Cardiovascular safety of type 2 diabetes medications: Review of existing literature and clinical implications

Hormones

Volumn 15, Issue 2, 2016, Pages 170-185

  Paredes, Sílvia ^a,b   Matta Coelho, Claudia ^a,c   Monteiro, Ana Margarida ^a   Brás, Alice ^b   Marques, Olinda ^a   Alves, Marta ^a   Ribeiro, Laura ^b,d  

^a HOSPITAL DE BRAGA   (Portugal)

^b University of Porto   (Portugal)

^c UNIVERSITY OF PORTO   (Portugal)

^d UNIVERSITY OF PORTO   (Portugal)

Author keywords

Antidiabetic drugs; Cardiovascular side effects and safety; Diabetes mellitus; Treatment outcome

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INSULIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; METFORMIN; SODIUM GLUCOSE TRANSPORTER 2 INHIBITOR; SULFONYLUREA; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

BODY WEIGHT; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; DIASTOLIC BLOOD PRESSURE; DIURESIS; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; EDEMA; FLUID RETENTION; GLUCOSE BLOOD LEVEL; HEART FAILURE; HEART PROTECTION; HOSPITAL ADMISSION; HUMAN; HYPOGLYCEMIA; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN SENSITIVITY; META ANALYSIS (TOPIC); MULTICENTER STUDY (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK REDUCTION; SYSTOLIC BLOOD PRESSURE; WEIGHT GAIN; CARDIOVASCULAR DISEASES; CHEMICALLY INDUCED; COMPLICATION; DIABETES MELLITUS, TYPE 2; MORTALITY; PATIENT SAFETY; RISK ASSESSMENT; RISK FACTOR; TREATMENT OUTCOME;

CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; PATIENT SAFETY; RISK ASSESSMENT; RISK FACTORS; TREATMENT OUTCOME;

EID: 84976518034     PISSN: 11093099     EISSN: None     Source Type: Journal    
DOI: 10.14310/horm.2002.1671     Document Type: Review

References (169)

