Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

Nutrition, Metabolism and Cardiovascular Diseases

Volumn 30, Issue 10, 2020, Pages 1622-1632

  Sarzani, Riccardo ^a,b   Giulietti, Federico ^a,b   Di Pentima, Chiara ^a,b   Spannella, Francesco ^a,b  

^a INRCA   (Italy)

^b UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

Author keywords

Cardiovascular disease; Diuretics; Heart failure; Natriuresis; Renal protection; Sodium glucose co transporter 2 inhibitors; Tubule glomerular feedback

Indexed keywords

DIURETIC AGENT; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; THIAZIDE DIURETIC AGENT; BIOLOGICAL MARKER;

ARTERIOLE; BLOOD PRESSURE; BLOOD VOLUME; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; GLUCOSURIA; HEART FAILURE; HEMODYNAMICS; HUMAN; KIDNEY FUNCTION; NATRIURESIS; OSMOTIC DIURESIS; PRIORITY JOURNAL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RENIN RELEASE; REVIEW; ADVERSE EVENT; BLOOD; DIABETIC NEPHROPATHY; DRUG EFFECT; GLUCOSE BLOOD LEVEL; KIDNEY PROXIMAL TUBULE; METABOLISM; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOPHYSIOLOGY; PROTECTION; RISK FACTOR; TREATMENT OUTCOME;

BIOMARKERS; BLOOD GLUCOSE; BLOOD PRESSURE; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DIABETIC NEPHROPATHIES; DIURETICS; HUMANS; KIDNEY TUBULES, PROXIMAL; PROTECTIVE FACTORS; RISK FACTORS; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TREATMENT OUTCOME;

EID: 85087304746     PISSN: 09394753     EISSN: 15903729     Source Type: Journal    
DOI: 10.1016/j.numecd.2020.05.030     Document Type: Review

References (113)

