomai F, Crea F, Gaspardone A et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation 90(2), 700-705 (1994). (Pubitemid 24242735)
41. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J. Am. Coll. Cardiol. 33(1), 119-124 (1999). (Pubitemid 29064081)
42. Klepzig H, Kober G, Matter C et al. Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. Eur. Heart J. 20(6), 439-446 (1999). (Pubitemid 29116540)
43. Schramm TK, Gislason GH, Vaag A et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur. Heart J. 32(15), 1900-1908 (2011).
44. Kenchaiah S, Evans JC, Levy D et al. Obesity and the risk of heart failure. N. Engl. J. Med. 347(5), 305-313 (2002). (Pubitemid 34815352)
45. American Diabetes Association. Standards of medical care in diabetes - 2009. Diabetes Care 32(Suppl. 1), S13-S61 (2009).
46. Kim YD, Park KG, Lee YS et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 57(2), 306-314 (2008).
47. Gundewar S, Calvert JW, Jha S et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ. Res. 104(3), 403-411 (2009) • This study demonstrated that metformin could improve left ventricular function and survival during ischemic-induced heart failure due to activation of AMPK. Furthermore, this study was instrumental in shifting views regarding metformin's contraindication in patients with T2DM and heart failure.
48. Ussher JR, Jaswal JS, Wagg CS et al. Role of the atypical protein kinase Czeta in regulation of 5'-AMP-activated protein kinase in cardiac and skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 297(2), E349-E357 (2009).
49. Yin M, Van Der Horst IC, Van Melle JP et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am. J. Physiol. Heart Circ. Physiol. 301(2), H459-H468 (2011).
50. Calvert JW, Gundewar S, Jha S et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 57(3), 696-705 (2008).
51. An D, Kewalramani G, Chan JK et al. Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3. Diabetologia 49(9), 2174-2184 (2006). (Pubitemid 44168486)
52. Xie Z, Lau K, Eby B et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60(6), 1770-1778 (2011).
53. Xiao H, Ma X, Feng W et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc. Res. 87(3), 504-513 (2010).
54. Agard C, Rolli-Derkinderen M, Dumas-De-La-Roque E et al. Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension. Br. J. Pharmacol. 158(5), 1285-1294 (2009).
55. Eurich DT, McAlister FA, Blackburn DF et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 335(7618), 497 (2007).
56. Evans JM, Doney AS, Alzadjali MA et al. Effect of Metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am. J. Cardiol. 106(7), 1006-1010 (2010).
57. Andersson C, Sogaard P, Hoffmann S et al. Metformin is associated with improved left ventricular diastolic function measured by tissue Doppler imaging in patients with diabetes. Eur. J. Endocrinol. 163(4), 593-599 (2010).
58. Romero SP, Andrey JL, Garcia-Egido A et al. Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensity-matched study in the community. Int. J. Cardiol. doi:10.1016/j. ijcard.2011.10.141 (2011) (Epub ahead of print).
59. Boussageon R, Supper I, Bejan-Angoulvant T et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 9 e1001204 (2012).
60. Minatoguchi S, Arai M, Uno Y et al. A novel anti-diabetic drug, miglitol, markedly reduces myocardial infarct size in rabbits. Br. J. Pharmacol. 128(8), 1667-1672 (1999). (Pubitemid 30011879)
61. Wang N, Minatoguchi S, Chen X et al. Antidiabetic drug miglitol inhibits myocardial apoptosis involving decreased hydroxyl radical production and Bax expression in an ischaemia/reperfusion rabbit heart. Br. J. Pharmacol. 142(6), 983-990 (2004). (Pubitemid 39037048)
62. Liao Y, Takashima S, Zhao H et al. Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice. Cardiovasc. Res. 70(1), 107-116 (2006).
63. Iwasa M, Kobayashi H, Yasuda S et al. Antidiabetic drug voglibose is protective against ischemia-reperfusion injury through glucagon-like peptide 1 receptors and the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathway in rabbits. J. Cardiovasc. Pharmacol. 55(6), 625-634 (2010).
64. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290(4), 486-494 (2003). (Pubitemid 37430502)
65. Shimabukuro M, Higa N, Chinen I, Yamakawa K, Takasu N. Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study. J. Clin. Endocrinol. Metab. 91(3), 837-842 (2006). (Pubitemid 43357747)
66. Hiki M, Shimada K, Kiyanagi T et al. Single administration of alpha-glucosidase inhibitors on endothelial function and incretin secretion in diabetic patients with coronary artery disease - Juntendo University trial: effects of miglitol on endothelial vascular reactivity in type 2 diabetic patients with coronary heart disease (J-MACH). Circ. J. 74(7), 1471-1478 (2010).
67. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 132(6), 2131-2157 (2007). (Pubitemid 46711096)
68. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr. Rev. 33(2), 187-215 (2012).
69. Griffioen KJ, Wan R, Okun E et al. GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons. Cardiovasc. Res. 89(1), 72-78 (2011).
70. Yamamoto H, Lee CE, Marcus JN et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J. Clin. Invest. 110(1), 43-52 (2002). (Pubitemid 34743464)
71. Hirata K, Kume S, Araki S et al. Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem. Biophys. Res. Commun. 380(1), 44-49 (2009).
72. Arakawa M, Mita T, Azuma K et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59(4), 1030-1037 (2010).
73. Bao W, Aravindhan K, Alsaid H et al. 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 6(8), e23570 (2011).
74. Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 54(1), 146-151 (2005). (Pubitemid 40105106)
75. 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. 53(6), 501-510 (2009).
76. Kavianipour M, Ehlers MR, Malmberg K et al. Glucagon-like peptide-1 (7-36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium. Peptides 24(4), 569-578 (2003). (Pubitemid 36829346)
77. 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. 9, 31 (2009).
78. 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 117(18), 2340-2350 (2008). (Pubitemid 351653542)
79. 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 58(4), 975-983 (2009).
80. 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 110(8), 955-961 (2004). (Pubitemid 39128621)
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. 1(3), 153-160 (2008).
82. Ban K, Kim KH, Cho CK et al. Glucagonlike peptide (GLP)-1 (9-36) amide-mediated cytoprotection is blocked by exendin (9-39) yet does not require the known GLP-1 receptor. Endocrinology 151(4), 1520-1531 (2010).
83. 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 109(8), 962-965 (2004). (Pubitemid 38282847)
84. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J. Card. Fail. 12(9), 694-699 (2006). (Pubitemid 44881367)
85. Lonborg J, Vejlstrup N, Kelbaek H et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur. Heart J. 33(12), 1491-1499 (2012) •• This randomized, double-blind, placebocontrolled clinical trial is the largest to date for GLP-1R activation in patients with acute myocardial infarction, demonstrating a positive effect of exenatide to increase the myocardial salvage index when administered during reperfusion.
86. Halbirk M, Norrelund H, Moller N et al. 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. 298(3), H1096-H1102 (2010).
87. Zhu L, Tamvakopoulos C, Xie D et al. The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J. Biol. Chem. 278(25), 22418-22423 (2003). (Pubitemid 36830293)
88. Brandt I, Lambeir AM, Maes MB, Scharpe S, De Meester I. Peptide substrates of dipeptidyl peptidases. Adv. Exp. Med. Biol. 575, 3-18 (2006).
89. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47, 1663-1670 (1998). (Pubitemid 28476238)
90. Zaruba MM, Theiss HD, Vallaster M et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4(4), 313-323 (2009).
91. Theiss HD, Vallaster M, Rischpler C et al. Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis. Stem Cell Res. 7(3), 244-255 (2011).
92. Sauve M, Ban K, Momen MA et al. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 59(4), 1063-1073 (2010).
93. Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKAdependent, whereas the protective effect of pioglitazone is p artially dependent on PKA. Am. J. Physiol. Heart Circ. Physiol. 298(5), H1454-H1465 (2010).
94. Lenski M, Kazakov A, Marx N, Bohm M, Laufs U. Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J. Mol. Cell. Cardiol. 51(6), 906-918 (2011).
