1932

Abstract

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose–dependent and –independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

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2021-02-10
2024-12-06
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Literature Cited

  1. 1. 
    Laiteerapong N, Ham SA, Gao Y, Moffet HH, Liu JY et al. 2019. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study). Diabetes Care 42:416–26
    [Google Scholar]
  2. 2. 
    Gerstein HC, Miller ME, Byington RP, Goff DC Jr., Bigger JT et al. 2008. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358:2545–59
    [Google Scholar]
  3. 3. 
    Vallon V, Thomson SC. 2017. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 60:215–25
    [Google Scholar]
  4. 4. 
    US Food and Drug Admin 2008. Guidance for industry on diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes; availability. Fed. Regist. 73: https://www.govinfo.gov/content/pkg/FR-2008-12-19/pdf/E8-30086.pdf
    [Google Scholar]
  5. 5. 
    Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET et al. 2019. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380:347–57
    [Google Scholar]
  6. 6. 
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E et al. 2015. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373:2117–28
    [Google Scholar]
  7. 7. 
    Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M et al. 2016. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375:323–34
    [Google Scholar]
  8. 8. 
    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G et al. 2017. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377:644–57
    [Google Scholar]
  9. 9. 
    Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I et al. 2019. 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 7:606–17
    [Google Scholar]
  10. 10. 
    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL et al. 2019. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380:2295–306
    [Google Scholar]
  11. 11. 
    Toyama T, Neuen BL, Jun M, Ohkuma T, Neal B et al. 2019. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and meta-analysis. Diabetes Obes. Metab. 21:1237–50
    [Google Scholar]
  12. 12. 
    Heerspink HJL, Stefánsson BV, Correa-Rotter MDR, Chertow GM, Greene T et al. 2020. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383:1436–46
    [Google Scholar]
  13. 13. 
    Vallon V. 2020. Glucose transporters in the kidney in health and disease. Pflügers Arch 472:1345–70
    [Google Scholar]
  14. 14. 
    Vallon V, Platt KA, Cunard R, Schroth J, Whaley J et al. 2011. SGLT2 mediates glucose reabsorption in the early proximal tubule. J. Am. Soc. Nephrol. 22:104–12
    [Google Scholar]
  15. 15. 
    Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K et al. 2014. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am. J. Physiol. Ren. Physiol. 306:F188–93
    [Google Scholar]
  16. 16. 
    Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A et al. 2012. Na+-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61:187–96
    [Google Scholar]
  17. 17. 
    Umino H, Hasegawa K, Minakuchi H, Muraoka H, Kawaguchi T et al. 2018. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces Sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci. Rep. 8:6791
    [Google Scholar]
  18. 18. 
    Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J 2005. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54:3427–34
    [Google Scholar]
  19. 19. 
    Wang XX, Levi J, Luo Y, Myakala K, Herman-Edelstein M et al. 2017. SGLT2 expression is increased in human diabetic nephropathy: SGLT2 inhibition decreases renal lipid accumulation, inflammation and the development of nephropathy in diabetic mice. J Biol. Chem. 292:5335–48
    [Google Scholar]
  20. 20. 
    Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J et al. 2014. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am. J. Physiol. Ren. Physiol. 306:F194–204
    [Google Scholar]
  21. 21. 
    Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA et al. 2013. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am. J. Physiol. Ren. Physiol. 304:F156–67
    [Google Scholar]
  22. 22. 
    Wen L, Zhang Z, Peng R, Zhang L, Liu H et al. 2019. Whole transcriptome analysis of diabetic nephropathy in the db/db mouse model of type 2 diabetes. J. Cell Biochem 120:17520–33
    [Google Scholar]
  23. 23. 
    Vallon V, Thomson SC. 2020. The tubular hypothesis of nephron filtration and diabetic nephropathy. Nat. Rev. Nephrol. 16:317–36
    [Google Scholar]
  24. 24. 