1. Centers for Disease Control and Prevention, 2011 National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States (Accessed 2 May 2015).
2. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, 2008 Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory-Information/Guidances/ucm071627.pdf (Accessed: 2 May 2015).
3. European Medicine Agency, Committee for Medicinal Products for Human Use, 2010 Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/02/WC500073570.pdf (Accessed: 2 May 2015).
4. Paneni F, 2014 2013 ESC/EASD guidelines on the management of diabetes and cardiovascular disease: established knowledge and evidence gaps. Diab Vasc Dis Res 11: 5-10.
5. Inzucchi SE, Bergenstal RM, Buse JB, et al, 2015 Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38: 140-149.
6. Handelsman Y, Bloomgarden ZT, Grunberger G, et al, 2015 American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocrine practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 21: Suppl 1: 1-87.
7. Gardner D, Shoback D 2011 Greenspan’s Basic and Clinical Endocrinology, The McGraw-Hill Companies; pp, 579-581.
8. Rensing KL, Reuwer AQ, Arsenault BJ, et al, 2011 Reducing cardiovascular disease risk in patients with type 2 diabetes and concomitant macrovascular disease: can insulin be too much of a good thing? Diabetes Obes Metab 13: 1073-1087.
9. Cruz AB, Amatuzio DS, Grande F, Hay LJ, 1961 Effect of intra-arterial insulin on tissue cholesterol and fatty acids in alloxan-diabetic dogs. Circ Res 9: 39-43.
10. Mather KJ, Steinberg HO, Baron AD, 2013 Insulin resistance in the vasculature. J Clin Invest 123: 1003-1004.
11. Hopkins PN, 2013 Molecular biology of atherosclerosis. Physiol Rev 93: 1317-1542.
12. Baldi S, Natali A, Buzzigoli G, Galvan AQ, Sironi AM, Ferrannini E, 1996 In vivo effect of insulin on intracellular calcium concentrations: relation to insulin resistance. Metabolism 45: 1402-1407.
13. Brunton SA, 2012 Hypoglycemic potential of current and emerging pharmacotherapies in type 2 diabetes mellitus. Postgrad Med 124: 74-83.
14. Gamble JM, Simpson SH, Eurich DT, Majumdar SR, Johnson JA, 2010 Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. Diabetes Obes Metab 12: 47-53.
15. Turnbull FM, Abraira C, Anderson RJ, et al, 2009 Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52: 2288-2298.
16. Roumie CL, Greevy RA, Grijalva CG, et al, 2014 Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA - J Am Med Assoc 311: 2288-2296.
17. Siraj ES, Rubin DJ, Riddle MC, Miller ME, et al, 2015 Insulin dose and cardiovascular mortality in the ACCORD trial. Diabetes Care 38: 2000-2008.
18. 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: 837-853.
19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA, 2008 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359: 1577-1589.
20. Gerstein HC, Bosch J, Dagenais GR, et al, 2012 Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367: 319-328.
21. 2016, Cardiovascular and other outcomes postintervention with insulin glargine and omega-3 fatty acids (ORIGINALE). Diabetes Care 39: 709-716.
22. Raz I, Wilson PW, Strojek K, et al, 2009 Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 32: 381-386.
23. Novo Nordisk, 2013 A trial comparing cardiovascular safety of insulin degludec versus insuline glargine in subjects with type 2 diabetes at high risk of cardiovascular events (DEVOTE) https://clinicaltrials.gov/ct2/show/NCT01959529 (Accessed: 16 December 2015).
24. Hundal RS, Krssak M, Dufour S, et al, 2000 Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49: 2063-2069.
25. Charles MA, Eschwège E, Grandmottet P, et al, 2000 Treatment with metformin of non-diabetic men with hypertension, hypertriglyceridaemia and central fat distribution: the BIGPRO 1.2 trial. Diabetes Metab Res Rev 16: 2-7.
26. Seifarth C, Schehler B, Schneider HJ, 2013 Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocr Diab 121: 27-31.
27. Lawrence JM, Reid J, Taylor GJ, Stirling C, Reckless JP, 2004 Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes care 27: 41-46.
28. Ajjan RA, Grant PJ, 2006 Cardiovascular disease prevention in patients with type 2 diabetes: The role of oral anti-diabetic agents. Diab Vasc Dis Res 3: 147-158.
29. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D, 2005 Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 3: CD002966.
30. Kinaan M, Ding H, Triggle CR, 2015 Metformin: An old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med Princ Pract 24: 401-15.
31. Carter AM, Bennett CE, Bostock JA, Grant PJ, 2005 Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabetic Med 22: 1282-1284.
32. de Jager J, Kooy A, Schalkwijk C, et al, 2014 Longterm effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med 275: 59-70.
33. Hocking ED, Chakrabarti R, Evans J, Fearnley GR, 1967 Effect of biguanides and atromid on fibrinolysis. J Atheroscler Res 7: 121-130.
34. Tousoulis D., Kampoli AM, Stefanadis C, 2012 Diabetes mellitus and vascular endothelial dysfunction: current perspectives. Curr Vasc Pharmacol 10: 19-32.
35. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). The Lancet 352: 854-865.
36. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW, 2008 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359: 1577-1589.
37. McAlister FA, Eurich DT, Majumdar SR, Johnson JA, 2008 The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur J Heart Fail 10: 703-708.
38. Hong J, Zhang Y, Lai S, et al, 2013 Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes care 36: 1304-1311.
39. Kooy A, de Jager J, Lehert P, et al, 2009 Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 169: 616-625.
40. Selvin E, Bolen S, Yeh HC, et al, 2008 Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 168: 2070-2080.
41. Lamanna C, Monami M, Marchionni N, Mannucci E, 2011 Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 13: 221-228.
42. Kahn SE, Haffner SM, Heise MA, et al, 2006 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355: 2427-2443.
43. Evans JM, Ogston SA, Emslie-Smith A, Morris AD, 2006 Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49: 930-936.
44. Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A, 2011 Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circulation Heart Failure 4: 53-58.
45. Romero SP, Andrey JL, Garcia-Egido A, et al, 2013 Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensitymatched study in the community. Int J Cardiol 166: 404-412.
46. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM, 2005 Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111: 583-590.
47. Eurich DT, Weir DL, Majumdar SR, et al, 2013 Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 6: 395-402.
48. McMurray JJ, Adamopoulos S, Anker SD, et al, 2012 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33: 1787-1847.
49. Pantalone KM, Kattan MW, Yu C, et al, 2012 Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 14: 803-809.
50. Ladeiras-Lopes R, Fontes-Carvalho R, Bettencourt N, Sampaio F, Gama V, Leite-Moreira AF, 2014 METformin in DIastolic Dysfunction of MEtabolic syndrome (MET-DIME) trial: rationale and study design: METDIME trial. Cardiovasc Drugs Ther 28: 191-196
51. Lexis CP, van der Horst IC, Lipsic E, et al, 2012 Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther 26: 417-426.
52. Medical Research Council (MRC) (UK). The Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) - Glucose lowering in those at risk of diabetes. ISRCTN34875079. http://www.isrctn.com/ISRCTN34875079. (Accessed 18 July 2015).
53. Seino S, Takahashi H, Takahashi T, Shibasaki T, 2012 Treating diabetes today: a matter of selectivity of sulphonylureas. Diabetes Obes Metab 14 Suppl 1: 9-13.
54. Thulé P UG, 2014 Sulfonylureas: a new look at old therapy. Curr Diab Rep 14: 1-8.
55. Muller G, Satoh Y, Geisen K, 1995 Extrapancreatic effects of sulfonylureas--a comparison between glimepiride and conventional sulfonylureas. Diabetes Res Clin Pr 28: Suppl: S115-137.
56. Campbell DB, Lavielle R, Nathan C, 1991 The mode of action and clinical pharmacology of gliclazide: a review. Diabetes Res Clin Pr 14: Suppl 2: S21-36.
57. Inzucchi SE, 2002 Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA - J Am Med Assoc 287: 360-372.
58. Triggle CR, Ding H, 2014 Cardiovascular impact of drugs used in the treatment of diabetes. Therapeutic Advances in Chronic Disease 5: 245-268.
59. Basit A, Riaz M, Fawwad A, 2012 Glimepiride: evidence-based facts, trends, and observations (GIFTS). [corrected]. Vascular Health and Risk Management 8: 463-472.
60. Zhang F, Xiang H, Fan Y, et al, 2013 The effects of sulfonylureas plus metformin on lipids, blood pressure, and adverse events in type 2 diabetes: a meta-analysis of randomized controlled trials. Endocrine 44: 648-658.
61. Chen YH, Du L, Geng XY, et al, 2015 Effects of sulfonylureas on lipids in Type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Journal of Evidence-Based Medicine 8: 134-48.
62. Monami M, Genovese S, Mannucci E, 2013 Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 15: 938-953.
63. Schramm TK, Gislason GH, Vaag A, et al, 2011 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: 1900-1908.
64. Klepzig H, Kober G, Matter C, et al, 1999 Sulfonylureas and ischaemic preconditioning; a double-blind, placebocontrolled evaluation of glimepiride and glibenclamide. Eur Heart J 20: 439-446.
65. Fisman EZ, Tenenbaum A, 2009 A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. Cardiovasc Diabetol 8: 1-13.
66. Meier JJ, Gallwitz B, Schmidt WE, Mugge A, Nauck MA, 2004 Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important? Heart 90: 9-12.
67. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR, Jr., 1999 Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 33: 119-124.
68. Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ, 2014 Association between first-line monotherapy with sulphonylurea versus metformin and risk of all-cause mortality and cardiovascular events: a retrospective, observational study. Diabetes Obes Metab 16: 957-962.
