Lessons from the trials for the desirable effects of sodium glucose co-transporter 2 inhibitors on diabetic cardiovascular events and renal dysfunction

International Journal of Molecular Sciences

Volumn 20, Issue 22, 2019, Pages

  Wakisaka, Masanori ^a   Kamouchi, Masahiro ^b   Kitazono, Takanari ^b  

^a Wakisaka Naika Clinic of Internal Medicine   (Japan)

^b KYUSHU UNIVERSITY   (Japan)

Author keywords

Capillary leakage; Diabetic cardiomyopathy; Diabetic nephropathy; Diabetic retinopathy; Fibrosis; Heart failure; Mesangial cells; Microaneurysm; Pericytes; Sodium glucose co transporter 2

Indexed keywords

ALBUMIN; CANAGLIFLOZIN; CREATININE; DAPAGLIFLOZIN; EMPAGLIFLOZIN; PLACEBO; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; GLUCOSE; SLC5A2 PROTEIN, HUMAN; SODIUM; SODIUM GLUCOSE COTRANSPORTER 2;

CELL MEMBRANE PERMEABILITY; CELL PHAGOCYTOSIS; CHRONIC KIDNEY FAILURE; DIABETIC CARDIOMYOPATHY; DIABETIC NEPHROPATHY; DIABETIC RETINOPATHY; END STAGE RENAL DISEASE; ESTIMATED GLOMERULAR FILTRATION RATE; FAMILIAL DISEASE; GLUCOSE INTAKE; GLUCOSE METABOLISM; HAZARD RATIO; HEART FAILURE; HUMAN; HYPERTENSION; KIDNEY FIBROSIS; MACROALBUMINURIA; MICROALBUMINURIA; MICROVASCULATURE; NEOVASCULARIZATION (PATHOLOGY); NONHUMAN; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; CARDIAC MUSCLE; METABOLISM; PATHOLOGY; RANDOMIZED CONTROLLED TRIAL (TOPIC);

DIABETIC CARDIOMYOPATHIES; DIABETIC NEPHROPATHIES; GLUCOSE; HEART FAILURE; HUMANS; MYOCARDIUM; RANDOMIZED CONTROLLED TRIALS AS TOPIC; SODIUM; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS;

EID: 85074894120     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms20225668     Document Type: Review

References (107)

