Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: A systematic review of data from preclinical studies

Cardiovascular Research

Volumn 115, Issue 2, 2019, Pages 266-276

  Chin, Ken Lee ^a   Ofori Asenso, Richard ^a   Hopper, Ingrid ^a   Von Lueder, Thomas G ^a,b   Reid, Christopher M ^a,c   Zoungas, Sophia ^a,d   Wang, Bing H ^a   Liew, Danny ^a  

^a MONASH UNIVERSITY   (Australia)

^b OSLO UNIVERSITY HOSPITAL   (Norway)

^c CURTIN UNIVERSITY   (Australia)

^d GEORGE INSTITUTE FOR GLOBAL HEALTH   (Australia)

Author keywords

Cardiovascular diseases; Preclinical; Sodium glucose cotransporter 2 inhibitors; Systematic review

Indexed keywords

NATRIURETIC FACTOR; NEUROHORMONE; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; STAT3 PROTEIN;

ADRENERGIC SYSTEM; APOPTOSIS; ATHEROSCLEROSIS; BLOOD PRESSURE; CELL ADHESION; CIRCADIAN RHYTHM; DIABETES MELLITUS; ENDOPLASMIC RETICULUM STRESS; FATTY ACID OXIDATION; GLUCOSE TRANSPORT; GLYCEMIC CONTROL; HEART FUNCTION; HEART PROTECTION; HUMAN; INFLAMMATION; ION EXCHANGE; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SYMPATHETIC TONE; SYSTEMATIC REVIEW; VASODILATATION; ANIMAL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR SYSTEM; DRUG EFFECT; METABOLISM; PATHOPHYSIOLOGY; PHARMACOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; SIGNAL TRANSDUCTION; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS;

EID: 85060373069     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvy295     Document Type: Review

References (73)

