Impact of glucose-lowering therapies on risk of stroke in type 2 diabetes

Diabetes and Metabolism

Volumn 43, Issue 4, 2017, Pages 299-313

  Bonnet, F ^a,b   Scheen, A J ^c,d  

^a RENNES UNIVERSITY HOSPITAL   (France)

^b CENTRE FOR RESEARCH IN EPIDEMIOLOGY AND POPULATION HEALTH   (France)

^c UNIVERSITY OF LIÈGE   (Belgium)

^d UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Antidiabetic agents; Clinical trial; Comprehensive review; Stroke; Type 2 diabetes

Indexed keywords

ACARBOSE; ALOGLIPTIN; ALPHA GLUCOSIDASE INHIBITOR; ANTIDIABETIC AGENT; CHLORPROPAMIDE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EMPAGLIFLOZIN; EXENDIN 4; GLIBENCLAMIDE; GLIMEPIRIDE; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INSULIN; LIRAGLUTIDE; METFORMIN; NATEGLINIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; REPAGLINIDE; ROSIGLITAZONE; SAXAGLIPTIN; SEMAGLUTIDE; SITAGLIPTIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SULFONYLUREA;

BRAIN ISCHEMIA; CARDIOVASCULAR EFFECT; CEREBROVASCULAR ACCIDENT; COMBINATION DRUG THERAPY; DRUG EFFECT; HUMAN; LIFESTYLE MODIFICATION; MONOTHERAPY; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; REVIEW; RISK FACTOR; TREATMENT OUTCOME; BLOOD; COMPLICATION; GLUCOSE BLOOD LEVEL; RISK;

BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; RISK; STROKE;

EID: 85019478970     PISSN: 12623636     EISSN: 18781780     Source Type: Journal    
DOI: 10.1016/j.diabet.2017.04.004     Document Type: Review

References (135)