1. Cho, N.H.; Shaw, J.E.; Karuranga, S,; Huang, Y.; da Rocha Fernandes, J.D.; Ohlrogge, A.W.; Malanda, B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 2018, 138, 271–281.
2. Umanath, K.; Lewis, J.B. Update on Diabetic Nephropathy: Core Curriculum 2018. Am. J. Kidney Dis. 2018, 71, 884–895.
3. Hölscher, M.E.; Bode, C.; Bugger, H. Diabetic Cardiomyopathy: Does the Type of Diabetes Matter? Int. J. Mol. Sci. 2016, 17, 2136. pii: E2136. doi: 10.3390/ijms17122136.
4. Wong, T.Y.; Cheung, C.M.; Larsen, M.; Sharma, S.; Simó, R. Diabetic retinopathy. Nat. Rev. Dis. Primers 2016, 2, 16012. doi: 10.1038/nrdp.2016.12.
5. Thomas, W.; Shen, Y.; Molitch, M.E.; Steffes, M.W. Rise in albuminuria and blood pressure in patients who progressed to diabetic nephropathy in the Diabetes Control and Complications Trial. J. Am. Soc. Nephrol. 2001, 12, 333–340.
6. UK Prospective Diabetes Study (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 1998, 352, 837–853.
7. Rossetti, L.; Smith, D.; Shulman, G.I.; Papachristou, D.; DeFronzo, R.A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 1987, 79, 1510–1515.
8. Defronzo, R.A.; Davidson, J.A.; Del Prato, S. The role of the kidneys in glucose homeostasis: A new path towards normalization glycaemia. Diabetes Obes. Metab. 2012, 14, 5–14.
9. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New Engl. J. Med. 2015, 373, 2117–2128.
10. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Desai, M.; Shaw, W.; Vercruysse, F.; Yee, J.; et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New. Engl. J. Med. 2017, 377, 644–657.
11. Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; Bhatt, D.L.; et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2019, 380, 347–357.
12. Mahaffey, K.W.; Neal, B.; Perkovic,V.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Fabbrini, E.; Sun, T.; Li, Q.; et al. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018, 137, 323–334.
13. Verma, S.; McMurray, J.J.V. The Serendipitous Story of SGLT2 Inhibitors in Heart Failure. Circulation 2019, 139, 2537–2541.
14. Cherney, D.; Lund, S.S.; Perkins, B.A.; Groop, P.H.; Cooper, M.E., Kaspers, S.; Pfarr, E.; Woerle, H.J.; von Eynatten, M. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia 2016, 59, 1860–1870.
15. Reddy, M.A.; Zhang, E.; Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 2015, 58, 443–455.
16. Kannel, W.B.; Hjortland, M.; Castelli, W.P. Role of diabetes in congestive heart failure: The Framingham study. Am. J. Cardiol. 1974, 34, 29–34.
17. Seneviratne, B.I. Diabetic cardiomyopathy: The preclinical phase. Br. Med. J. 1977, 1, 1444–1446.
18. Bouchard, A.; Sanz, N.; Botvinick, E.H.; Phillips, N.; Heilbron, D.; Byrd, B.F. 3rd; Karam, J.H., Schiller, N.B. Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old. Am. J. Med. 1989, 87, 160–166.
19. van Hoeven, K.H.; Factor, S.M. A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation 1990, 82, 848–855.
20. Tate, M.; Grieve, D.J.; Ritchie, R.H. Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin. Sci. 2017, 131, 897–915.
21. Regan, T.J.; Lyons, M.M.; Ahmed, S.S.; Levinson, G.E.; Oldewurtel, H.A.; Ahmad, M.R.; Ahmad, M.R.; Haider, B. Evidence for cardiomyopathy in familial diabetes mellitus. J. Clin. Invest. 1977, 60, 884–899.
22. Kawaguchi, M.; Techigawara, M.; Ishihata, T.; Asakura, T.; Saito, F.; Maehara, K.; Maruyama Y. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels 1997, 12, 267–274.
23. Factor, S.M.; Okun, E.M.; Minase, T. Capillary Microaneurysm in the Human Diabetic Heart. New. Engl. J. Med. 1980, 302, 384–388.
24. Frank, R.N. Diabetic Retinopathy. N. Engl. J. Med. 2004, 350, 48–58.
25. Cheung, N.; Wang, J.J.; Rogers, S.L. Diabetic retinopathy and risk of heart failure. J. Am. Coll. Cardiol. 2008, 51, 1573–1578.
26. Tryniszewski, W.; Kuśmierczyk, J.; Maziarz, Z. Correlation of the severity of diabetic retinopathy and the heart muscle perfusion in patients with type 2 diabetes. J. Diabetes Complicat. 2011, 25, 253–257.