1. Cosentino, F., Grant, P.J., Aboyans, V., Bailey, C.J., Ceriello, A., Delgado, V., et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 41 (2020), 255–323.
2. Buse, J.B., Wexler, D.J., Tsapas, A., Rossing, P., Mingrone, G., Mathieu, C., et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 63 (2020), 221–228.
3. 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.
4. Neal, B., Perkovic, V., Mahaffey, K.W., de Zeeuw, D., Fulcher, G., Erondu, N., et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377 (2017), 644–657.
5. Wiviott, S.D., Raz, I., Bonaca, M.P., Mosenzon, O., Kato, E.T., Cahn, A., et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380 (2019), 347–357.
6. Neuen, B.L., Young, T., Heerspink, H.J.L., Neal, B., Perkovic, V., Billot, L., et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 7 (2019), 845–854.
7. Rahmoune, H., Thompson, P.W., Ward, J.M., Smith, C.D., Hong, G., Brown, J., Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54 (2005), 3427–3434.
8. Norton, L., Shannon, C.E., Fourcaudot, M., Hu, C., Wang, N., Ren, W., et al. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects. Diabetes Obes Metabol 19 (2017), 1322–1326.
9. Brown, E., Rajeev, S.P., Cuthbertson, D.J., Wilding, J.P.H., A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors. Diabetes. Obes Metabol 21:Suppl 2 (2019), 9–18.
10. Napolitano, A., Miller, S., Murgatroyd, P.R., Hussey, E., Dobbins, R.L., Bullmore, E.T., et al. Exploring glycosuria as a mechanism for weight and fat mass reduction. A pilot study with remogliflozin etabonate and sergliflozin etabonate in healthy obese subjects. J Clinic Transl Endocrinol 1 (2014), e3–e8.
11. Silva Dos Santos, D., Polidoro, J.Z., Borges Junior, F.A., Girardi, A.C.C., Cardioprotection conferred by SGLT2 inhibitors: a renal proximal tubule perspective. Am J Physiol Cell Physiol, 2019.
12. Lambers Heerspink, H.J., de Zeeuw, D., Wie, L., Leslie, B., List, J., Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metabol 15 (2013), 853–862.
13. Tanaka, H., Takano, K., Iijima, H., Kubo, H., Maruyama, N., Hashimoto, T., et al. Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther 34 (2017), 436–451.
14. Masuda, T., Muto, S., Fukuda, K., Watanabe, M., Ohara, K., Koepsell, H., et al. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol Rep, 8, 2020, e14360.
15. Rajasekeran, H., Lytvyn, Y., Bozovic, A., Lovshin, J.A., Diamandis, E., Cattran, D., et al. Urinary adenosine excretion in type 1 diabetes. Am J Physiol Ren Physiol 313 (2017), F184–F191.
16. Skrtic, M., Yang, G.K., Perkins, B.A., Soleymanlou, N., Lytvyn, Y., von Eynatten, M., et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia 57 (2014), 2599–2602.
17. Cherney, D.Z., Perkins, B.A., Soleymanlou, N., Maione, M., Lai, V., Lee, A., et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129 (2014), 587–597.
18. van Baar, M.J.B., Scholtes, R.A., van Raalte, D.H., SGLT2 inhibitors' interaction with other renoactive drugs in type 2 diabetes patients: still a lot to learn. Kidney Int 96 (2019), 283–286.
19. Kidokoro, K., Cherney, D.Z.I., Bozovic, A., Nagasu, H., Satoh, M., Kanda, E., et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation 140 (2019), 303–315.
20. van Bommel, E.J.M., Muskiet, M.H.A., van Baar, M.J.B., Tonneijck, L., Smits, M.M., Emanuel, A.L., et al. 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, 2019.
21. Spannella, F., Giulietti, F., Balietti, P., Borioni, E., Lombardi, F.E., Ricci, M., et al. Plasma renin activity to plasma aldosterone concentration ratio correlates with night-time and pulse pressures in essential hypertensive patients treated with angiotensin-converting enzyme inhibitors/AT1 blockers. J Hypertens 35 (2017), 2315–2322.
22. Schork, A., Saynisch, J., Vosseler, A., Jaghutriz, B.A., Heyne, N., Peter, A., et al. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol, 18, 2019, 46.
23. Sha, S., Polidori, D., Heise, T., Natarajan, J., Farrell, K., Wang, S.S., et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metabol 16 (2014), 1087–1095.