1. Norhammar, A., Bodegard, J., Nystrom, T., Thuresson, M., Eriksson, J.W., Nathanson, D., Incidence, prevalence and mortality of type 2 diabetes requiring glucose-lowering treatment, and associated risks of cardiovascular complications: a nationwide study in Sweden, 2006–2013. Diabetologia 59 (2016), 1692–1701.
2. Policardo, L., Seghieri, G., Anichini, R., De Bellis, A., Franconi, F., Francesconi, P., et al. Effect of diabetes on hospitalization for ischemic stroke and related in-hospital mortality: a study in Tuscany, Italy, over years 2004–2011. Diabetes Metab Res Rev 31 (2015), 280–286.
3. ORIGIN Trial Investigators, Gerstein, H.C., Bosch, J., Dagenais, G.R., Diaz, R., Jung, H., et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 367 (2012), 319–328.
4. Scheen, A.J., Charbonnel, B., Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. Diabetes Metab 40 (2014), 176–185.
5. Turnbull, F.M., Abraira, C., Anderson, R.J., Byington, R.P., Chalmers, J.P., Duckworth, W.C., et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52 (2009), 2288–2298.
6. Hsu, P.F., Sung, S.H., Cheng, H.M., Yeh, J.S., Liu, W.L., Chan, W.L., et al. Association of clinical symptomatic hypoglycemia with cardiovascular events and total mortality in type 2 diabetes: a nationwide population-based study. Diabetes Care 36 (2013), 894–900.
7. Boussageon, R., Supper, I., Bejan-Angoulvant, T., Kellou, N., Cucherat, M., Boissel, J.P., et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med, 9, 2012, e1001204.
8. Venna, V.R., Li, J., Hammond, M.D., Mancini, N.S., McCullough, L.D., Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci 39 (2014), 2129–2138.
9. Abdelsaid, M., Prakash, R., Li, W., Coucha, M., Hafez, S., Johnson, M.H., et al. Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes 64 (2015), 1804–1817.
10. UKPDS Group, 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 (1998), 854–865.
11. Cryer, D.R., Nicholas, S.P., Henry, D.H., Mills, D.J., Stadel, B.V., Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 28 (2005), 539–543.
12. Kahn, S.E., Haffner, S.M., Heise, M.A., Herman, W.H., Holman, R.R., Jones, N.P., et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355 (2006), 2427–2443.
13. Fung, C.S., Wan, E.Y., Wong, C.K., Jiao, F., Chan, A.K., Effect of metformin monotherapy on cardiovascular diseases and mortality: a retrospective cohort study on Chinese type 2 diabetes mellitus patients. Cardiovasc Diabetol, 14, 2015, 137.
14. Cheng, Y.Y., Leu, H.B., Chen, T.J., Chen, C.L., Kuo, C.H., Lee, S.D., et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis 23 (2014), e99–e105.
15. Floyd, J.S., Wiggins, K.L., Christiansen, M., Dublin, S., Longstreth, W.T., Smith, N.L., et al. Case-control study of oral glucose-lowering drugs in combination with long-acting insulin and the risks of incident myocardial infarction and incident stroke. Pharmacoepidemiol Drug Saf 25 (2016), 151–160.
16. Mima, Y., Kuwashiro, T., Yasaka, M., Tsurusaki, Y., Nakamura, A., Wakugawa, Y., et al. Impact of metformin on the severity and outcomes of acute ischemic stroke in patients with type 2 diabetes mellitus. J Stroke Cerebrovasc Dis 25 (2016), 436–446.
17. Ye, F., Luo, Y.J., Xiao, J., Yu, N.W., Yi, G., Impact of insulin sensitizers on the incidence of dementia: a meta-analysis. Dement Geriatr Cogn Disord 41 (2016), 251–260.
18. Zawar, C., Plant, T.D., Schirra, C., Konnerth, A., Neumcke, B., Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. J Physiol 514:Pt 2 (1999), 327–341.
19. Sun, H.S., Feng, Z.P., Miki, T., Seino, S., French, R.J., Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol 95 (2006), 2590–2601.
20. UKPDS Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet Diabetes Endocrinol 352 (1998), 837–853.
21. Phung, O.J., Schwartzman, E., Allen, R.W., Engel, S.S., Rajpathak, S.N., Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 30 (2013), 1160–1171.
22. Liu, R., Wang, H., Xu, B., Chen, W., Turlova, E., Dong, N., et al. Cerebrovascular safety of sulfonylureas: the role of KATP channels in neuroprotection and the risk of stroke in patients with type 2 diabetes. Diabetes 65 (2016), 2795–2809.
