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Therapeutic targets to reduce cardiovascular disease in type 2 diabetes

Nature Reviews Drug Discovery volume 8, pages 361–367 (2009)Cite this article

Abstract

The potential cardiovascular risks that are associated with drugs for type 2 diabetes have recently raised considerable clinical and regulatory concerns. As some risk factors for cardiovascular disease and type 2 diabetes are related, identifying agents that target shared underlying pathways and processes is an attractive therapeutic strategy. In this article, we review the background to and the implications of recent regulatory guidance on the development of new drugs for diabetes, and discuss the potential cardiovascular effects of selected classes of diabetes drugs that are currently being investigated.

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Figure 1: Diabetes and cardiovascular disease: common risk factors and therapeutic targets.

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References

  1. Gu, K., Cowie, C. C. & Harris, M. I. Diabetes and decline in heart disease mortality in US adults. JAMA 281, 1291–1297 (1999).

    Article  CAS  Google Scholar 

  2. Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).

    Article  Google Scholar 

  3. Gore, M. O. & McGuire, D. K. The 10-year post-trial follow-up of the United Kingdom Prospective Diabetes Study (UKPDS): cardiovascular observations in context. Diab. Vasc. Dis. Res. 6, 53–55 (2009).

    Article  Google Scholar 

  4. Holman, R. R. et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).

    Article  CAS  Google Scholar 

  5. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

    Article  CAS  Google Scholar 

  6. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  Google Scholar 

  7. Gerstein, H. C. et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

    Article  CAS  Google Scholar 

  8. Fisman, E. Z., Motro, M. & Tenenbaum, A. Non-insulin antidiabetic therapy in cardiac patients: current problems and future prospects. Adv. Cardiol. 45, 154–170 (2008).

    Article  CAS  Google Scholar 

  9. Inzucchi, S. E. & McGuire, D. K. New drugs for the treatment of diabetes: part II: Incretin-based therapy and beyond. Circulation 117, 574–584 (2008).

    Article  Google Scholar 

  10. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).

  11. Holman, R. Metformin as first choice in oral diabetes treatment: the UKPDS experience. Journ. Annu. Diabetol. Hotel Dieu 13–20 (2007).

  12. Howes, L. G. Cardiovascular effects of sulphonylureas: role of K(ATP) channels. Diabetes Obes. Metab. 2, 67–73 (2000).

    Article  CAS  Google Scholar 

  13. Charles, M. A. Intensive insulin treatment in type 2 diabetes. Diabetes Technol. Ther. 7, 818–822 (2005).

    Article  Google Scholar 

  14. Erdmann, E. et al. PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Vasc. Health Risk Manag. 3, 355–370 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nissen, S. E. and Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).

    Article  CAS  Google Scholar 

  16. Doggrell, S. A. Muraglitazar: beneficial or detrimental in the treatment of type 2 diabetes? Expert Opin. Pharmacother. 7, 1229–1233 (2006).

    Article  CAS  Google Scholar 

  17. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    Article  CAS  Google Scholar 

  18. Kovesdy, C. P. & Kalantar-Zadeh, K. Novel targets and new potential: developments in the treatment of inflammation in chronic kidney disease. Expert Opin. Investig. Drugs 17, 451–67 (2008).

    Article  CAS  Google Scholar 

  19. Tousoulis, D., Charakida, M. & Stefanadis, C. Endothelial function and inflammation in coronary artery disease. Postgrad. Med. J. 84, 368–371 (2008).

    Article  CAS  Google Scholar 

  20. Balint, B. L. & Nagy, L. Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases. Endocr. Metab. Immune Disord. Drug Targets 6, 33–43 (2006).

    Article  CAS  Google Scholar 

  21. Nikolaidis, L. A. et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109, 962–965 (2004).

    Article  CAS  Google Scholar 

  22. Sokos, G. G. 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. 100, 824–829 (100).

    Article  CAS  Google Scholar 

  23. Sokos, G. G. et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J. Card. Fail. 12, 694–699 (2006).

    Article  CAS  Google Scholar 

  24. Nikolaidis, L. A. et al. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J. Pharmacol. Exp. Ther. 312, 303–308 (2005).

    Article  CAS  Google Scholar 

  25. Basu, A. et al. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am. J. Physiol. Endocrinol. Metab. 293, E1289–E1295 (2007).