24. Ansary, T.M., Nakano, D., Nishiyama, A., Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the renin-angiotensin system. Int J Mol Sci, 20, 2019.
25. Shin, S.J., Chung, S., Kim, S.J., Lee, E.M., Yoo, Y.H., Kim, J.W., et al. Effect of sodium-glucose Co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PloS One, 11, 2016, e0165703.
26. Li, L., Konishi, Y., Morikawa, T., Zhang, Y., Kitabayashi, C., Kobara, H., et al. Effect of a SGLT2 inhibitor on the systemic and intrarenal renin-angiotensin system in subtotally nephrectomized rats. J Pharmacol Sci 137 (2018), 220–223.
27. Satou, R., Cypress, M.W., Woods, T.C., Katsurada, A., Dugas, C.M., Fonseca, V.A., et al. Blockade of sodium-glucose cotransporter 2 suppresses high glucose-induced angiotensinogen augmentation in renal proximal tubular cells. Am J Physiol Ren Physiol 318 (2020), F67–F75.
28. Mullens, W., Damman, K., Harjola, V.P., Mebazaa, A., Brunner-La Rocca, H.P., Martens, P., et al. The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 21 (2019), 137–155.
29. Mayer, G.J., Wanner, C., Weir, M.R., Inzucchi, S.E., Koitka-Weber, A., Hantel, S., et al. Analysis from the EMPA-REG OUTCOME((R)) trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int 96 (2019), 489–504.
30. Wan, N., Rahman, A., Hitomi, H., Nishiyama, A., The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol, 9, 2018, 421.
31. Matthews, V.B., Elliot, R.H., Rudnicka, C., Hricova, J., Herat, L., Schlaich, M.P., Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens 35 (2017), 2059–2068.
32. Solomon, S.D., Vaduganathan, M., C, B.L., Packer, M., Zile, M., Swedberg, K., et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation 141 (2020), 352–361.
33. Vives, D., Farage, S., Motta, R., Lopes, A.G., Caruso-Neves, C., Atrial natriuretic peptides and urodilatin modulate proximal tubule Na(+)-ATPase activity through activation of the NPR-A/cGMP/PKG pathway. Peptides 31 (2010), 903–908.
34. Spannella, F., Marini, M., Giulietti, F., Rosettani, G., Francioni, M., Perna, G.P., et al. Renal effects of Sacubitril/Valsartan in heart failure with reduced ejection fraction: a real life 1-year follow-up study. Intern Emerg Med 14 (2019), 1287–1297.
35. Mazidi, M., Rezaie, P., Gao, H.K., Kengne, A.P., Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc, 6, 2017.
36. Ettehad, D., Emdin, C.A., Kiran, A., Anderson, S.G., Callender, T., Emberson, J., et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 387 (2016), 957–967.
37. Baker, W.L., Buckley, L.F., Kelly, M.S., Bucheit, J.D., Parod, E.D., Brown, R., et al. Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc, 6, 2017.
38. Mancia, G., Cannon, C.P., Tikkanen, I., Zeller, C., Ley, L., Woerle, H.J., et al. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension 68 (2016), 1355–1364.
39. Kario, K., Okada, K., Kato, M., Nishizawa, M., Yoshida, T., Asano, T., et al. 24-Hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study. Circulation, 2018.
40. Salles, G.F., Reboldi, G., Fagard, R.H., Cardoso, C.R., Pierdomenico, S.D., Verdecchia, P., et al. Prognostic effect of the nocturnal blood pressure fall in hypertensive patients: the ambulatory blood pressure collaboration in patients with hypertension (ABC-H) meta-analysis. Hypertension 67 (2016), 693–700.
41. Fedecostante, M., Spannella, F., Giulietti, F., Espinosa, E., Dessi-Fulgheri, P., Sarzani, R., Associations between body mass index, ambulatory blood pressure findings, and changes in cardiac structure: relevance of pulse and nighttime pressures. J Clin Hypertens 17 (2015), 147–153.
42. Georgianos, P.I., Agarwal, R., Ambulatory blood pressure reduction with SGLT-2 inhibitors: dose-response meta-analysis and comparative evaluation with low-dose hydrochlorothiazide. Diabetes Care 42 (2019), 693–700.
43. Ferdinand, K.C., Izzo, J.L., Lee, J., Meng, L., George, J., Salsali, A., et al. Antihyperglycemic and blood pressure effects of empagliflozin in black patients with type 2 diabetes mellitus and hypertension. Circulation 139 (2019), 2098–2109.