23. Bain, S., Druyts, E., Balijepalli, C., Baxter, C.A., Currie, C.J., Das, R., et al. Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycaemic drugs: a Bayesian meta-analysis of survival data. Diabetes Obes Metab 19 (2017), 329–335.
24. Roumie, C.L., Hung, A.M., Greevy, R.A., Grijalva, C.G., Liu, X., Murff, H.J., et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med 157 (2012), 601–610.
25. Morgan, C.L., Mukherjee, J., Jenkins-Jones, S., Holden, S.E., Currie, C.J., Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes Obes Metab 16 (2014), 977–983.
26. Yu, O.H., Yin, H., Azoulay, L., The combination of DPP-4 inhibitors versus sulfonylureas with metformin after failure of first-line treatment in the risk for major cardiovascular events and death. Can J Diabetes 39 (2015), 383–389.
27. Eriksson, J.W., Bodegard, J., Nathanson, D., Thuresson, M., Nystrom, T., Norhammar, A., Sulphonylurea compared to DPP-4 inhibitors in combination with metformin carries increased risk of severe hypoglycemia, cardiovascular events, and all-cause mortality. Diabetes Res Clin Pract 117 (2016), 39–47.
28. Weih, M., Amberger, N., Wegener, S., Dirnagl, U., Reuter, T., Einhaupl, K., Sulfonylurea drugs do not influence initial stroke severity and in-hospital outcome in stroke patients with diabetes. Stroke 32 (2001), 2029–2032.
29. Abdelmoneim, A.S., Eurich, D.T., Light, P.E., Senior, P.A., Seubert, J.M., Makowsky, M.J., et al. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab 17 (2015), 523–532.
30. Paolisso, G., Rizzo, M.R., Barbieri, M., Manzella, D., Ragno, E., Maugeri, D., Cardiovascular risk in type 2 diabetics and pharmacological regulation of mealtime glucose excursions. Diabetes Metab 29 (2003), 335–340.
31. Papanas, N., Maltezos, E., Oral antidiabetic agents: anti-atherosclerotic properties beyond glucose lowering?. Curr Pharm Des 15 (2009), 3179–3192.
32. Esposito, K., Giugliano, D., Nappo, F., Marfella, R., Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 110 (2004), 214–219.
33. Holman, R.R., Haffner, S.M., McMurray, J.J., Bethel, M.A., Holzhauer, B., Hua, T.A., et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 362 (2010), 1463–1476.
34. Standl, E., Theodorakis, M.J., Erbach, M., Schnell, O., Tuomilehto, J., On the potential of acarbose to reduce cardiovascular disease. Cardiovasc Diabetol, 13, 2014, 81.
35. Nyalala, J.O., Luo, S., Campbell, D.N., Brown, A.T., Moursi, M.M., The effects of acarbose treatment on intimal hyperplasia in a rat carotid endarterectomy model of diet-induced insulin resistance. Vasc Endovascular Surg 44 (2010), 560–567.
36. Hanefeld, M., Chiasson, J.L., Koehler, C., Henkel, E., Schaper, F., Temelkova-Kurktschiev, T., Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke 35 (2004), 1073–1078.
37. Koyasu, M., Ishii, H., Watarai, M., Takemoto, K., Inden, Y., Takeshita, K., et al. Impact of acarbose on carotid intima-media thickness in patients with newly diagnosed impaired glucose tolerance or mild type 2 diabetes mellitus: a one-year, prospective, randomized, open-label, parallel-group study in Japanese adults with established coronary artery disease. Clin Ther 32 (2010), 1610–1617.
38. Patel, Y.R., Kirkman, M.S., Considine, R.V., Hannon, T.S., Mather, K.J., Effect of acarbose to delay progression of carotid intima-media thickness in early diabetes. Diabetes Metab Res Rev 29 (2013), 582–591.
39. Patel, S.S., Cerebrovascular complications of diabetes: alpha glucosidase inhibitor as potential therapy. Horm Metab Res 48 (2016), 83–91.
40. Chiasson, J.L., Josse, R.G., 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 (2003), 486–494.
41. Kaiser, T., Sawicki, P.T., Stop, I., Acarbose for prevention of diabetes, hypertension and cardiovascular events? A critical analysis of the STOP-NIDDM data. Diabetologia 47 (2004), 575–580.
42. Chiasson, J.L., Josse, R.G., Gomis, R., Hanefeld, M., Karasik, A., Laakso, M., Acarbose for the prevention of Type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data. Diabetologia 47 (2004), 969–975 [discussion 76–7].