    Fattah H, Layton A, Vallon V 2019. How do kidneys adapt to a deficit or loss in nephron number. Physiology 34:189–97
    [Google Scholar]
  25. 25. 
    Osorio H, Bautista R, Rios A, Franco M, Santamaria J, Escalante B 2009. Effect of treatment with losartan on salt sensitivity and SGLT2 expression in hypertensive diabetic rats. Diabetes Res. Clin. Pract. 86:e46–49
    [Google Scholar]
  26. 26. 
    Freitas HS, Anhe GF, Melo KF, Okamoto MM, Oliveira-Souza M et al. 2008. Na+-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1α expression and activity. Endocrinology 149:717–24
    [Google Scholar]
  27. 27. 
    Freitas HS, Schaan BD, David-Silva A, Sabino-Silva R, Okamoto MM et al. 2009. SLC2A2 gene expression in kidney of diabetic rats is regulated by HNF-1α and HNF-3β. Mol. Cell. Endocrinol. 305:63–70
    [Google Scholar]
  28. 28. 
    Ghezzi C, Wright EM. 2012. Regulation of the human Na+ dependent glucose cotransporter hSGLT2. Am. J. Physiol. Cell Physiol. 303:C348–54
    [Google Scholar]
  29. 29. 
    Masuda T, Watanabe Y, Fukuda K, Watanabe M, Onishi A et al. 2018. Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat. Am. J. Physiol. Ren. Physiol. 315:F653–64
    [Google Scholar]
  30. 30. 
    Onishi A, Fu Y, Darshi M, Crespo-Masip M, Huang W et al. 2019. Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice. Am. J. Physiol. Ren. Physiol. 317:F419–F34
    [Google Scholar]
  31. 31. 
    Ghezzi C, Hirayama BA, Gorraitz E, Loo DD, Liang Y, Wright EM 2014. SGLT2 inhibitors act from the extracellular surface of the cell membrane. Physiol. Rep. 2:e12058
    [Google Scholar]
  32. 32. 
    Fu Y, Breljak D, Onishi A, Batz F, Patel R et al. 2018. The organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin. Am. J. Physiol. Ren. Physiol. 315:F386–94
    [Google Scholar]
  33. 33. 
    Kellett GL, Brot-Laroche E, Mace OJ, Leturque A 2008. Sugar absorption in the intestine: the role of GLUT2. Annu. Rev. Nutr. 28:35–54
    [Google Scholar]
  34. 34. 
    Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M et al. 2020. A role for the tubular Na+-H+-exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am. J. Physiol. Ren. Physiol. 319:F712–28
    [Google Scholar]
  35. 35. 
    Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK 2015. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care 38:316–22
    [Google Scholar]
  36. 36. 
    Qiu H, Novikov A, Vallon V 2017. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab. Res. Rev. 33:e2886
    [Google Scholar]
  37. 37. 
    Ferrannini E, Mark M, Mayoux E 2016. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 39:1108–14
    [Google Scholar]
  38. 38. 
    Tomita I, Kume S, Sugahara S, Osawa N, Yamahara K et al. 2020. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab 32:404–19.e6
    [Google Scholar]
  39. 39. 
    Vallon V, Richter K, Blantz RC, Thomson S, Osswald H 1999. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J. Am. Soc. Nephrol. 10:2569–76
    [Google Scholar]
  40. 40. 
    Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J et al. 2012. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302:R75–83
    [Google Scholar]
  41. 41. 
    Song P, Huang W, Onishi A, Patel R, Kim Y et al. 2019. Knockout of Na-glucose-cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase-1 in macula densa and glomerular hyperfiltration. Am. J. Physiol. Ren. Physiol. 317:F207–17
    [Google Scholar]
  42. 42. 
    Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V et al. 2014. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:587–97
    [Google Scholar]
  43. 43. 
    van Bommel EJM, Muskiet MHA, van Baar MJB, Tonneijck L, Smits MM et al. 2020. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int 97:202–12
    [Google Scholar]
  44. 44. 
    Vallon V, Muhlbauer B, Osswald H 2006. Adenosine and kidney function. Physiol. Rev. 86:901–40
    [Google Scholar]
  45. 45. 
    Ren Y, Garvin JL, Carretero OA 2001. Efferent arteriole tubuloglomerular feedback in the renal nephron. Kidney Int 59:222–29
    [Google Scholar]
  46. 46. 
    Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M et al. 2019. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation 140:303–15
    [Google Scholar]
  47. 47. 
    Thomson SC, Vallon V. 2020. Effects of acute SGLT2 blockade and dietary NaCl on glomerular hemodynamics in diabetic rats. FASEB J 34:Suppl. 11 Abstr .)
    [Google Scholar]
  48. 48. 
    Thomson S, Vallon V, Blantz RC 1996. Asymmetry of tubuloglomerular feedback effector mechanism with respect to ambient tubular flow. Am. J. Physiol. 271:F1123–30
    [Google Scholar]
  49. 49. 
    Perkovic V, Jardine M, Vijapurkar U, Meininger G 2015. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr. Med. Res. Opin. 31:2219–31
    [Google Scholar]
  50. 50. 
    Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V 2018. Canagliflozin slows progression of renal function decline independently of glycemic effects. J. Am. Soc. Nephrol. 28:368–75
    [Google Scholar]
  51. 51. 
    Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L 2016. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J. Nephrol. 29:391–400
    [Google Scholar]
  52. 52. 
    Yale JF, Bakris G, Cariou B, Yue D, David-Neto E et al. 2013. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab. 15:463–73
    [Google Scholar]
  53. 53. 
    Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H et al. 2014. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2:369–84
    [Google Scholar]
  54. 54. 
    Zhang J, Wei J, Jiang S, Xu L, Wang L et al. 2019. Macula densa SGLT1-NOS1-TGF pathway—a new mechanism for glomerular hyperfiltration during hyperglycemia. J. Am. Soc. Nephrol. 30:578–93
    [Google Scholar]
  55. 55. 
    Cassis P, Locatelli M, Cerullo D, Corna D, Buelli S et al. 2018. SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy. JCI. Insight 3:e98720
    [Google Scholar]
  56. 56. 
    Layton AT, Vallon V, Edwards A 2015. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am. J. Physiol. Ren. Physiol. 308:F1343–57
    [Google Scholar]
  57. 57. 
    Layton AT, Vallon V, Edwards A 2016. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am. J. Physiol. Ren. Physiol. 310:F1269–83
    [Google Scholar]
  58. 58. 
    Neill O, Fasching A, Pihl L, Patinha D, Franzen S, Palm F 2015. Acute SGLT inhibition normalizes oxygen tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am. J. Physiol. Ren. Physiol. 309:F227–34
    [Google Scholar]
  59. 59. 
    Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y et al. 2019. Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci. Rep. 9:14754
    [Google Scholar]
  60. 60. 
    Pruijm M, Milani B, Pivin E, Podhajska A, Vogt B et al. 2018. Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease. Kidney Int 93:932–40
    [Google Scholar]
  61. 61. 
    Gilbert RE, Thorpe KE. 2019. Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: a meta-analysis of cardiovascular outcome trials. Diabetes Obes. Metab. 21:1996–2000
    [Google Scholar]
  62. 62. 
    Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V et al. 2019. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 7:845–54
    [Google Scholar]
  63. 63. 
    Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL 2018. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes. Metab. 20:1988–93
    [Google Scholar]
  64. 64. 
    Satirapoj B, Korkiatpitak P, Supasyndh O 2019. Effect of sodium-glucose cotransporter 2 inhibitor on proximal tubular function and injury in patients with type 2 diabetes: a randomized controlled trial. Clin. Kidney J. 12:326–32
    [Google Scholar]
  65. 65. 