69. Roumie CL, Hung AM, Greevy RA, et al, 2012 Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med 157: 601-610.
70. 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.
71. Seong JM, Choi NK, Shin JY, et al, 2015 Differential cardiovascular outcomes after dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone therapy, all in combination with metformin, for type 2 diabetes: a population-based cohort study. PloS One 10: e0124287.
72. Patel A, MacMahon S, Chalmers J, et al, 2008 Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358: 2560-2572.
73. Kahn SE, Haffner SM, Heise MA, et al, 2006 Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355: 2427-2443.
74. Duckworth W, Abraira C, Moritz T, et al, 2009 Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360: 129-139.
75. Yki-Jarvinen H, 2004 Thiazolidinediones. N Engl J Med 351: 1106-1118.
76. European Medicines Agency, 2010 European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. Anti-diabetes medication to be taken off the market http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC500096996.pdf (Accessed: 23 June 2015).
77. European Medicines Agency, 2012 Anexx. Conditions or restrictions with regard to the safe and effective use of the medicinal product to be implemented by the member states http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Conditions_imposed_on_member_states_for_safe_and_effective_use/human/002277/WC500126044.pdf (Accessed: 23 June 2015).
78. Food and Drug Administration, 2011 FDA Drug Safety Communication: Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm#aihp (Accessed: 23 June 2015).
79. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA, 2001 Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 134: 61-71.
80. Goldberg RB, Kendall DM, Deeg MA, et al, 2005 A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28: 1547-1554.
81. Shimono D, Kuwamura N, Nakamura Y, Koshiyama H, 2001 Lack of effect of pioglitazone on postprandial triglyceride levels in type 2 diabetes. Diabetes Care 24: 971.
82. van Wijk JP, de Koning EJ, Castro Cabezas M, Rabelink TJ, 2005 Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care 28: 844-849.
83. Punthakee Z, Almeras N, Despres JP, et al, 2014 Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a substudy of the DREAM trial. Diabetic Med 31: 1086-1092.
84. Qayyum R, Adomaityte J, 2006 A meta-analysis of the effect of thiazolidinediones on blood pressure. J Clin Hypertens (Greenwich) 8: 19-28.
85. Chiquette E, Ramirez G, Defronzo R, 2004 A metaanalysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 164: 2097-2104.
86. Mazzone T, Meyer PM, Feinstein SB, et al, 2006 Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA - J Am Med Assoc 296: 2572-2581.
87. Nesto RW, Bell D, Bonow RO, et al, 2003 Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation 108: 2941-2948.
88. Gerstein HC, Yusuf S, Bosch J, et al, 2006 Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368: 1096-1105.
89. Home PD, Pocock SJ, Beck-Nielsen H, et al, 2009 Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373: 2125-2135.
90. Mahaffey KW, Hafley G, Dickerson S, et al, 2013 Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 166: 240-249 e241.
91. Nissen SE, Wolski K, 2007 Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356: 2457-2471.
92. Nissen SE, Wolski K, 2010 Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 170: 1191-1201.
93. Singh S, Loke YK, Furberg CD, 2007 Long-term risk of cardiovascular events with rosiglitazone: a metaanalysis. JAMA - J Am Med Assoc 298: 1189-1195.
94. Dahabreh IJ, Economopoulos K, 2008 Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone. Clin Trials 5: 116-120.
95. Bach RG, Brooks MM, Lombardero M, et al, 2013 Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation 128: 785-794.
96. Dormandy JA, Charbonnel B, Eckland DJ, et al, 2005 Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro-Vascular Events): a randomised controlled trial. Lancet 366: 1279-1289.
97. Wilcox R, Bousser MG, Betteridge DJ, et al, 2007 Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 38: 865-873.
98. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, 2007 The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 49: 1772-1780.
99. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE, 2007 Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA - J Am Med Assoc 298: 1180-1188.
100. Yoshii H, Onuma T, Yamazaki T, et al, 2014 Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study. J Atheroscler Thromb 21: 563-573.
101. Lago RM, Singh PP, Nesto RW, 2007 Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370: 1129-1136.
102. Liu J, Wang LN, 2014 Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Db Syst Rev 1: CD010693.
103. Scheen AJ, 2015 A review of gliptins for 2014. Expert Opin Pharmaco 16: 43-62.
104. Drucker DJ, Nauck MA, 2006 The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696-1705.