44. Kohan, D.E., Fioretto, P., Tang, W., List, J.F., Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85 (2014), 962–971.
45. Kawasoe, S., Maruguchi, Y., Kajiya, S., Uenomachi, H., Miyata, M., Kawasoe, M., et al. Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes. BMC Pharmacol Toxicol, 18, 2017, 23.
46. Simmonds, S.S., Lay, J., Stocker, S.D., Dietary salt intake exaggerates sympathetic reflexes and increases blood pressure variability in normotensive rats. Hypertension 64 (2014), 583–589.
47. Bordicchia, M., Ceresiani, M., Pavani, M., Minardi, D., Polito, M., Wabitsch, M., et al. Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway. Am J Physiol Regul Integr Comp Physiol 311 (2016), R104–R114.
48. Santos-Gallego, C.G., Requena-Ibanez, J.A., San Antonio, R., Ishikawa, K., Watanabe, S., Picatoste, B., et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 73 (2019), 1931–1944.
49. Cherney, D.Z., Perkins, B.A., Soleymanlou, N., Har, R., Fagan, N., Johansen, O.E., et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol, 13, 2014, 28.
50. Shigiyama, F., Kumashiro, N., Miyagi, M., Ikehara, K., Kanda, E., Uchino, H., et al. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc Diabetol, 16, 2017, 84.
51. Webster, A.C., Nagler, E.V., Morton, R.L., Masson, P., Chronic kidney disease. Lancet 389 (2017), 1238–1252.
52. Neuen, B.L., Ohkuma, T., Neal, B., Matthews, D.R., de Zeeuw, D., Mahaffey, K.W., et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation 138 (2018), 1537–1550.
53. Wanner, C., Inzucchi, S.E., Lachin, J.M., Fitchett, D., von Eynatten, M., Mattheus, M., et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375 (2016), 323–334.
54. Perkovic, V., Jardine, M.J., Neal, B., Bompoint, S., Heerspink, H.J.L., Charytan, D.M., et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380 (2019), 2295–2306.
55. Cannon, C.P., Perkovic, V., Agarwal, R., Baldassarre, J., Bakris, G., Charytan, D.M., et al. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE trial. Circulation 141 (2020), 407–410.
56. Lewis, E.J., Hunsicker, L.G., Clarke, W.R., Berl, T., Pohl, M.A., Lewis, J.B., et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345 (2001), 851–860.
57. Heerspink, H.J.L., Karasik, A., Thuresson, M., Melzer-Cohen, C., Chodick, G., Khunti, K., et al. Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study. Lancet Diabetes Endocrinol 8 (2020), 27–35.
58. Fioretto, P., Del Prato, S., Buse, J.B., Goldenberg, R., Giorgino, F., Reyner, D., et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): the DERIVE Study. Diabetes Obes Metabol 20 (2018), 2532–2540.
59. Cherney, D.Z.I., Zinman, B., Inzucchi, S.E., Koitka-Weber, A., Mattheus, M., von Eynatten, M., et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 5 (2017), 610–621.
60. Heerspink, H.J.L., Perco, P., Mulder, S., Leierer, J., Hansen, M.K., Heinzel, A., et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia 62 (2019), 1154–1166.
61. Lee, Y.H., Kim, S.H., Kang, J.M., Heo, J.H., Kim, D.J., Park, S.H., et al. Empagliflozin attenuates diabetic tubulopathy by improving mitochondrial fragmentation and autophagy. Am J Physiol Ren Physiol 317 (2019), F767–F780.
62. Herrington, W.G., Preiss, D., Haynes, R., von Eynatten, M., Staplin, N., Hauske, S.J., et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J 11 (2018), 749–761.
63. Pecoits-Filho, R., Perkovic, V., Are SGLT2 inhibitors ready for prime time for CKD?. Clin J Am Soc Nephrol: CJASN 13 (2018), 318–320.
64. Zelniker, T.A., Wiviott, S.D., Raz, I., Im, K., Goodrich, E.L., Bonaca, M.P., et al. 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 (2019), 31–39.
65. Guo, M., Ding, J., Li, J., Wang, J., Zhang, T., Liu, C., et al. SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metabol 20 (2018), 1977–1982.
66. Zhou, Z., Lindley, R.I., Radholm, K., Jenkins, B., Watson, J., Perkovic, V., et al. Canagliflozin and stroke in type 2 diabetes mellitus. Stroke 50 (2019), 396–404.
67. Mishriky, B.M., Powell, J.R., Wittwer, J.A., Chu, J.X., Sewell, K.A., Wu, Q., et al. Do GLP-1RAs and SGLT-2is reduce cardiovascular events in black patients with type 2 diabetes? A systematic review and meta-analysis. Diabetes Obes Metabol 21 (2019), 2274–2283.