    Zhang Y, Nakano D, Guan Y, Hitomi H, Uemura A et al. 2018. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int 94:524–35
    [Google Scholar]
  66. 66. 
    Nespoux J, Patel R, Zhang H, Huang W, Freeman B et al. 2020. Gene knockout of the Na+-glucose cotransporter SGLT2 in a murine model of acute kidney injury induced by ischemia-reperfusion. Am. J. Physiol. Ren. Physiol. 318:F1100–12
    [Google Scholar]
  67. 67. 
    Nespoux J, Patel R, Hudkins KL, Huang W, Freeman B et al. 2019. Gene deletion of the Na+-glucose cotransporter SGLT1 ameliorates kidney recovery in a murine model of acute kidney injury induced by ischemia-reperfusion. Am. J. Physiol. Ren. Physiol. 316:F1201–10
    [Google Scholar]
  68. 68. 
    Darshi M, Onishi A, Kim JJ, Pham J, Van Espen BF et al. 2017. Metabolic reprogramming in diabetic kidney disease can be restored via SGLT2 inhibition. J. Am. Soc. Nephrol.28(Abstr. Suppl.) 439: (Abstr.)
    [Google Scholar]
  69. 69. 
    Mulder S, Heerspink HJL, Darshi M, Kim JJ, Laverman GD et al. 2019. Effects of dapagliflozin on urinary metabolites in people with type 2 diabetes. Diabetes Obes. Metab. 21:2422–28
    [Google Scholar]
  70. 70. 
    Lee YH, Kim SH, Kang JM, Heo JH, Kim DJ et al. 2019. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am. J. Physiol. Ren. Physiol. 317:F767–80
    [Google Scholar]
  71. 71. 
    Takagi S, Li J, Takagaki Y, Kitada M, Nitta K et al. 2018. Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high-fat diet. J. Diabetes Investig. 9:1025–32
    [Google Scholar]
  72. 72. 
    Novikov A, Fu Y, Huang W, Freeman B, Patel R et al. 2019. SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am. J. Physiol. Ren. Physiol. 316:F173–85
    [Google Scholar]
  73. 73. 
    Lytvyn Y, Skrtic M, Yang GK, Yip PM, Perkins BA, Cherney DZ 2015. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am. J. Physiol. Ren. Physiol. 308:F77–83
    [Google Scholar]
  74. 74. 
    Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi JI et al. 2014. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm. Drug Dispos. 35:391–404
    [Google Scholar]
  75. 75. 
    Toyoki D, Shibata S, Kuribayashi-Okuma E, Xu N, Ishizawa K et al. 2017. Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2. Am. J. Physiol. Ren. Physiol. 313:F826–34
    [Google Scholar]
  76. 76. 
    Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic G 2014. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J. Am. Soc. Nephrol. 25:2028–39
    [Google Scholar]
  77. 77. 
    Coady MJ, El TA, Santer R, Bissonnette P, Sasseville LJ et al. 2017. MAP17 is a necessary activator of renal Na+/glucose cotransporter SGLT2. J. Am. Soc. Nephrol. 28:85–93
    [Google Scholar]
  78. 78. 
    Fu Y, Gerasimova M, Mayoux E, Masuda T, Vallon V 2014. SGLT2 inhibitor empagliflozin increases renal NHE3 phosphorylation in diabetic Akita mice: possible implications for the prevention of glomerular hyperfiltration. Diabetes 63:S1A132
    [Google Scholar]
  79. 79. 
    Rajasekeran H, Lytvyn Y, Bozovic A, Lovshin JA, Diamandis E et al. 2017. Urinary adenosine excretion in type 1 diabetes. Am. J. Physiol. Ren. Physiol. 313:F184–91
    [Google Scholar]
  80. 80. 
    Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E et al. 2018. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 41:356–63
    [Google Scholar]
  81. 81. 