43. Hanefeld, M., Schaper, F., Koehler, C., Effect of acarbose on vascular disease in patients with abnormal glucose tolerance. Cardiovasc Drugs Ther 22 (2008), 225–231.
44. Holman, R.R., Bethel, M.A., Chan, J.C., Chiasson, J.L., Doran, Z., Ge, J., et al. Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial. Am Heart J, 2014, 168 23–9-e2.
45. Chang, C.H., Chang, Y.C., Lin, J.W., Chen, S.T., Chuang, L.M., Lai, M.S., Cardiovascular risk associated with acarbose versus metformin as the first-line treatment in patients with type 2 diabetes: a nationwide cohort study. J Clin Endocrinol Metab 100 (2015), 1121–1129.
46. Ou, H.T., Chang, K.C., Li, C.Y., Wu, J.S., Comparative cardiovascular risks of dipeptidyl peptidase-4 inhibitors with other second and third line antidiabetic drugs in patients with type 2 diabetes. Br J Clin Pharmacol, 2017, 10.1111/bcp.13241 [Epub ahead of print].
47. Scheen, A.J., Esser, N., Paquot, N., Antidiabetic agents: potential anti-inflammatory activity beyond glucose control. Diabetes Metab 41 (2015), 183–194.
48. Duan, S.Z., Usher, M.G., Mortensen, R.M., Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ Res 102 (2008), 283–294.
49. Soccio, R.E., Chen, E.R., Lazar, M.A., Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 20 (2014), 573–591.
50. White, A.T., Murphy, A.N., Administration of thiazolidinediones for neuroprotection in ischemic stroke: a pre-clinical systematic review. J Neurochem 115 (2010), 845–853.
51. Stojanovic, M., Prostran, M., Radenkovic, M., Thiazolidinediones improve flow-mediated dilation: a meta-analysis of randomized clinical trials. Eur J Clin Pharmacol 72 (2016), 385–398.
52. Webb, D.R., Davies, M.J., Gray, L.J., Abrams, K.R., Srinivasan, B., Das, S., et al. Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones. Diabetes Obes Metab 12 (2010), 124–132.
53. Dormandy, J.A., Charbonnel, B., Eckland, D.J., Erdmann, E., Massi-Benedetti, M., Moules, I.K., et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366 (2005), 1279–1289.
54. Scheen, A.J., Outcomes and lessons from the PROactive study. Diabetes Res Clin Pract 98 (2012), 175–186.
55. Wilcox, R., Bousser, M.G., Betteridge, D.J., Schernthaner, G., Pirags, V., Kupfer, S., et al. 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 (2007), 865–873.
56. Tanaka, R., Yamashiro, K., Okuma, Y., Shimura, H., Nakamura, S., Ueno, Y., et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT Study. J Atheroscler Thromb 22 (2015), 1305–1316.
57. Liu, J., Wang, L.N., Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database Syst Rev, 2015, CD010693.
58. Kernan, W.N., Viscoli, C.M., Furie, K.L., Young, L.H., Inzucchi, S.E., Gorman, M., et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374 (2016), 1321–1331.
59. Katsiki, N., Mikhailidis, D.P., Pioglitazone in patients with insulin resistance after ischemic stroke or transient ischemic attack: a comment on the IRIS trial. J Diabetes Complications 31 (2017), 1–3.
60. Home, P.D., Pocock, S.J., Beck-Nielsen, H., Curtis, P.S., Gomis, R., Hanefeld, M., et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373 (2009), 2125–2135.
61. Mahaffey, K.W., Hafley, G., Dickerson, S., Burns, S., Tourt-Uhlig, S., White, J., et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J, 2013, 166 240–9.e1.
62. Lincoff, A.M., Wolski, K., Nicholls, S.J., Nissen, S.E., Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298 (2007), 1180–1188.
63. Liao, H.W., Saver, J.L., Wu, Y.L., Chen, T.H., Lee, M., Ovbiagele, B., Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open, 7, 2017, e013927.
64. Azoulay, L., Schneider-Lindner, V., Dell'aniello, S., Filion, K.B., Suissa, S., Thiazolidinediones and the risk of incident strokes in patients with type 2 diabetes: a nested case-control study. Pharmacoepidemiol Drug Saf 19 (2010), 343–350.
65. Vanasse, A., Carpentier, A.C., Courteau, J., Asghari, S., Stroke and cardiovascular morbidity and mortality associated with rosiglitazone use in elderly diabetic patients. Diab Vasc Dis Res 6 (2009), 87–93.