27. Zhang, J.; Hill, C.E. Differential connexin expression in preglomerular and postglomerular vasculature: Accentuation during diabetes. Kidney Int. 2005, 68, 1171–1185.
28. Wakisaka, M.; He, Q.; Spiro, M.J.; Spiro R.G,. Glucose entry into rat mesangial cells is mediated by both Na (+)-coupled and facilitative transporters. Diabetologia 1995, 38, 291–297.
29. Wakisaka, M.; Nagao, T.; Yoshinari, M. Sodium Glucose Cotransporter 2 (SGLT2) Plays as a Physiological Glucose Sensor and Regulates Cellular Contractility in Rat Mesangial Cells. PLoS ONE 2016, 11, e0151585.
30. Maki, T.; Maeno, S.; Maeda, Y.; Yamato, M.; Sonoda, N.; Ogawa, Y.; Wakisaka, M.; Inoguci. T. Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells. Sci. Rep. 2019, 9, 4703. doi: 10.1038/s41598-019-41253-7.
31. +-dependent glucose uptake and collagen synthesis by cultured bovine retinal pericytes. Biochim. Biophys. Acta. 1997, 1362, 87–96.
32. Wakisaka, M.; Kitazono, T.; Kato, M.; Nakamura, U.; Yoshioka, M.; Uchizono, Y.; Yoshinari, M. Sodium-coupled glucose transporter as a functional glucose sensor of retinal microvascular circulation. Circ. Res. 2001, 88, 1183–1188.
33. Ghezzi, C.; Loo, D.D.F.; Wright, E.M. Physiology of renal glucose handling via SGLT1, SGLT2 and GLUT2. Diabetologia 2018, 61, 2087–2097.
34. Wanner, C.; Inzucchi, S.E.; Lachin, J.M.; Fitchett, D.; von Eynatten, M.; Mattheus, M.; Hantel, S.; Woerle, H.J.; Broedl, U.C.; von Eynatten, M.; et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 323–334.
35. Perkovic, V.; de Zeeuw, D.; Mahaffey, K.W.; Fulcher, G.; Erondu, N.; Shaw, W.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Zinman, B. Canagliflozin and renal outcomes in type 2 diabetes: Results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018, 6, 691–704.
36. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G., Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306.
37. Mosenzon, O.; Wiviott, S.D.; Cahn, A.; Rozenberg, A.; Yanuv, I.; Goodrich, E.L.; Murphy, S.A.; Heerspink, H.J.L.; Zelniker, T.A.; Dwyer, J.P.; et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: An analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019, 7, 606–617. doi: 10.1016/S2213-8587(19)30180-9.
38. Humphreys, B.D. Targeting pericyte differentiation as a strategy to modulate kidney fibrosis in diabetic nephropathy. Semin. Nephrol. 2012, 32, 463–470.
39. Hayashi, T.; Sohmiya, K.; Ukimura, A.; Endoh, S.; Mori, T.; Shimomura, H.; Okabe, M.; Terasaki F.; Kitaura Y. Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart. Heart 2003, 89, 1236–1242.
40. Yoon, Y.S.; Uchida, S.; Masuo, O.; Cejna, M.; Park, J.S.; Gwon, H.C.; Kirchmair, R.; Bahlman, F.; Walter, D.; Curry, C.; et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 2005, 111, 2073–2085.
41. Karamitsos, T.D.; Karvounis, H.I.; Dalamanga, E.G.; Papadopoulos, C.E.; Didangellos, T.P.; Karamitsos, D.T.; Parharidis, G.E.; Louridas, G.E. Early diastolic impairment of diabetic heart: The significance of right ventricle. Int. J. Cardiol. 2007, 114, 218–223.
42. Zabalgoitia, M.; Ismaeil, M.F.; Anderson, L.; Maklady, F.A. Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. Am. J. Cardiol. 2001, 87, 320–323.
43. Stratton, I.M.; Adler, A.I.; Neil, H.A.; Yudkin, J.S.; Matthews, D.R.; Cull, C.A.; Hadden, D.; Turner, R.C.; Holman, R.R. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. Br. Med. J. 2000, 321, 405–412.
44. Iribarren, C.; Karter, A.J.; Go, A.S.; Ferrara, A.; Liu, J.Y.; Sidney, S.; Selby, J.V. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001, 103, 2668–2673.
45. Aguilar, D.; Bozkurt, B.; Ramasubbu, K.; Deswal, A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J. Am. Coll. Cardiol. 2009, 54, 422–428.
46. Tomova, G.S.; Nimbal, V.; Horwich, T.B. Relation between hemoglobin a(1c) and outcomes in heart failure patients with and without diabetes mellitus. Am. J. Cardiol. 2012, 109, 1767–1773.