    Layton AT, Vallon V. 2018. SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism. Am. J. Physiol. Ren. Physiol. 314:F969–84
    [Google Scholar]
  82. 82. 
    Li J, Neal B, Perkovic V, de Zeeuw D, Neuen BL et al. 2020. Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney Int 98:769–77
    [Google Scholar]
  83. 83. 
    Li J, Woodward M, Perkovic V, Figtree GA, Heerspink HJL et al. 2020. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail 8:57–66
    [Google Scholar]
  84. 84. 
    Verma S, Mazer CD, Fitchett D, Inzucchi SE, Pfarr E et al. 2018. Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME(R) randomised trial. Diabetologia 61:1712–23
    [Google Scholar]
  85. 85. 
    Verma S, Mazer CD, Al-Omran M, Inzucchi SE, Fitchett D et al. 2018. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation 137:405–07
    [Google Scholar]
  86. 86. 
    Savarese G, Sattar N, Januzzi J, Verma S, Lund LH et al. 2019. Empagliflozin is associated with a lower risk of post-acute heart failure rehospitalization and mortality. Circulation 139:1458–60
    [Google Scholar]
  87. 87. 
    Stone JA, Houlden RL, Lin P, Udell JA, Verma S 2018. Cardiovascular protection in people with diabetes. Can. J. Diabetes 42:Suppl. 1S162–69
    [Google Scholar]
  88. 88. 
    Cherney DZI, Odutayo A, Verma S 2019. A big win for diabetic kidney disease: CREDENCE. Cell Metab 29:1024–27
    [Google Scholar]
  89. 89. 
    Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL et al. 2019. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393:31–39
    [Google Scholar]
  90. 90. 
    McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN et al. 2019. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381:1995–2008
    [Google Scholar]
  91. 91. 
    Verma S. 2020. The DAPA-HF trial marks the beginning of a new era in the treatment of heart failure with reduced ejection fraction. Cardiovasc Res 116:e8–10
    [Google Scholar]
  92. 92. 
    O'Meara E, McDonald M, Chan M, Ducharme A, Ezekowitz JA et al. 2020. CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis. Can. J. Cardiol. 36:159–69
    [Google Scholar]
  93. 93. 
    Docherty KF, Jhund PS, Inzucchi SE, Kober L, Kosiborod MN et al. 2020. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur. Heart J. 41:2379–92
    [Google Scholar]
  94. 94. 
    Kosiborod MN, Jhund PS, Docherty KF, Diez M, Petrie MC et al. 2020. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation 141:90–99
    [Google Scholar]
  95. 95. 
    Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ et al. 2020. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383:1413–24
    [Google Scholar]
  96. 96. 
    Lam CSP, Chandramouli C, Ahooja V, Verma S 2019. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J. Am. Heart Assoc. 8:e013389
    [Google Scholar]
  97. 97. 
    Packer M. 2020. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: a paradigm shift in understanding their mechanism of action. Diabetes Care 43:508–11
    [Google Scholar]
  98. 98. 
    Ferrannini E. 2017. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab 26:27–38
    [Google Scholar]
  99. 99. 
    Verma S, McMurray JJV. 2019. The serendipitous story of SGLT2 inhibitors in heart failure. Circulation 139:2537–41
    [Google Scholar]
  100. 100. 
    Lopaschuk GD, Verma S. 2020. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl. Sci. 5:632–44
    [Google Scholar]
  101. 101. 
    Verma S. 2019. Potential mechanisms of sodium-glucose co-transporter 2 inhibitor-related cardiovascular benefits. Am. J. Cardiol. 124:Suppl. 1S36–44
    [Google Scholar]
  102. 102. 
    Butler J, Handelsman Y, Bakris G, Verma S 2020. Use of sodium–glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure. Eur. J. Heart Fail. 22:604–17
    [Google Scholar]
  103. 103. 