66. Lu, C.J., Sun, Y., Muo, C.H., Chen, R.C., Chen, P.C., Hsu, C.Y., Risk of stroke with thiazolidinediones: a ten-year nationwide population-based cohort study. Cerebrovasc Dis 36 (2013), 145–151.
67. Gallagher, A.M., Smeeth, L., Seabroke, S., Leufkens, H.G., van Staa, T.P., Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data. PLoS One, 6, 2011, e28157.
68. Graham, D.J., Ouellet-Hellstrom, R., MaCurdy, T.E., Ali, F., Sholley, C., Worrall, C., et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304 (2010), 411–418.
69. Pladevall, M., Riera-Guardia, N., Margulis, A.V., Varas-Lorenzo, C., Calingaert, B., Perez-Gutthann, S., Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. BMC Cardiovasc Disord, 16, 2016, 14.
70. Lee, J., Reding, M., Effects of thiazolidinediones on stroke recovery: a case-matched controlled study. Neurochem Res 32 (2007), 635–638.
71. Culman, J., Zhao, Y., Gohlke, P., Herdegen, T., PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol Sci 28 (2007), 244–249.
72. Heneka, M.T., Fink, A., Doblhammer, G., Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 78 (2015), 284–294.
73. Chou, P.S., Ho, B.L., Yang, Y.H., Effects of pioglitazone on the incidence of dementia in patients with diabetes. J Diabetes Complications, 2017, 10.1016/j.jdiacomp.2017.01.006 pii: S1056-8727(16)30675-4. [Epub ahead of print].
74. Scheen, A.J., Cardiovascular effects of gliptins. Nat Rev Cardiol 10 (2013), 73–84.
75. Ussher, J.R., Drucker, D.J., Cardiovascular biology of the incretin system. Endocr Rev 33 (2012), 187–215.
76. Ussher, J.R., Drucker, D.J., Cardiovascular actions of incretin-based therapies. Circ Res 114 (2014), 1788–1803.
77. Darsalia, V., Ortsater, H., Olverling, A., Darlof, E., Wolbert, P., Nystrom, T., et al. The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride. Diabetes 62 (2013), 1289–1296.
78. Darsalia, V., Larsson, M., Lietzau, G., Nathanson, D., Nystrom, T., Klein, T., et al. Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor. Diabetes Obes Metab 18 (2016), 537–541.
79. Jain, S., Sharma, B., Neuroprotective effect of selective DPP-4 inhibitor in experimental vascular dementia. Physiol Behav 152 (2015), 182–193.
80. Tsai, T.H., Sun, C.K., Su, C.H., Sung, P.H., Chua, S., Zhen, Y.Y., et al. Sitagliptin attenuated brain damage and cognitive impairment in mice with chronic cerebral hypo-perfusion through suppressing oxidative stress and inflammatory reaction. J Hypertens 33 (2015), 1001–1013.
81. Barbieri, M., Rizzo, M.R., Marfella, R., Boccardi, V., Esposito, A., Pansini, A., et al. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 227 (2013), 349–354.
82. Mita, T., Katakami, N., Shiraiwa, T., Yoshii, H., Onuma, T., Kuribayashi, N., et al. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE): a randomized controlled trial. Diabetes Care 39 (2016), 455–464.
83. Mita, T., Katakami, N., Yoshii, H., Onuma, T., Kaneto, H., Osonoi, T., et al. Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A). Diabetes Care 39 (2016), 139–148.
84. Oyama, J., Murohara, T., Kitakaze, M., Ishizu, T., Sato, Y., Kitagawa, K., et al. The effect of sitagliptin on carotid artery atherosclerosis in type 2 diabetes: the PROLOGUE randomized controlled trial. PLoS Med, 13, 2016, e1002051.
85. White, W.B., Cannon, C.P., Heller, S.R., Nissen, S.E., Bergenstal, R.M., Bakris, G.L., et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369 (2013), 1327–1335.
86. Scirica, B.M., Bhatt, D.L., Braunwald, E., Steg, P.G., Davidson, J., Hirshberg, B., et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369 (2013), 1317–1326.
87. Green, J.B., Bethel, M.A., Armstrong, P.W., Buse, J.B., Engel, S.S., Garg, J., et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373 (2015), 232–242.
88. Monami, M., Ahren, B., Dicembrini, I., Mannucci, E., Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 15 (2013), 112–120.
89. Barkas, F., Elisaf, M., Tsimihodimos, V., Milionis, H., Dipeptidyl peptidase-4 inhibitors and protection against stroke: a systematic review and meta-analysis. Diabetes Metab 43 (2017), 1–8.