47. Turnbull, F.M.; Abraira, C.; Anderson, R.J.; Byington, R.P.; Chalmers, J.P.; Duckworth, W.C.; Evans, G.W.; Gerstein, H.C.; Holman, R.R.; Moritz, T.E.; et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009, 52, 2288–2298.
48. Bahtiyar, G.; Gutterman, D.; Lebovitz, H. Heart Failure: A Major Cardiovascular Complication of Diabetes Mellitus. Curr. Diab. Rep. 2016, 16, 116. doi: 10.1007/s11892-016-0809-4
49. Rådholm, K.; Figtree, G.; Perkovic, V.; Solomon, S.D.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Matthews, D.R.; Shaw, W.; Neal, B. Effects of Canagliflozin on Heart Failure Outcomes Associated with Preserved and Reduced Ejection Fraction in Type 2 Diabetes: Results from the CANVAS Program. Circulation 2019, 138, 458–468.
50. Hoenig, M.R.; Bianchi, C.; Rosenzweig, A.; Sellke, E.W. The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure. Curr. Vasc. Pharmacol. 2008, 6, 292–300.
51. Sharma, K.; Kass, D.A. Unmet needs in cardiovascular science and medicine. Circ. Res. 2014, 115, 79–96.
52. Kemp, C.D.; Conte, J.V. The pathophysiology of heart failure. Cardiovasc. Pathol. 2012, 21, 365–371.
53. Mentz, R.J.; O’Connor, C.M. Pathophysiology and clinical evaluation of acute heart failure. Nat. Rev. Cardiol. 2016, 13, 28–35.
54. Lee, J.F.; Barrett-O'Keefe, Z.; Garten R.S,. Evidence of microvascular dysfunction in heart failure with preserved ejection fraction. Heart 2016, 102, 278–284.
55. Molitch, M.E.; Adler, A.I.; Flyvbjerg, A.; Nelson, R.G.; So, W.Y.; Wanner, C.; Kasiske, B.L.; Wheeler, D.C., de Zeeuw, D.; Mogensen, C.E. Diabetic Kidney Disease– A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2015, 87, 20–30.
56. Simonson, M.S. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int. 2007, 71, 846–854.
57. Singh, D.K.; Winocour, P; Farrington, K. Mechanisms of disease: The hypoxic tubular hypothesis of diabetic nephropathy. Nat. Clin. Pract. Nephrol. 2008, 4, 216–226.
58. Kawakami, T.; Mimura, I.; Shoji, K., Tanaka T., Nangaku M.; Hypoxia and fibrosis in chronic kidney disease: Crossing at pericytes. Kidney Int. Suppl. 2014, 4, 107–112.
59. Gnudi, L.; Thomas, S.M.; Viberti, G. Mehanical forces in diabetic kidney disease: A trigger for impaired glucose metabolism. J. Am. Soc. Nephrol. 2007, 18, 2226–2232.
60. Bankir, L.; Roussel, R.; Bouby, N. Protein-and diabetes-induced glomerular hyperfiltration: Role of glucagon, vasopressin, and urea. Am. J. Physiol. Renal. Physiol. 2015, 309, F2–F23.
61. Gnudi, L.; Karalliedde, J. Beat it early: Putative renoprotective haemodynamic effects of oral hypoglycaemic agents. Nephrol. Dial. Transplant. 2016, 31, 1036–1043.
62. Ouardani, M.; Travo, P.; Rakotoarivony, J.; Leung-Tack, J. Decrease of bradykinin-induced glomerular contraction in diabetic rat: A new cellular interpretation. Eur. J. Cell Biol. 1997, 73, 232–239.
63. Dunlop, M.E.; Muggli, E.E. Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress. Kidney Int. 2000, 57, 464–475.
64. Ayo, S.H.; Radnik, R.A.; Garoni, J.A.; Glass, W.F. 2nd; Kreisberg, J.I. High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am. J. Pathol. 1990, 136, 1339–1348.
65. Stockand J.D., Sansom S.C. Glomerular mesangial cells: electrophysiology and regulation of contraction. Physiol. Rev. 1998, 78, 723-744.
66. Sano, M., Takei, M., Shiraishi, Y., Suzuki, Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J. Clin. Med. Res. 2016, 8, 844–847.
67. Zelickson, A.S. A tubular structure in the endothelial cells and pericytes of human capillaries. J. Invest. Dermatol. 1966, 46, 167–185.
68. Stamenkovic, I.; Skalli, O.; Gabbiani, G. Distribution of intermediate filament proteins in normal and diseased human glomeruli. Am. J. Pathol. 1986, 125, 465–475.
69. Banerjee, S.K.; McGaffin, K.R.; Pastor-Soler, N.M.; Ahmad, F. SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc. Res. 2009, 84, 111–118.