    Article  CAS  Google Scholar 

  26. Ban, K. 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 117, 2340–2350 (2008).

    Article  CAS  Google Scholar 

  27. Cabou, C. et al. Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity. Diabetes 57, 2577–2587 (2008).

    Article  CAS  Google Scholar 

  28. Idris, I. & Donnelly, R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes. Metab. 11, 79–88 (2009).

    Article  CAS  Google Scholar 

  29. Ikari, A. et al. Recovery from heat shock injury by activation of Na+-glucose cotransporter in renal epithelial cells. Biochim. Biophys. Acta 1643, 47–53 (2003).

    Article  CAS  Google Scholar 

  30. Arakawa, K. et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na+-glucose cotransporter inhibitor T-1095. Br. J. Pharmacol. 132, 578–586 (2001).

    Article  CAS  Google Scholar 

  31. Vemula, S. et al. A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J. Pharmacol. Exp. Ther. 328, 487–495 (2009).

    Article  CAS  Google Scholar 

  32. Zhou, L. et al. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J. Cell. Biochem. 90, 339–346 (2003).

    Article  CAS  Google Scholar 

  33. Davies, M. J., Post-prandial hyperglycaemia and prevention of cardiovascular disease. Diabet. Med. 22, S6–S9 (2005).

    Article  Google Scholar 

  34. Tilg, H. & Moschen, A. R. Inflammatory mechanisms in the regulation of insulin resistance. Mol. Med. 14, 222–231 (2008).

    Article  CAS  Google Scholar 

  35. Ahn, K. S., Sethi, G. & Aggarwal, B. B. Nuclear factor-kappa B: from clone to clinic. Curr. Mol. Med. 7, 619–637 (2007).

    Article  CAS  Google Scholar 

  36. Schreiber, S. Activation of nuclear factor kappaB as a target for anti-inflammatory therapy. Gut 44, 309–310 (1999).

    Article  CAS  Google Scholar 

  37. Fleischman, A. et al. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008).

    Article  CAS  Google Scholar 

  38. Sauter, N. S. et al. The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 149, 2208–2218 (2008).

    Article  CAS  Google Scholar 

  39. Fearon, W. F. & Fearon, D. T. Inflammation and cardiovascular disease: role of the interleukin-1 receptor antagonist. Circulation 117, 2577–2579 (2008).

    Article  Google Scholar 

  40. Ikonomidis, I. et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117, 2662–2669 (2008).

    Article  CAS  Google Scholar 

  41. Haigis, M. C. & Guarente, L. P. Mammalian sirtuins — emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006).

    Article  CAS  Google Scholar 

  42. Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007).

    Article  CAS  Google Scholar 

  43. Yoshizaki, T. et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol. Cell. Biol. 29, 1363–1374 (2008).

    Article  Google Scholar 

  44. Ota, H. et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell Cardiol. 43, 571–579 (2007).

    Article  CAS  Google Scholar 

  45. Zhang, Q. J. et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc. Res. 80, 191–199 (2008).

    Article  CAS  Google Scholar 

  46. Rush, J. W. et al. Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels in aorta of spontaneously hypertensive rats. Exp. Biol. Med. 232, 814–822 (2007).

    CAS  Google Scholar 

  47. Potente, M. & Dimmeler, S. Emerging roles of SIRT1 in vascular endothelial homeostasis. Cell Cycle 7, 2117–2122 (2008).

    Article  CAS  Google Scholar 

  48. Atanasov, A. G. & Odermatt, A. Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity? Endocr. Metab. Immune Disord. Drug Targets 7, 125–140 (2007).

    Article  CAS  Google Scholar 

  49. Su, X. et al. Discovery of novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. Mol. Cell. Endocrinol. 301, 169–173 (2008).

    Article  Google Scholar 

  50. Hermanowski-Vosatka, A. et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J. Exp. Med. 202, 517–527 (2005).

    Article  CAS  Google Scholar 

  51. Higgins, L. S. & Mantzoros, C. S. The development of INT131 as a selective PPARγ modulator: approach to a safer insulin sensitizer. 26 Aug 2008 (doi:10.1155/2008/936906).

    Article  Google Scholar 

  52. Nissen, S. E., Wolski, K. & Topol, E. J. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294, 2581–2586 (2005).

    Article  CAS  Google Scholar 

  53. Donnelly, R. Effect of pioglitazone on the drivers of cardiovascular risk in type 2 diabetes. Int. J. Clin. Pract. 61, 1160–1169 (2007).