    Verma S, McMurray JJV. 2018. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 61:2108–17
    [Google Scholar]
  104. 104. 
    Verma S, Sharma A, Kanumilli N, Butler J 2019. Predictors of heart failure development in type 2 diabetes: a practical approach. Curr. Opin. Cardiol. 34:578–83
    [Google Scholar]
  105. 105. 
    Verma S, Wanner C, Zwiener I, Ofstad AP, George JT et al. 2019. Influence of microvascular disease on cardiovascular events in type 2 diabetes. J. Am. Coll. Cardiol. 73:2780–82
    [Google Scholar]
  106. 106. 
    Dickhout JG, Carlisle RE, Austin RC 2011. Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ. Res. 108:629–42
    [Google Scholar]
  107. 107. 
    Opingari E, Verma S, Connelly KA, Mazer CD, Teoh H et al. 2020. The impact of empagliflozin on kidney injury molecule-1: a subanalysis of the Effects of Empagliflozin on Cardiac Structure, Function, and Circulating Biomarkers in Patients with Type 2 Diabetes CardioLink-6 trial. Nephrol. Dial Transplant. 35:895–97
    [Google Scholar]
  108. 108. 
    Patel VB, Shah S, Verma S, Oudit GY 2017. Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease. Heart Fail Rev 22:889–902
    [Google Scholar]
  109. 109. 
    Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A et al. 2014. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Investig. 124:499–508
    [Google Scholar]
  110. 110. 
    Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E et al. 2017. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 40:771–76
    [Google Scholar]
  111. 111. 
    Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW 2018. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes. Metab. 20:479–87
    [Google Scholar]
  112. 112. 
    Heerspink HJL, de Zeeuw D, Wie L, Leslie B, List J 2013. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab. 15:853–62
    [Google Scholar]
  113. 113. 
    Abraham WT, Lauwaars ME, Kim JK, Pena RL, Schrier RW 1995. Reversal of atrial natriuretic peptide resistance by increasing distal tubular sodium delivery in patients with decompensated cirrhosis. Hepatology 22:737–43
    [Google Scholar]
  114. 114. 
    Shi X, Verma S, Yun J, Brand-Arzamendi K, Singh KK et al. 2017. Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: Clues to the EMPA-REG OUTCOME trial. Mol. Cell. Biochem. 433:97–102
    [Google Scholar]
  115. 115. 
    Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N et al. 2019. Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease. Circulation 141:704–7
    [Google Scholar]
  116. 116. 
    Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M et al. 2020. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J. Clin. Endocrinol. Metab. 105:e1056–63
    [Google Scholar]
  117. 117. 
    Hess DA, Terenzi DC, Trac JZ, Quan A, Mason T et al. 2019. SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metab 30:609–13
    [Google Scholar]
  118. 118. 
    Goldenberg RM, Berard LD, Cheng AYY, Gilbert JD, Verma S et al. 2016. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin. Ther. 38:2654–64.e1
    [Google Scholar]
  119. 119. 
    Lopaschuk GD, Verma S. 2016. Empagliflozin's fuel hypothesis: not so soon. Cell Metab 24:200–2
    [Google Scholar]
  120. 120. 
    Ferrannini E, Mark M, Mayoux E 2016. Response to Comment on Ferrannini et al. CV protection in the EMPA-REG OUTCOME Trial: a “thrifty substrate” hypothesis. Diabetes Care 39:e226
    [Google Scholar]
  121. 121. 
    Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH et al. 2019. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 139:2129–41
    [Google Scholar]
  122. 122. 
    Verma S, Rawat S, Ho KL, Wagg CS, Zhang L et al. 2018. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl. Sci. 3:575–87
    [Google Scholar]
  123. 123. 
    Santos-Gallego CG, Requena-Ibanez JA, San AR, Ishikawa K, Watanabe S et al. 2019. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J. Am. Coll. Cardiol. 73:1931–44
    [Google Scholar]
  124. 124. 