70. Kashiwagi, Y.; Nagoshi, T.; Yoshino, T.; Tanaka, T.D.; Ito, K.; Harada, T.; Takahashi, H.; Ikegami, M.; Anzawa, R.; Yoshimura, M. Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice. PLoS ONE 2015, 10, e0130605. doi: 10.1371/journal.pone.0130605.
71. Schlondorff, D. The glomerular mesangial cell: An expanding role for a specialized pericyte. FASEB J. 1987, 1, 272–281.
72. van Dijk, C.G.; Nieuweboer, F.E.; Pei, J.Y.; Xu, Y.J.; Burgisser, P.; van Mulligen. E.; Duncker, D.J.; Verhaar, M.C.; Cheng, C. Mural cell: Pericyte function in health and disease. Int. J. Cardiol. 2015, 190, 75–89.
73. Wakisaka, M.; Yoshinari, M.; Asano, T.; Iino, K.; Nakamura, S.; Takata, Y.; Fujishima, M. Normalization of glucose entry under the high glucose condition by phlorizin attenuates the high glucose-induced morphological and functional changes of cultured bovine retinal pericytes. Biochim. Biophys. Acta 1999, 1453, 83–91.
74. Tang, L; Wu, Y.; Tian, M.; Sjöström, C.D.; Johansson, U.; Peng, X.R.; Smith, D.M.; Huang, Y. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2017, 313, E563–E576.
75. Li, C.; Zhang, J.; Xue, M.; Li, X.; Han, F.; Liu, X.; Xu, L.; Lu, Y.; Cheng, Y.; Li, T.; et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc. Diabetol. 2019, 18, 15. doi: 10.1186/s12933-019-0816-2.
76. Yamaji, T.; Fukuhara, T.; Kinoshita, M. Increased capillary permeability to albumin in diabetic rat myocardium. Circ. Res. 1993, 72, 947– 957.
77. Temm, C.; Dominguez, J.H. Microcirculation: Nexus of comorbidities in diabetes. Am. J. Physiol. Renal. Physiol. 2007, 293, F486–F493.
78. Yoshizumi, H.; Ejima, T.; Nagao, T.; Wakisaka, M. Recovery from Diabetic Macular Edema in a Diabetic Patient After Minimal Dose of a Sodium Glucose Co-Transporter 2 Inhibitor. Am. J. Case Rep. 2018, 19, 462– 466.
79. Chen, L.; LaRocque, L.M.; Efe, O.; Wang, J.; Sands, J.M.; Klein, J.D. Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats. Am. J. Med. Sci. 2016, 352, 517–523.
80. Chilton, R.J. Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes. Diabetes Obes. Metab. 2019, Aug 13. doi: 10.1111/dom.13854.
81. Patel, D.K.; Strong, J. The Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit. Diabetes Ther. 2019, 10, 1771–1792. doi: 10.1007/s13300-019-00686-z.
82. Kuriyama, C.; Xu, J.Z.; Lee, S.P.; Kuriyama, C.; Xu, J.Z.; Lee, S.P.; Nakayama, K.; Watanabe, Y.; Taniuchi, N.; Hikida, K.; et al. Analysis of the effect of canagliflozin on renal glucose reabsorption and progression of hyperglycemia in zucker diabetic Fatty rats. J. Pharmacol. Exp. Ther. 2014, 351, 423–431.
83. Inagaki, N.; Kondo, K.; Yoshinari, T.; Ishii, M.; Sakai, M.; Kuki, H.; Furihata, K. Pharmacokinetic and pharmacodynamic profiles of canagliflozin in Japanese patients with type 2 diabetes mellitus and moderate renal impairment. Clin. Drug. Investig. 2014, 34, 731–742.
84. Bozkurt, B.; Aguilar, D.; Deswal, A.; Dunbar, S.B.; Francis, G.S.; Horwich,T.; Jessup, M.; Kosiborod, M.; Pritchett, A.M.; Ramasubbu, K.; et al. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation 2016, 134, e535–e578.
85. Persso, F.; Lindhard, M.; Rossing, P.; Parving, H.H. Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic review. J. Renin. Angiotensin. Aldosterone. Syst. 2016, 17. doi: 10.1177/1470320316652047.
86. Wang, B.; Wang, F.; Zhang, Y.; Zhao, S.H.; Zhao, W.J.; Yan, S.L.; Wang, Y.G. Effects of RAS inhibitors on diabetic retinopathy: A systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015, 3, 263–274. doi: 10.1016/S2213-8587(14)70256-6.
87. +-glucose cotransporter in hypertension. Am. J. Physiol. Renal. Physiol. 2004, 286, F127–F133.
88. Wakisaka, M.; Yoshinari, M.; Nakamura, S.; Asano, T.; Sonoki, K.; Shi, A.H.; Iwase, M.; Takata, Y.; Fujishima, M. Suppression of sodium-dependent glucose uptake by captopril improves high-glucose-induced morphological and functional changes of cultured bovine retinal pericytes. Microvasc. Res. 1999, 58, 215–223.