    Article  CAS  Google Scholar 

  54. Forst, T. et al. Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk. Diab. Vasc. Dis. Res. 5, 298–303 (2008).

    Article  Google Scholar 

  55. Borboni, P. et al. Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system. Endocrinology 140, 5530–5537 (1999).

    Article  CAS  Google Scholar 

  56. Nakata, M. & Yada, T. PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential. Curr. Pharm. Des. 13, 1105–1112 (2007).

    Article  CAS  Google Scholar 

  57. Dvorakova, M. C. Cardioprotective role of the VIP signaling system. Drug News Perspect. 18, 387–391 (2005).

    Article  CAS  Google Scholar 

  58. Winzell, M. S. & Ahren, B. G-protein-coupled receptors and islet function — implications for treatment of type 2 diabetes. Pharmacol. Ther. 116, 437–448 (2007).

    Article  CAS  Google Scholar 

  59. Gardiner, S. M. et al. Regional haemodynamic responses to pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide in conscious rats. Br. J. Pharmacol. 111, 589–597 (1994).

    Article  CAS  Google Scholar 

  60. Dvorakova, M. C. et al. Down-regulation of vasoactive intestinal peptide and altered expression of its receptors in rat diabetic cardiomyopathy. Cell Tissue Res. 323, 383–393 (2006).

    Article  CAS  Google Scholar 

  61. Pacher, P. et al. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension 52, 601–607 (2008).

    Article  CAS  Google Scholar 

  62. Mach, F. & Steffens, S. The role of the endocannabinoid system in atherosclerosis. J. Neuroendocrinol. 20, S53–S57 (2008).

    Article  Google Scholar 

  63. Viveros, M. P. et al. Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications. Endocr. Metab. Immune Disord. Drug Targets 8, 220–230 (2008).

    Article  CAS  Google Scholar 

  64. Sugamura, K. et al. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation 119, 28–36 (2009).

    Article  CAS  Google Scholar 

  65. Nissen, S. E. et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299, 1547–1560 (2008).

    Article  CAS  Google Scholar 

  66. Mitchell, P. B. & Morris, M. J. Depression and anxiety with rimonabant. Lancet 370, 1671–1672 (2007).

    Article  Google Scholar 

  67. Grimsby, J., Berthel, S. J. & Sarabu, R. Glucokinase activators for the potential treatment of type 2 diabetes. Curr. Top. Med. Chem. 8, 1524–1532 (2008).

    Article  CAS  Google Scholar 

  68. Kodra, J. T. et al. Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor. J. Med. Chem. 51, 5387–5396 (2008).

    Article  CAS  Google Scholar 

  69. Kaidanovich-Beilin, O. & Eldar-Finkelman, H. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. J. Pharmacol. Exp. Ther. 316, 17–24 (2006).

    Article  CAS  Google Scholar 

  70. Gupta, S. K. et al. Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent salsalate: a pilot study. AIDS 22, 653–655 (2008).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Cyrus DeSouza is at the University of Nebraska Medical Center, Omaha, Nebraska, USA and at Omaha Veteran Affairs Medical Center, Omaha, Nebraska, USA.,

    Cyrus DeSouza

  2. Vivian Fonseca is at Tulane University Health Sciences Center, 1430 Tulane Avenue, SL 53 New Orleans, Los Angeles, USA.,

    Vivian Fonseca

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  1. Cyrus DeSouza
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  2. Vivian Fonseca
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Correspondence to Vivian Fonseca.

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Competing interests

The research of V.F. at Tulane University is supported by grants from GlaxoSmithKline, Novartis, Novo–Nordisk, Takeda, Astra–Zeneca, Pfizer, Sanofi–Aventis, Eli Lilly, Daiichi–Sankyo, the National Institutes of Health and the American Diabetes Association.

V.F. has received honoraria for consulting and lectures from GlaxoSmithKline, Novartis, Takeda, Pfizer, Sanofi–Aventis and Eli Lilly.

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Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes

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DeSouza, C., Fonseca, V. Therapeutic targets to reduce cardiovascular disease in type 2 diabetes. Nat Rev Drug Discov 8, 361–367 (2009). https://doi.org/10.1038/nrd2872

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