    Trum M, Wagner S, Maier LS, Mustroph J 2020. CaMKII and GLUT1 in heart failure and the role of gliflozins. Biochim. Biophys. Acta Mol. Basis Dis. 1866:165729
    [Google Scholar]
  125. 125. 
    Kappel BA, Lehrke M, Schutt K, Artati A, Adamski J et al. 2017. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation 136:969–72
    [Google Scholar]
  126. 126. 
    Verma S. 2020. Are the cardiorenal benefits of SGLT2 inhibitors due to inhibition of the sympathetic nervous system. JACC Basic Transl. Sci. 5:180–82
    [Google Scholar]
  127. 127. 
    Herat LY, Magno AL, Rudnicka C, Hricova J, Carnagarin R et al. 2020. SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl. Sci. 5:169–79
    [Google Scholar]
  128. 128. 
    Jordan J, Tank J, Heusser K, Heise T, Wanner C et al. 2017. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J. Am. Soc. Hypertens. 11:604–12
    [Google Scholar]
  129. 129. 
    Garg V, Verma S, Connelly KA, Yan AT, Sikand A et al. 2020. Does empagliflozin modulate the autonomic system among patients with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis. Metab. Open 7:100039
    [Google Scholar]
  130. 130. 
    Chiba Y, Yamada T, Tsukita S, Takahashi K, Munakata Y et al. 2016. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PLOS ONE 11:e0150756
    [Google Scholar]
  131. 131. 
    Bohm M, Slawik J, Brueckmann M, Mattheus M, George JT et al. 2020. Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: data from the EMPA-REG OUTCOME trial. Eur. J. Heart Fail. 22:126–35
    [Google Scholar]
  132. 132. 
    Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT et al. 2018. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 61:722–26
    [Google Scholar]
  133. 133. 
    Iborra-Egea O, Santiago-Vacas E, Yurista SR, Lupon J, Packer M et al. 2019. Unraveling the molecular mechanism of action of empagliflozin in heart failure with reduced ejection fraction with or without diabetes. JACC Basic Transl. Sci. 4:831–40
    [Google Scholar]
  134. 134. 
    Byrne NJ, Matsumura N, Maayah ZH, Ferdaoussi M, Takahara S et al. 2020. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ. Heart Fail. 13:e006277
    [Google Scholar]
  135. 135. 
    Byrne NJ, Soni S, Takahara S, Ferdaoussi M, Al Batran R et al. 2020. Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart failure. Circ. Heart Fail. 13: https://doi.org/10.1161/CIRCHEARTFAILURE.119.006573
    [Crossref] [Google Scholar]
  136. 136. 
    Kang S, Verma S, Hassanabad AF, Teng G, Belke DD et al. 2020. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results. Can. J. Cardiol.543–53
    [Google Scholar]
  137. 137. 
    Byrne NJ, Parajuli N, Levasseur JL, Boisvenue J, Beker D et al. 2017. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. JACC Basic Transl. Sci. 2:347–54
    [Google Scholar]
  138. 138. 
    Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN et al. 2019. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic Transl. Sci. 4:27–37
    [Google Scholar]
  139. 139. 
    Verma S, Mazer CD, Bhatt DL, Raj SR, Yan AT et al. 2019. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and left ventricular hypertrophy: a subanalysis of the EMPA-REG OUTCOME trial. Diabetes Care 42:e42–44
    [Google Scholar]
  140. 140. 
    Kumar N, Garg A, Bhatt DL, Sabongui S, Gupta N et al. 2018. Empagliflozin improves cardiorespiratory fitness in type 2 diabetes: translational implications. Can. J. Physiol. Pharmacol. 96:1184–87
    [Google Scholar]
  141. 141. 
    Verma S, Mazer CD, Yan AT, Mason T, Garg V et al. 2019. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation 140:1693–702
    [Google Scholar]
  142. 142. 