95. Shah Z, Kampfrath T, Deiuliis JA et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124(21), 2338-2349 (2011).
96. Russell-Jones D, Cuddihy RM, Hanefeld M et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care 35(2), 252-258 (2012).
97. 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 3(2), 195-201 (2010).
98. Theiss HD, Brenner C, Engelmann MG et al. 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. 145(2), 282-284 (2010).
99. Defronzo RA. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care 34(4), 789-794 (2011).
100. Lokhandwala MF, Tadepalli AS, Jandhyala BS. Cardiovascular actions of bromocriptine: evidence for a neurogenic mechanism. J. Pharmacol. Exp. Ther. 211(3), 620-625 (1979). (Pubitemid 10177931)
101. Roquebert J, Alaoui K, Moran Benito A. Cardiovascular effects of bromocriptine in rats: role of peripheral adrenergic and dopaminergic receptors. J. Auton. Pharmacol. 10(2), 85-96 (1990). (Pubitemid 20212608)
102. Li HZ, Guo J, Gao J et al. Role of dopamine D2 receptors in ischemia/reperfusion induced apoptosis of cultured neonatal rat cardiomyocytes. J. Biomed. Sci. 18, 18 (2011).
103. Gaziano JM, Cincotta AH, O'Connor CM et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 33(7), 1503-1508 (2010).
104. Sliwa K, Blauwet L, Tibazarwa K et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation 121(13), 1465-1473 (2010).
105. Tan LC, Ng KK, Au WL, Lee RK, Chan YH, Tan NC. Bromocriptine use and the risk of valvular heart disease. Mov. Disord. 24(3), 344-349 (2009).
106. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest. 93(1), 397-404 (1994).
107. Burki TK. FDA rejects novel diabetes drug over safety fears. Lancet 379(9815), 507 (2012).
108. Madrazo JA, Kelly DP. The PPAR trio: regulators of myocardial energy metabolism in health and disease. J. Mol. Cell. Cardiol. 44(6), 968-975 (2008).
109. Wayman NS, Hattori Y, McDonald MC et al. Ligands of the peroxisome proliferatoractivated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. 16(9), 1027-1040 (2002). (Pubitemid 34753509)
110. Prasad MR, Clement R, Otani H et al. Improved myocardial performance induced by clofibrate during reperfusion after acute myocardial infarction. Can. J. Physiol. Pharmacol. 66(12), 1518-1523 (1988). (Pubitemid 19046763)
111. Schoonjans K, Staels B, Grimaldi P, Auwerx J. Acyl-CoA synthetase mRNA expression is controlled by fibric-acid derivatives, feeding and liver proliferation. Eur. J. Biochem. 216(2), 615-622 (1993). (Pubitemid 23276310)
112. Finck BN, Bernal-Mizrachi C, Han DH et al. A potential link between muscle peroxisome proliferator - activated receptor-alpha signaling and obesity-related diabetes. Cell Metab. 1(2), 133-144 (2005). (Pubitemid 43960595)
113. Finck BN, Lehman JJ, Leone TC et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J. Clin. Invest. 109(1), 121-130 (2002). (Pubitemid 34052548)
114. Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD. Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia. Am. J. Physiol. Heart Circ. Physiol. 290(1), H87-H95 (2006).
115. Loichot C, Jesel L, Tesse A et al. Deletion of peroxisome proliferator-activated receptoralpha induces an alteration of cardiac functions. Am. J. Physiol. Heart Circ. Physiol. 291(1), H161-H166 (2006).
116. Luquet S, Lopez-Soriano J, Holst D et al. Roles of peroxisome proliferator-activated receptor delta (PPARdelta) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome. Biochimie 86(11), 833-837 (2004). (Pubitemid 39602763)
117. Kramer DK, Al-Khalili L, Guigas B, Leng Y, Garcia-Roves PM, Krook A. Role of AMP kinase and PPARdelta in the regulation of lipid and glucose metabolism in human skeletal muscle. J. Biol. Chem. 282(27), 19313-19320 (2007). (Pubitemid 47100082)
118. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J. Clin. Invest. 116(3), 590-597 (2006). (Pubitemid 43326863)
119. Liu J, Wang P, Luo J et al. Peroxisome proliferator-activated receptor beta/delta activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition. Hypertension 57(2), 223-230 (2011).