105. Fadini GP, Avogaro A, 2011 Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vasc Pharmacol 55: 10-16.
106. De Falco E, Porcelli D, Torella AR, et al, 2004 SDF-1 involvement in endothelial phenotype and ischemiainduced recruitment of bone marrow progenitor cells. Blood 104: 3472-3482.
107. Brown NJ, Gainer JV, Stein CM, Vaughan DE, 1999 Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension 33: 1431-1435.
108. Koska J, Sands M, Burciu C, Reaven P, 2015 Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes. Diab Vasc Dis Res 12: 154-163.
109. Ogawa S, Ishiki M, Nako K, et al, 2011 Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. Tohoku J Exp Med 223: 133-135.
110. Monami M, Lamanna C, Desideri CM, Mannucci E, 2012 DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther 29: 14-25.
111. Bennett WL, Maruthur NM, Singh S, et al, 2011 Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 154: 602-613.
112. Ta NN, Schuyler CA, Li Y, Lopes-Virella MF, Huang Y, 2011 DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J Cardiovasc Pharm 58: 157-166.
113. Shah Z, Kampfrath T, Deiuliis JA, et al, 2011 Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 124: 2338-2349.
114. Barbieri M, Rizzo MR, Marfella R, et al, 2013 Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 227: 349-354.
115. Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM, 2015 Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. The Lancet Diabetes & Endocrinology 3: 356-366.
116. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA, 2014 Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. The Lancet Diabetes & Endocrinology 2: 843-851.
117. Monami M, Dicembrini I, Mannucci E, 2014 Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovas: NMCD 24: 689-697.
118. Scirica BM, Bhatt DL, Braunwald E, et al, 2013 Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369: 1317-1326.
119. White WB, Cannon CP, Heller SR, et al, 2013 Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369: 1327-1335.
120. Green JB, Bethel MA, Armstrong PW, et al, 2015 Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 373: 232-42.
121. Rosenstock J, Marx N, Neubacher D, et al, 2015 Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol 14: 57.
122. ClinicalTrials.gov, 2013 Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA). NCT01897532 https://clinicaltrials.gov/ct2/show/NCT01897532?term=CARMELINA&rank=1 (Accessed: 20 July 2015).
123. Rosenstock J, Marx N, Kahn SE, et al, 2013 Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the activecomparator CAROLINA trial. Diab Vasc Dis Res 10: 289-301.
124. Seufert J, Gallwitz B, 2014 The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab 16: 673-688.
125. Ryan D, Acosta A, 2015 GLP-1 receptor agonists: Nonglycemic clinical effects in weight loss and beyond. Obesity (Silver Spring) 23: 1119-1129
126. Rosenstock J, Balas B, Charbonnel B, et al, 2013 The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial. Diabetes care 36: 498-504.
127. Nauck MAPJSG, et al, 2012 The once-weekly human GLP-1 analogue semaglutide provides significant reductions in HbA1c and body weight in patients with type 2 diabetes. Abstracts of the 48th EASD (European Association for the Study of Diabetes) Annual Meeting of the European Association for the Study of Diabetes. Diabetologia 55: Suppl.: S7.
128. Choi IY PS TM, Hwang SY, Kim JY, Lee YM, Kwon SC, 2015 Superagonistic Mechanism of Increased Glucodynamic and Weight Loss Effects of LAPSCAExendin-4 (HM11260C) [Abstract]. Diabetes care 64 (Suppl 1).
129. Amori RE, Lau J, Pittas AG, 2007 Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA - J Am Med Assoc 298: 194-206.
130. Monami M, Marchionni N, Mannucci E, 2009 Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol 160: 909-917.
131. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A, 2011 Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Db Syst Rev CD006423.
132. Katout M, Zhu H, Rutsky J, et al, 2014 Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens 27: 130-139.
133. Sun F, Wu S, Wang J, et al, 2015 Effect of glucagonlike peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther 37: 225-241; e228.
134. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E, 2014 Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 16: 38-47.
135. Lorber D, 2013 GLP-1 receptor agonists: effects on cardiovascular risk reduction. Cardiovasc Ther 31: 238-249.
136. Avogaro A, Vigili de Kreutzenberg S, Fadini GP, 2014 Cardiovascular actions of GLP-1 and incretin-based pharmacotherapy. Curr Diab Rep 14: 483.
137. Herzlinger S, Horton ES, 2013 Extraglycemic effects of glp-1-based therapeutics: addressing metabolic and cardiovascular risks associated with type 2 diabetes. Diabetes Res Clin Pr 100: 1-10.
138. Hansen J, Brock B, Botker HE, Gjedde A, Rungby J, Gejl M, 2014 Impact of glucagon-like peptide-1 on myocardial glucose metabolism revisited. Rev Endocr Metab Dis 15: 219-231.