89. Abdul-Ghani, M.; DeFronzo, R.A.; Del Prato, S.; Chilton, R.; Singh, R.; Ryder, R.E.J. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care 2017, 40, 813–820.
90. Dormandy, J.A.; Charbonnel, B.; Eckland, D.J.; Erdmann, E.; Massi-Benedetti, M.; Moules, I.K.; Skene, A.M.; Tan, M.H.; Lefèbvre, P.J.; Murray, G.D.; 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 2005, 366, 1279–1289.
91. Kernan, W.N.; Viscoli, C.M.; Furie, K.L.; Young, L.H.; Inzucchi, S.E.; Gorman, M.; Guarino, P.D.; Lovejoy, A.M.; Peduzzi, P.N.; Conwit, R.; et al.Pioglitazone after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 2016, 374, 1321–1331.
92. Bełtowski, J.; Rachańczyk, J.; Włodarczyk, M. Thiazolidinedione-induced fluid retention: Recent insights into the molecular mechanisms. PPAR Res. 2013, 2013, doi: dx.doi.org/10.1155/2013/628628
93. Hartung, D.M.; Touchette, D.R.; Bultemeier, N.C.; Haxby, D.G. Risk of hospitalization for heart failure associated with thiazolidinedione therapy: A medicaid claims-based case-control study. Pharmacotherapy 2005, 25, 1329–1336.
94. Hanefeld, M.; Brunetti, P.; Schernthaner, G.H.; Matthews, D.R.; Charbonnel, B.H.; QUARTET Study Group. One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes. Diabetes Care 2004, 27, 141–147.
95. Schernthaner, G.; Matthews, D.R.; Charbonnel, B.; Hanefeld, M.; Brunetti, P.; Quartet [corrected] Study Group. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: A double-blind, randomized trial. J. Clin. Endocrinol. Metab. 2004, 89, 6068–6076.
96. Schneider, C.A.; Ferrannini, E.; Defronzo, R.; Hanefeld, M.; Brunetti, P.; Quartet [corrected] Study Group. Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J. Am. Soc. Nephrol. 2008, 19, 182–187.
97. Barak, Y. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 1999, 4, 585– 595.
98. Iijima,, K.; Yoshizumi, M.; Ako, J.; Eto, M.; Kim, S.; Hashimoto, M.; Sugimoto, N.; Liang, Y.Q.; Sudoh, N.; Toba, K.; et al. Expression of peroxisome proliferator-activated receptorγ (PPARγ) in rat aortic smooth muscle cells. Biochem. Biophys. Res. Commun. 1998, 247, 353–356.
99. Ricote, M.; Li, A.C.; Willson, T.M.; Kelly, C.J.; Glass, C.K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 1998, 391, 79–82.
100. Gensch, C.; Clever, Y.P.; Werner, C.; Hanhoun, M.; Böhm, M.; Laufs, U. The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 2007, 192, 67–74.
101. .; Kinoshita, H.; Yamada, S.; Morita, Y.; Nishida, S.; Motoshima, H.; Kondo, T.; et al. Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ. Atherosclerosis 2019, 286, 30–39.
102. Asano, T.; Wakisaka. M.; Yoshinari, M.; Iino, K.; Sonoki, K.; Iwase, M.; Fujishima, M. Peroxisome proliferator-activated receptor γ1 (PPARγ1) expresses in rat mesangial cells and PPARγ agonists modulate its differentiation. Biochim. Biophys. Acta 2000, 1497, 148–154.
103. Farrington-Rock, C.; Crofts, N.J.; Doherty, M.J.; Ashton, B.A.; Griffin-Jones, C.; Canfield, A.E. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 2004, 110, 2226–2232.
104. Ueta, M.; Wakisaka, M.; Ago, T.; Kitazono, T.; Nakamura, U.; Yoshinari, M.; Iwase,M.; Iida, M.; PPARγ ligands attenuate mesangial contractile dysfunction in high glucose. Kidney Int. 2004, 65, 961–971.
105. Asano, T.; Wakisaka, M.; Yoshinari, M.; Nakamura, S.; Doi, Y.; Fujishima, M. Troglitazone enhances glycolysis and improves intracellular glucose metabolism in rat mesangial cells. Metabolism 2000, 49, 308– 313.
106. Dello Russo, C.; Gavrilyuk, V.; Weinberg, G.; Almeida, A.; Bolanos, J.P.; Palmer, J.; Pelligrino, D.; Galea, E.; Feinstein, D.L. Peroxisome proliferator-activated receptor γ thiazolidinedione agonists increase glucose metabolism in astrocytes. J. Biol. Chem. 2003, 278, 5828–5836.
107. DeFronzo, R.A.; Chilton, R.; Norton, L.; Clarke, G.; Ryder, R.E.; Abdul-Ghani, M. Revitalization of pioglitazone: The optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor. Diabetes Obes. Metab. 2016, 18, 454–462.