120. Cheng L, Ding G, Qin Q et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat. Med. 10(11), 1245-1250 (2004). (Pubitemid 39540443)
121. Wang P, Liu J, Li Y et al. Peroxisome proliferator-activated receptor {delta} is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart. Circ. Res. 106(5), 911-919 (2010).
122. Pellieux C, Montessuit C, Papageorgiou I, Lerch R. Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-alpha. Cardiovasc. Res. 82(2), 341-350 (2009).
123. Burkart EM, Sambandam N, Han X et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J. Clin. Invest. 117(12), 3930-3939 (2007) • This study demonstrated that PPARb/d activation in mice regulates a distinct metabolic profile in mice different from PPARa, which resulted in increased glucose utilization and protection against both obesity-induced cardiac dysfunction and acute myocardial infarction. (Pubitemid 350224102)
124. Ussher JR, Lopaschuk GD. Clinical implications of energetic problems in cardiovascular disease. Heart Metab. 32, 9-17 (2006).
125. Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell. Biol. 9(3), 193-205 (2008). (Pubitemid 351301824)
126. Ussher JR, Lopaschuk GD. The malonyl CoA axis as a potential target for treating ischaemic heart disease. Cardiovasc. Res. 79(2), 259-268 (2008). (Pubitemid 351951618)
127. Ussher JR, Lopaschuk GD. Targeting malonyl CoA inhibition of mitochondrial fatty acid uptake as an approach to treat cardiac ischemia/reperfusion. Basic Res. Cardiol. 104(2), 203-210 (2009).
128. Bouzakri K, Austin R, Rune A et al. Malonyl CoenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes 57(6), 1508-1516 (2008).
129. Koves TR, Ussher JR, Noland RC et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 7(1), 45-56 (2008).
130. Ussher JR, Koves TR, Cadete VJ et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59(10), 2453-2464 (2010).
131. Lopaschuk GD, Ussher JR, Jaswal JS. Targeting intermediary metabolism in the hypothalamus as a mechanism to regulate appetite. Pharmacol. Rev. 62(2), 237-264 (2010).
132. Dyck JR, Cheng JF, Stanley WC et al. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ. Res. 94(9), e78-e84 (2004) • This study demonstrated that novel malonyl CoA decarboxylase inhibitors protect against ischemia/reperfusion injury due to inhibition of fatty acid oxidation and a secondary stimulation of glucose oxidation.
133. Ussher JR, Wang W, Gandhi M et al. Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc. Res. 94(2), 359-369 (2012).
134. Ussher JR, Koves TR, Jaswal JS et al. Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase. Diabetes 58(8), 1766-1775 (2009).
135. Zhang L, Ussher JR, Oka T, Cadete VJ, Wagg C, Lopaschuk GD. Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation. Cardiovasc. Res. 89(1), 148-156 (2011).
136. Sutendra G, Bonnet S, Rochefort G et al. Fatty acid oxidation and
137. Sutendra G, Dromparis P, Wright P et al. The role of Nogo and the mitochondriaendoplasmic reticulum unit in pulmonary hypertension. Sci. Transl. Med. 3(88), 88ra55 (2011).
138. An J, Muoio DM, Shiota M et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10(3), 268-274 (2004). (Pubitemid 38667617)
139. Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J. Cardiovasc. Pharmacol. 28(3), 353-362 (1996). (Pubitemid 26317432)
140. Ning Y, Zhen W, Fu Z et al. Ranolazine increases beta-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J. Pharmacol. Exp. Ther. 337(1), 50-58 (2011).
141. Chisholm JW, Goldfine AB, Dhalla AK et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care 33(6), 1163-1168 (2010).
142. Morrow DA, Scirica BM, Chaitman BR et al. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation 119(15), 2032-2039 (2009).
143. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur. Heart J. 27(1), 42-48 (2006). (Pubitemid 41785931)
144. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90(1), 207-258 (2010).