    Bami K, Gandhi S, Leong-Poi H, Yan AT, Ho E et al. 2020. Effects of empagliflozin on left ventricular remodeling in patients with type 2 diabetes and coronary artery disease: echocardiographic substudy of the EMPA-HEART CardioLink-6 randomized clinical trial. J. Am. Soc. Echocardiogr. 33:64446
    [Google Scholar]
  143. 143. 
    Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M et al. 2016. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: An important clue to the EMPA-REG OUTCOME trial. Diabetes Care 39:e212–13
    [Google Scholar]
  144. 144. 
    Verma S, Maitland A, Weisel RD, Li SH, Fedak PW et al. 2002. Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism. J. Thorac. Cardiovasc. Surg. 123:1120–24
    [Google Scholar]
  145. 145. 
    Connelly KA, Yan AT, Leiter LA, Bhatt DL, Verma S 2015. Cardiovascular implications of hypoglycemia in diabetes mellitus. Circulation 132:2345–50
    [Google Scholar]
  146. 146. 
    Verma S, Mazer CD, Bhatt DL 2018. The perils of polyvascular disease in type 2 diabetes. Lancet Diabetes Endocrinol 6:914–16
    [Google Scholar]
  147. 147. 
    Chowdhury B, Luu AZ, Luu VZ, Kabir MG, Pan Y et al. 2020. The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension. Biochem. Biophys. Res. Commun. 524:50–56
    [Google Scholar]
  148. 148. 
    Cooper S, Teoh H, Campeau MA, Verma S, Leask RL 2019. Empagliflozin restores the integrity of the endothelial glycocalyx in vitro. Mol. Cell. Biochem. 459:121–30
    [Google Scholar]
  149. 149. 
    Cherney DZI, Perkins BA, Soleymanlou N, Har R, Fagan 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
    [Google Scholar]
  150. 150. 
    Pfeifer M, Townsend RR, Davies MJ, Vijapurkar U, Ren J 2017. Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc. Diabetol. 16:29
    [Google Scholar]
  151. 151. 
    Mancini SJ, Boyd D, Katwan OJ, Strembitska A, Almabrouk TA et al. 2018. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci. Rep. 8:5276
    [Google Scholar]
  152. 152. 
    Behnammanesh G, Durante ZE, Peyton KJ, Martinez-Lemus LA, Brown SM et al. 2019. Canagliflozin inhibits human endothelial cell proliferation and tube formation. Front. Pharmacol. 10:362
    [Google Scholar]
  153. 153. 
    Tanaka A, Shimabukuro M, Machii N, Teragawa H, Okada Y et al. 2019. Effect of empagliflozin on endothelial function in patients with type 2 diabetes and cardiovascular disease: results from the multicenter, randomized, placebo-controlled, double-blind EMBLEM trial. Diabetes Care 42:e159–61
    [Google Scholar]
  154. 154. 
    Sanchez RA, Sanchez MJ, Ramirez AJ 2018. Canagliflozin ameliorates arterial stiffness by reducing serum uric acid in type 2 diabetic patients. Diabetes 67:Suppl. 11216–P (Abstr.)
    [Google Scholar]
  155. 155. 
    Verma S, Ji Q, Bhatt DL, Mazer CD, Al-Omran M et al. 2020. The association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA-REG OUTCOME. Diabetes Obes. Metab. 22:1207–14
    [Google Scholar]
  156. 156. 
    Sherman SE, Bell GI, Teoh H, Al-Omran M, Connelly KA et al. 2018. Canagliflozin improves the recovery of blood flow in an experimental model of severe limb ischemia. JACC Basic Transl. Sci. 3:327–29
    [Google Scholar]
  157. 157. 
    Striepe K, Jumar A, Ott C, Karg MV, Schneider MP et al. 2017. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation 136:1167–69
    [Google Scholar]
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