90. Seong, J.M., Choi, N.K., Shin, J.Y., Chang, Y., Kim, Y.J., Lee, J., et al. 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, 2015, e0124287.
91. Williams, R., de Vries, F., Kothny, W., Serban, C., Lopez-Leon, S., Chu, C., et al. Cardiovascular safety of vildagliptin in patients with type 2 diabetes: a European multi-database, non-interventional post-authorization safety study. Diabetes Obes Metab, 2017, 10.1111/dom.12951 [Epub ahead of print].
92. Michel, M.C., Mayoux, E., Vallon, V., A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. Naunyn Schmiedebergs Arch Pharmacol 388 (2015), 801–816.
93. Scheen, A.J., Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75 (2015), 33–59.
94. Inzucchi, S.E., Zinman, B., Wanner, C., Ferrari, R., Fitchett, D., Hantel, S., et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 12 (2015), 90–100.
95. Lin, B., Koibuchi, N., Hasegawa, Y., Sueta, D., Toyama, K., Uekawa, K., et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol, 13, 2014, 148.
96. Oelze, M., Kroller-Schon, S., Welschof, P., Jansen, T., Hausding, M., Mikhed, Y., et al. 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, 2014, e112394.
97. Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373 (2015), 2117–2128.
98. Scheen, A.J., Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Res Clin Pract 121 (2016), 204–214.
99. Scheen, A.J., Delanaye, P., Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab 43 (2017), 99–109.
100. Zinman, B., Inzucchi, S.E., Lachin, J.M., Wanner, C., Fitchett, D., Kohler, S., et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke, 2017, 10.1161/STROKEAHA.116.015756 pii: STROKEAHA.116.015756. [Epub ahead of print].
101. Imprialos, K.P., Boutari, C., Stavropoulos, K., Doumas, M., Karagiannis, A.I., Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?. J Neurol Neurosurg Psychiatry 88 (2017), 249–253.
102. Scheen, A.J., Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab 42 (2016), 71–76.
103. Abdul-Ghani, M., Del Prato, S., Chilton, R., DeFronzo, R.A., SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care 39 (2016), 717–725.
104. Sattar, N., McLaren, J., Kristensen, S.L., Preiss, D., McMurray, J.J., SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms?. Diabetologia 59 (2016), 1333–1339.
105. Wu, J.H., Foote, C., Blomster, J., Toyama, T., Perkovic, V., Sundstrom, J., et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 4 (2016), 411–419.
106. Sonesson, C., Johansson, P.A., Johnsson, E., Gause-Nilsson, I., Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol, 15, 2016, 37.
107. Saad, M., Mahmoud, A.N., Elgendy, I.Y., Abuzaid, A., Barakat, A.F., Elgendy, A.Y., et al. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol 228 (2017), 352–358.
108. Monami, M., Dicembrini, I., Mannucci, E., Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol 54 (2017), 19–36.
109. Marso, S.P., Daniels, G.H., Brown-Frandsen, K., Kristensen, P., Mann, J.F., Nauck, M.A., et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375 (2016), 311–322.
110. Marso, S.P., Bain, S.C., Consoli, A., Eliaschewitz, F.G., Jodar, E., Leiter, L.A., et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375 (2016), 1834–1844.
111. Li, Y., Perry, T., Kindy, M.S., Harvey, B.K., Tweedie, D., Holloway, H.W., et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A 106 (2009), 1285–1290.
112. Lee, C.H., Yan, B., Yoo, K.Y., Choi, J.H., Kwon, S.H., Her, S., et al. Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia. J Neurosci Res 89 (2011), 1103–1113.
113. Darsalia, V., Mansouri, S., Ortsater, H., Olverling, A., Nozadze, N., Kappe, C., et al. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in type 2 diabetic rats. Clin Sci (Lond) 122 (2012), 473–483.
114. Briyal, S., Shah, S., Gulati, A., Neuroprotective and anti-apoptotic effects of liraglutide in the rat brain following focal cerebral ischemia. Neuroscience 281 (2014), 269–281.