139. Lebovitz HE, Banerji MA, 2012 Non-insulin injectable treatments (glucagon-like peptide-1 and its analogs) and cardiovascular disease. Diabetes Technol Ther 14: Suppl 1: 43-50.
140. Angeli FS, Shannon RP, 2014 Incretin-based therapies: can we achieve glycemic control and cardioprotection? J Endocrinol 221: T17-30.
141. clinicalTrials.gov, 2010 Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010(Lixisenatide) (ELIXA). NCT01147250 https://clinicaltrials.gov/ct2/show/NCT01147250?term=ELIXA&rank=1: (Accessed: 13 July 2015).
142. clinicalTrials.gov, 2010 Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation (LEADER®). NCT01179048 https://clinicaltrials.gov/ct2/show/NCT01179048?term=NCT01179048&rank=1: (Accessed: 13 July 2015).
143. clinicalTrials.gov, 2012 Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN™ 6). NCT01720446 https://clinicaltrials.gov/ct2/show/NCT01720446?term=NCT01720446&rank=1: (Accessed: 13 July 2015).
144. clinicalTrials.gov, 2011 Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND). NCT01394952 https://clinicaltrials.gov/ct2/show/NCT01394952?term=NCT01394952&rank=1: (Accessed: 13 July 2015).
145. clinicalTrials.gov, 2010 Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus. NCT01144338 https://clinicaltrials.gov/ct2/show/NCT01144338?term=NCT01144338&rank=1: (Accessed: 13 July 2015).
146. Sanofi Media Releases, 2015 Sanofi’s Lyxumia® (lixisenatide) Demonstrated Cardiovascular Safety in People with Type 2 Diabetes and High CV Risk http://en.sanofi.com/NasdaQ_OMX/local/press_releases/sanofis_lyxumia_lixisenatide_d_1926874_08-06-2015!18_16_00.aspx (Accessed: 21 July 2015).
147. Sun F, Yu K, Wu S, et al, 2012 Cardiovascular safety and glycemic control of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus: a pairwise and network meta-analysis. Diabetes Res Clin Pr 98: 386-395.
148. Monami M, Cremasco F, Lamanna C, et al, 2011 Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Experimental diabetes research 2011: 215764.
149. Jung CH, Jang JE, Park JY, 2014 A novel therapeutic agent for type 2 diabetes mellitus: sglt2 inhibitor. Diabetes Metab J 38: 261-273.
150. Inzucchi SE, Zinman B, Wanner C, et al, 2015 SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 12: 90-100.
151. Lajara R, 2014 The potential role of sodium glucose co-transporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. Expert Opin Pharmaco 15: 2565-2585.
152. Misra M, 2013 SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus. J Pharm Pharmacol 65: 317-327.
153. Lexicon Pharmaceutical, Safety and Efficacy of LX4211 in patients with inadequately controlled type 1 diabetes mellitus https://www.clinicaltrials.gov/ct2/show/NCT01742208 (Accessed: 9 June 2015).
154. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R, 2014 Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis 64: 16-24.
155. Ferrannini E, Muscelli E, Frascerra S, et al, 2014 Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 124: 499-508.
156. Foote C, Perkovic V, Neal B, 2012 Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab Vasc Dis Res 9: 117-123.
157. Brooks M, 2015 SGLT2 Inhibitor Diabetes Drugs May Cause Ketoacidosis: FDA http://www.medscape.com/viewarticle/844754 (Accessed: 18 July 2015).
158. Vasilakou D, Karagiannis T, Athanasiadou E, et al, 2013 Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159: 262-274.
159. Oliva RV, Bakris GL, 2014 Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. Journal of the American Society of Hypertension: JASH 8: 330-339.
160. Oelze M, Kroller-Schon S, Welschof P, et al, 2014 The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PloS One 9: e112394.
161. Cherney DZ, Perkins BA, Soleymanlou N, et al, 2014 The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 13: 28.
162. List JF, Woo V, Morales E, Tang W, Fiedorek FT, 2009 Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32: 650-657.
163. Bolinder J, Ljunggren O, Johansson L, et al, 2014 Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16: 159-169.
164. Yale JF, Bakris G, Cariou B, et al, 2013 Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 15: 463-473.
165. Zinman B, Wanner C, Lachin JM, et al, 2015 Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117-2128.
166. Dziuba J, Alperin P, Racketa J, et al, 2014 Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab 16: 628-635
167. clinicalTrials.gov, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) NCT01730534 https://clinicaltrials.gov/ct2/show/NCT01730534 (Accessed: 9 June 2015).
168. clinicalTrials.gov, CANVAS - CANagliflozin cardioVascular Assessment Study NCT01032629 https://clinicaltrials.gov/ct2/show/NCT01032629?term=CANVAS+-+CANagliflozin+cardioVascular+Assessment+Study&rank=1 (Accessed: 9 June 2015).
169. clinicalTrials.gov, Cardiovascular Outcomes Following Treatment With Ertugliflozin in Participants With Type 2 Diabetes Mellitus and Established Vascular Disease (MK-8835-004) NCT01986881 https://clinicaltrials.gov/ct2/show/NCT01986881?term=NCT01986881&rank=1 (Accessed: 9 June 2015).