68. Mahaffey, K.W., Jardine, M.J., Bompoint, S., Cannon, C.P., Neal, B., Heerspink, H.J.L., et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 140 (2019), 739–750.
69. Furtado, R.H.M., Bonaca, M.P., Raz, I., Zelniker, T.A., Mosenzon, O., Cahn, A., et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation 139 (2019), 2516–2527.
70. Sano, M., Goto, S., Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139 (2019), 1985–1987.
71. Mazer, C.D., Hare, G.M.T., Connelly, P.W., Gilbert, R.E., Shehata, N., Quan, A., et al. Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease. Circulation, 2019.
72. Ghanim, H., Abuaysheh, S., Hejna, J., Green, K., Batra, M., Makdissi, A., et al. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metabol, 2020.
73. Inzucchi, S.E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41 (2018), 356–363.
74. Lega, I.C., Bronskill, S.E., Campitelli, M.A., Guan, J., Stall, N.M., Lam, K., et al. Sodium glucose cotransporter 2 inhibitors and risk of genital mycotic and urinary tract infection: a population-based study of older women and men with diabetes. Diabetes Obes Metabol 21 (2019), 2394–2404.
75. McGill, J.B., Subramanian, S., Safety of sodium-glucose Co-transporter 2 inhibitors. Am J Cardiol 124:Suppl 1 (2019), S45–S52.
76. Ryan, P.B., Buse, J.B., Schuemie, M.J., DeFalco, F., Yuan, Z., Stang, P.E., et al. Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metabol 20 (2018), 2585–2597.
77. Zelniker, T.A., Wiviott, S.D., Raz, I., Im, K., Goodrich, E.L., Furtado, R.H.M., et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 139 (2019), 2022–2031.
78. Butler, J., Packer, M., Greene, S.J., Fiuzat, M., Anker, S.D., Anstrom, K.J., et al. Heart failure end points in cardiovascular outcome trials of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a critical evaluation of clinical and regulatory issues. Circulation 140 (2019), 2108–2118.
79. McMurray, J.J.V., Solomon, S.D., Inzucchi, S.E., Kober, L., Kosiborod, M.N., Martinez, F.A., et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381 (2019), 1995–2008.
80. Nassif, M.E., Windsor, S.L., Tang, F., Khariton, Y., Husain, M., Inzucchi, S.E., et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation 140 (2019), 1463–1476.
81. Kosiborod, M.N., Jhund, P., Docherty, K.F., Diez, M., Petrie, M.C., Verma, S., et al. 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, 2019.
82. Lewis, E.F., Claggett, B.L., McMurray, J.J.V., Packer, M., Lefkowitz, M.P., Rouleau, J.L., et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail, 10, 2017.
83. Martinez, F.A., Serenelli, M., Nicolau, J.C., Petrie, M.C., Chiang, C.E., Tereshchenko, S., et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation, 2019.
84. Rieg, T., Masuda, T., Gerasimova, M., Mayoux, E., Platt, K., Powell, D.R., et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Ren Physiol 306 (2014), F188–F193.
85. Spannella, F., Giulietti, F., Balietti, P., Cocci, G., Landi, L., Lombardi, F.E., et al. Renin-angiotensin system blockers and statins are associated with lower in-hospital mortality in very elderly hypertensives. J Am Med Dir Assoc 19 (2018), 342–347.
86. Matsumura, K., Sugiura, T., Effect of sodium glucose cotransporter 2 inhibitors on cardiac function and cardiovascular outcome: a systematic review. Cardiovasc Ultrasound, 17, 2019, 26.
87. Pabel, S., Wagner, S., Bollenberg, H., Bengel, P., Kovacs, A., Schach, C., et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail 20 (2018), 1690–1700.
88. Verma, S., Mazer, C.D., Yan, A.T., Mason, T., Garg, V., Teoh, H., et al. 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 (2019), 1693–1702.
89. Zelniker, T.A., Braunwald, E., Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol 75 (2020), 422–434.
90. Hallow, K.M., Helmlinger, G., Greasley, P.J., McMurray, J.J.V., Boulton, D.W., Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metabol 20 (2018), 479–487.