115. Zhang, H., Liu, Y., Guan, S., Qu, D., Wang, L., Wang, X., et al. An orally active allosteric GLP-1 receptor agonist is neuroprotective in cellular and rodent models of stroke. PLoS One, 11, 2016, e0148827.
116. Cameron-Vendrig, A., Reheman, A., Siraj, M.A., Xu, X.R., Wang, Y., Lei, X., et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes 65 (2016), 1714–1723.
117. Pfeffer, M.A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H.C., Kober, L.V., et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373 (2015), 2247–2257.
118. Monami, M., Dicembrini, I., Nardini, C., Fiordelli, I., Mannucci, E., Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomised clinical trials. Diabetes Obes Metab 16 (2014), 38–47.
119. Wang, B., Zhong, J., Lin, H., Zhao, Z., Yan, Z., He, H., et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab 15 (2013), 737–749.
120. Chaudhuri, A., Ghanim, H., Vora, M., Sia, C.L., Korzeniewski, K., Dhindsa, S., et al. Exenatide exerts a potent antiinflammatory effect. J Clin Endocrinol Metab 97 (2012), 198–207.
121. Scheen, A.J., Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf 14 (2015), 505–524.
122. Paul, S.K., Klein, K., Maggs, D., Best, J.H., The association of the treatment with glucagon-like peptide-1 receptor agonist exenatide or insulin with cardiovascular outcomes in patients with type 2 diabetes: a retrospective observational study. Cardiovasc Diabetol, 14, 2015, 10.
123. Kaplan, M., Aviram, M., Hayek, T., Oxidative stress and macrophage foam cell formation during diabetes mellitus-induced atherogenesis: role of insulin therapy. Pharmacol Ther 136 (2012), 175–185.
124. Wang, X., Yu, C., Zhang, B., Wang, Y., The injurious effects of hyperinsulinism on blood vessels. Cell Biochem Biophys 69 (2014), 213–218.
125. Monnier, L., Hanefeld, M., Schnell, O., Colette, C., Owens, D., Insulin and atherosclerosis: how are they related?. Diabetes Metab 39 (2013), 111–117.
126. Muniyappa, R., Montagnani, M., Koh, K.K., Quon, M.J., Cardiovascular actions of insulin. Endocr Rev 28 (2007), 463–491.
127. Collino, M., Aragno, M., Castiglia, S., Tomasinelli, C., Thiemermann, C., Boccuzzi, G., et al. Insulin reduces cerebral ischemia/reperfusion injury in the hippocampus of diabetic rats: a role for glycogen synthase kinase-3beta. Diabetes 58 (2009), 235–242.
128. Huang, S.S., Lu, Y.J., Huang, J.P., Wu, Y.T., Day, Y.J., Hung, L.M., The essential role of endothelial nitric oxide synthase activation in insulin-mediated neuroprotection against ischemic stroke in diabetes. J Vasc Surg 59 (2014), 483–491.
129. Hung, L.M., Huang, J.P., Liao, J.M., Yang, M.H., Li, D.E., Day, Y.J., et al. Insulin renders diabetic rats resistant to acute ischemic stroke by arresting nitric oxide reaction with superoxide to form peroxynitrite. J Biomed Sci, 21, 2014, 92.
130. Gerstein, H.C., Miller, M.E., Byington, R.P., Goff, D.C. Jr., Bigger, J.T., Buse, J.B., et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358 (2008), 2545–2559.
131. Patel, A., MacMahon, S., Chalmers, J., Neal, B., Billot, L., Woodward, M., et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358 (2008), 2560–2572.
132. Dangas, G.D., Farkouh, M.E., Sleeper, L.A., Yang, M., Schoos, M.M., Macaya, C., et al. Long-term outcome of PCI versus CABG in insulin and non-insulin-treated diabetic patients: results from the FREEDOM trial. J Am Coll Cardiol 64 (2014), 1189–1197.
133. Munnee, K., Bundhun, P.K., Quan, H., Tang, Z., Comparing the clinical outcomes between insulin-treated and non-insulin-treated patients with type 2 diabetes mellitus after coronary artery bypass surgery: a systematic review and meta-analysis. Medicine (Baltimore), 95, 2016, e3006.
134. Floyd, J.S., Wiggins, K.L., Sitlani, C.M., Flory, J.H., Dublin, S., Smith, N.L., et al. Case-control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke. Diabetes Obes Metab 17 (2015), 1194–1197.
135. Freemantle, N., Danchin, N., Calvi-Gries, F., Vincent, M., Home, P.D., Relationship of glycaemic control and hypoglycaemic episodes to 4-year cardiovascular outcomes in people with type 2 diabetes starting insulin. Diabetes Obes Metab 18 (2016), 152–158.