91. Karg, M.V., Bosch, A., Kannenkeril, D., Striepe, K., Ott, C., Schneider, M.P., et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol, 17, 2018, 5.
92. Cherney, D.Z., Odutayo, A., Aronson, R., Ezekowitz, J., Parker, J.D., Sodium glucose cotransporter-2 inhibition and cardiorenal protection: JACC review topic of the week. J Am Coll Cardiol 74 (2019), 2511–2524.
93. Wakisaka, M., Kamouchi, M., Kitazono, T., Lessons from the trials for the desirable effects of sodium glucose Co-transporter 2 inhibitors on diabetic cardiovascular events and renal dysfunction. Int J Mol Sci, 20, 2019.
94. Kato, E.T., Silverman, M.G., Mosenzon, O., Zelniker, T.A., Cahn, A., Furtado, R.H.M., et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 139 (2019), 2528–2536.
95. Meems, L.M.G., Burnett, J.C. Jr., Innovative therapeutics: designer natriuretic peptides. JACC Basic Transl Sci 1 (2016), 557–567.
96. Seferovic, P.M., Ponikowski, P., Anker, S.D., Bauersachs, J., Chioncel, O., Cleland, J.G.F., et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 21 (2019), 1169–1186.
97. Uthman, L., Nederlof, R., Eerbeek, O., Baartscheer, A., Schumacher, C., Buchholtz, N., et al. Delayed ischaemic contracture onset by empagliflozin associates with NHE1 inhibition and is dependent on insulin in isolated mouse hearts. Cardiovasc Res 115 (2019), 1533–1545.
98. Ye, Y., Bajaj, M., Yang, H.C., Perez-Polo, J.R., Birnbaum, Y., SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther 31 (2017), 119–132.
99. Mustroph, J., Wagemann, O., Lucht, C.M., Trum, M., Hammer, K.P., Sag, C.M., et al. Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes. ESC Heart Fail 5 (2018), 642–648.
100. Ferrannini, E., Baldi, S., Frascerra, S., Astiarraga, B., Heise, T., Bizzotto, R., et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65 (2016), 1190–1195.
101. Solini, A., Seghieri, M., Giannini, L., Biancalana, E., Parolini, F., Rossi, C., et al. The effects of dapagliflozin on systemic and renal vascular function display an epigenetic signature. J Clin Endocrinol Metabol 104 (2019), 4253–4263.
102. Braunwald, E., Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis 62 (2019), 298–302.
103. Bonnet, F., Scheen, A.J., Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease. Diabetes Metabol 44 (2018), 457–464.
104. El-Daly, M., Pulakazhi Venu, V.K., Saifeddine, M., Mihara, K., Kang, S., Fedak, P.W.M., et al. Hyperglycaemic impairment of PAR2-mediated vasodilation: prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress. Vasc Pharmacol 109 (2018), 56–71.
105. Sato, T., Aizawa, Y., Yuasa, S., Kishi, S., Fuse, K., Fujita, S., et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol, 17, 2018, 6.
106. Hess, D.A., Terenzi, D.C., Trac, J.Z., Quan, A., Mason, T., Al-Omran, M., et al. SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metabol 30 (2019), 609–613.
107. Vergara, A., Jacobs-Cacha, C., Soler, M.J., Sodium-glucose cotransporter inhibitors: beyond glycaemic control. Clin Kidney J 12 (2019), 322–325.
108. Woods, T.C., Satou, R., Miyata, K., Katsurada, A., Dugas, C.M., Klingenberg, N.C., et al. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol 49 (2019), 331–342.
109. Shibusawa, R., Yamada, E., Okada, S., Nakajima, Y., Bastie, C.C., Maeshima, A., et al. Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death. Sci Rep, 9, 2019, 9887.
110. Novikov, A., Fu, Y., Huang, W., Freeman, B., Patel, R., van Ginkel, C., et al. SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Ren Physiol 316 (2019), F173–F185.
111. Evans, M., Morgan, A.R., Yousef, Z., What next after metformin? Thinking beyond glycaemia: are SGLT2 inhibitors the answer? Diabetes therapy : research, treatment and education of diabetes and related disorders., 10, 2019, 1719–1731.
112. Cherney, D.Z.I., Cooper, M.E., Tikkanen, I., Pfarr, E., Johansen, O.E., Woerle, H.J., et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 93 (2018), 231–244.
113. Latva-Rasku, A., Honka, M.J., Kullberg, J., Mononen, N., Lehtimaki, T., Saltevo, J., et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care 42 (2019), 931–937.