1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657.
3. Raz I, Wiviott SD. Dapagliflozin Effect on Cardiovascular Events. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients with Type 2 Diabetes. https: //clin icaltrials. gov/ct2/show/NCT01730534? term=DECLARE-TIMI&rank=1 (19 April 2018, date last accessed).
4. Ghosh RK, Bandyopadhyay D, Hajra A, Biswas M, Gupta A. Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: a comprehensive review of clinical and preclinical studies. Int J Cardiol 2016; 212: 29-36.
5. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P; on behalf of the CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017; 136: 249-259.
6. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol 2017; 120: S28-S36.
7. Wu JHY, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, Neal B. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and metaanalysis. Lancet Diabetes Endocrinol 2016; 4: 411-419.
8. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, Al-Ani M, Mentias A, Nairooz R, Bavry AA, Mukherjee D. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol 2017; 228: 352-358.
9. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA Statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: W-65-W-94.
10. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Ann Intern Med 2009; 151: 264-269.
11. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. Osteoarthritis Cartilage 2012; 20: 256-260.
12. Sena ES, Currie GL, McCann SK, Macleod MR, Howells DW. Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically. J Cereb Blood Flow Metab 2014; 34: 737-742.
13. Abu Seif AM, Sharaf HH, Awad AY, El-Kotby HM. Efficacy and safety of canagliflozin compared to vildagliptin in treatment of experimentally induced diabetes in albino rats. Diabetic Medicine 2017; 34: 80.
14. Azuma K, Kawamori R, Toyofuku Y, Kitahara Y, Sato F, Shimizu T, Miura K, Mine T, Tanaka Y, Mitsumata M, Watada H. Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arterioscler Thromb Vasc Biol 2006; 26: 2275-2280.
15. Banerjee SK, McGaffin KR, Wang D, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucose transporter that contributes critically to the pathophysiology of heart disease. J Mol Cell Cardiol 2009; 1: S9-S10.
16. Chan JSD, Chenier I, Ghosh A, Wu CH, Lo CS, Zhao S, Chiasson JL, Filep JG, Ingelfinger JR, Zhang SL. Canagliflozin, a sodium-glucose co-transporter 2 (SGLT-2) blocker, normalizes blood glucose without affecting systemic blood pressure, oxidative stress, intrarenal angiotensinogen gene expression and kidney injury in type 1 diabetic mice. Nephrol Dial Transplant 2016; 31: i214.
17. Demarco VG, Aroor AR, Nistala R, Garro M, Mayoux EW, Whaley-Connell A, Sowers JR. Sodium glucose transporter type 2 (SGLT2) inhibitor, empagliflozin, improves diastolic function in female diabetic DB/DB mice. Diabetes 2015; 64: A552.
18. Di Franco A, Cantini G, Raimondi L, Mannucci E, Luconi M. The sodium-dependent glucose transporters (SGLT) as a new promising pharmacological target in human ischaemic hearts. Diabetologia 2017; 60 (1 Suppl 1): S424.
19. Elliott RH, Matthews VB, Rudnicka C, Schlaich MP. Is it time to think about the sodium glucose co-transporter 2 sympathetically? Nephrology 2016; 21: 286-294.
20. European Medicines Agency. Assessment Report. Forxiga. Dapagliflozin. London: European Medicines Agency; 2012. http: //www. ema. europa. eu/docs/en-GB/docu ment-library/EPAR-Public-assessment-report/human/002322/WC500136024. pdf (30 January 2018, date last accessed).
21. European Medicines Agency. Assessment Report. Jardiance. International Non-proprietary Name: Empagliflozin. London: European Medicines Agency; 2014. http: //www. ema. eu ropa. eu/docs/en-GB/document-library/EPAR-Public-assessment-report/human/ 002677/WC500168594. pdf (30 January 2018, date last accessed).
22. European Medicines Agency. Assessment Report. Canagliflozin. International Nonproprietary Name: Canagliflozin. London: European Medicines Agency; 2013. http: // www. ema. europa. eu/docs/en-GB/document-library/EPAR-Public-assessment-report/ human/002649/WC500156457. pdf (30 January 2018, date last accessed).
23. Gerasimova M, Rose M, Koepsell H, Masuda T, Mayoux E, Thomson S, Rieg T, Vallon V. What makes SGLT2 inhibition so effective in lowering blood glucose in diabetes? FASEB J 2014; 28(1 Suppl 1).
24. Hamouda NN, Sydorenko V, Qureshi MA, Alkaabi JM, Oz M, Howarth FC. Dapagliflozin reduces the amplitude of shortening and Ca(2) transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem 2015; 400: 57-68.
25. Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, Choi SH, Jang HC, Lee HS, Park KS, Kim YB, Lim S. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE-/-mice fed a western diet. Diabetologia 2017; 60: 364-376.
26. Han Y, Cho YE, Ayon R, Guo R, Youssef KD, Pan M, Dai A, Yuan JXJ, Makino A. SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol 2015; 309: L1027-L1036.
27. Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, Dollet L, Le May C, Toumaniantz G, Manrique A, Charpentier F, Staels B, Magré J, Cariou B, Prieur X. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes 2017; 66: 1030-1040.
28. Kamihara T, Bando YK, Nishiura K, Yasheng R, Kawase H, Murohara T. Impact of SGLT2 inhibitor on diabetic cardiomyopathy-role of glucagon-insulin axis. J Card Fail 2017; 23 (10 Suppl 1): S55-S56.
29. Kashiwagi Y, Nagoshi T, Yoshino T, Tanaka TD, 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.
30. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 2017; 104: 298-310.
31. Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Nakagawa T, Kusaka H, Kim-Mitsuyama S. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 2014; 13: 148.
32. Oelze M, Kröller-Schön S, Welschof P, Jansen T, Hausding M, Mikhed Y, Stamm P, Mader M, Zinßius E, Agdauletova S, Gottschlich A, Steven S, Schulz E, Bottari SP, Mayoux E, Münzel T, Daiber A. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One 2014; 9: e112394.
33. Pharmaceuticals and Medical Devices Agency. Report on the Deliberation Results. Dapagliflozin. Tokyo: Pharmaceuticals and Medical Devices Agency; 2014. http: //www. pmda. go. jp/files/000210230. pdf (30 January 2018, date last accessed).
34. Pharmaceuticals and Medical Devices Agency. Report on the Deliberation Results. Ipragliflozin. Tokyo: Pharmaceuticals and Medical Devices Agency; 2013. http: //www. pmda. go. jp/files/000206796. pdf (30 January 2018, date last accessed).
35. Rahman A, Fujisawa Y, Nakano D, Hitomi H, Nishiyama A. Effect of a selective SGLT2 inhibitor, luseogliflozin, on circadian rhythm of sympathetic nervous function and locomotor activities in metabolic syndrome rats. Clin Exp Pharmacol Physiol 2017; 44: 522-525.
36. Rahman A, Kittikulsuth W, Fujisawa Y, Sufiun A, Rafiq K, Hitomi H, Nakano D, Sohara E, Uchida S, Nishiyama A. Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome. J Hypertens 2016; 34: 893-906.
37. Shi X, Verma S, Yun J, Brand-Arzamendi K, Singh KK, Liu X, Garg A, Quan A, Wen XY. Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial? Mol Cell Biochem 2017; 433: 97-102.
38. Sowers J, Aroor A, Jia G, Nistala R, Garro M, Meininger G, Martinez-Lemus L, Mayoux E, Whaley-Connell A, DeMarco VG. Sodium glucose transporter type-2 (SGLT-2) inhibitor, empagliflozin, improves cardiovascular outcomes in female diabetic db/db mice independent of blood pressure reduction. Hypertension 2015; 66: AP233.
39. Takeshige Y, Fujisawa Y, Rahman A, Kittikulsuth W, Nakano D, Mori H, Masaki T, Ohmori K, Kohno M, Ogata H, Nishiyama A. A sodium-glucose co-transporter 2 inhibitor empagliflozin prevents abnormality of circadian rhythm of blood pressure in salt-treated obese rats. Hypertens Res 2016; 39: 415-422.
40. Terasaki M, Hiromura M, Mori Y, Kohashi K, Nagashima M, Kushima H, Watanabe T, Hirano T. Amelioration of hyperglycemia with a sodium-glucose cotransporter 2 inhibitor prevents macrophage-driven atherosclerosis through macrophage foam cell formation suppression in type 1 and type 2 diabetic mice. PLoS One 2015; 10: e0143396.
41. US Food and Drug Administration. Center for Drug Evaluation and Research. Approval Package for Empagliflozin. https: //www. accessdata. fda. gov/drugsatfda-docs/ nda/2014/204629orig1s000approv. pdf (30 January 2018, date last accessed).
42. US Food and Drug Administration. Center for Drug Evaluation and Research. Approval Package for Canagliflozin. https: //www. accessdata. fda. gov/drugsatfda-docs/ nda/2013/204042orig1s000approv. pdf (30 January 2018, date last accessed).
43. US Food and Drug Administration. Center for Drug Evaluation and Research. Approval Package for Dapagliflozin. https: //www. accessdata. fda. gov/drugsatfda-docs/ nda/2014/202293Orig1s000TOC. cfm (30 January 2018, date last accessed).
44. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. Drug-specific or class effects of SGLT2 inhibitors (SGLT2i) in the heart: SGLT2i inhibit NHE, reduce [Na]c and induce vasodilation in isolated mouse cardiomyocytes/hearts. Diabetologia 2017; 60 (1 Suppl 1): S86-S87.
45. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, Jancev M, Hollmann MW, Weber NC, Coronel R, Zuurbier CJ. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na/H exchanger, lowering of cytosolic Na and vasodilation. Diabetologia 2018; 61: 722-726.
46. Ye Y, Bajaj M, Yang HC, Perez-Polo JR, 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 2017; 31: 119-132.
47. Zhou Y, Wu W. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, protects against diabetic cardiomyopathy by inhibition of the endoplasmic reticulum stress pathway. Cell Physiol Biochem 2017; 41: 2503-2512.
48. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017; 2: 1025-1029.
49. Han SH, Quon MJ, Kim J-A, Koh KK. Adiponectin and cardiovascular disease: response to therapeutic interventions. J Am Coll Cardiol 2007; 49: 531-538.
50. Méry P-F, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca2 current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 1990; 345: 158-161.
51. Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC, Brammar GC, Lee F, Grant SL, Burrell LM, Jerums G, Osicka TM. Reduction of the accumulation of advanced glycation end products by ace inhibition in experimental diabetic nephropathy. Diabetes 2002; 51: 3274-3282.
52. Yamamoto Y, Yamagishi S, Yonekura H, Doi T, Tsuji H, Kato I, Takasawa S, Okamoto H, Abedin J, Tanaka N, Sakurai S, Migita H, Unoki H, Wang H, Zenda T, Wu PS, Segawa Y, Higashide T, Kawasaki K, Yamamoto H. Roles of the AGE-RAGE system in vascular injury in diabetes. Ann N Y Acad Sci 2000; 902: 163. 70.
53. Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan ALY, Fukami K, Thallas-Bonke V, Nawroth PP, Brownlee M, Bierhaus A, Cooper ME, Forbes JM. RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol 2009; 20: 742-752.
54. Ortega A, Roselló-Lletí E, Tarazón E, Molina-Navarro MM, Martínez-Dolz L, González-Juanatey JR, Lago F, Montoro-Mateos JD, Salvador A, Rivera M, Portolés M. Endoplasmic reticulum stress induces different molecular structural alterations in human dilated and ischemic cardiomyopathy. PLoS One 2014; 9: e107635.
55. Foote C, Perkovic V, Neal B. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab Vasc Dis Res 2012; 9: 117-123.
56. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero R-M, Woerle H-J, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015; 12: 90-100.
57. Inoue BH, dos Santos L, Pessoa TD, Antonio EL, Pacheco BPM, Savignano FA, Carraro-Lacroix LR, Tucci PJF, Malnic G, Girardi ACC. Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 2012; 302: R166-R174.
58. Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S. Activation of Na/H exchanger 1 is sufficient to generate Ca2 signals that induce cardiac hypertrophy and heart failure. Circ Res 2008; 103: 891-899.
59. Carreno JE, Verdugo FJ, Contreras F, Montellano FA, Veloso S, Schalper KA, Sandoval M, Villanueva S, Marusic E, Irarrazabal CE. Spironolactone inhibits the activity of the Na/H exchanger in the aorta of mineralocorticoid-induced hypertensive rats. J Renin Angiotensin Aldosterone Syst 2015; 16: 1225-1231.
60. Frigerio M, Roubina E. Drugs for left ventricular remodeling in heart failure. Am J Cardiol 2005; 96: 10L-18L.
61. Pant S, Deshmukh A, GuruMurthy GS, Pothineni NV, Watts TE, Romeo F, Mehta JL. Inflammation and atherosclerosis-revisited. J Cardiovasc Pharmacol Ther 2014; 19: 170-178.
62. Pothineni NVK, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J Am Coll Cardiol 2017; 69: 2759-2768.
63. Choromanska B, Mysliwiec P, Choromanska K, Dadan J, Chabowski A. The role of CD36 receptor in the pathogenesis of atherosclerosis. Adv Clin Exp Med 2017; 26: 717-722.
64. Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, Mirzaei H. NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol 2018; 233: 2116-2132.
65. Febbraio M, Guy E, Silverstein RL. Stem cell transplantation reveals that absence of macrophage CD36 is protective against atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 2333-2338.
66. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124: 499-508.
67. Perreault L. EMPA-REG OUTCOME: the endocrinologist's point of view. Am J Med 2017; 130: S51-S56.
68. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a "Thrifty substrate" hypothesis. Dia Care 2016; 39: 1108-1114.
69. Kosiborod M. Empagliflozin Impact on Hemodynamics in Patients With Diabetes and Heart Failure (EMBRACE-HF). https: //clinicaltrials. gov/ct2/show/NCT03030222? term=SGLT2&draw=3&rank=140 (9 April 2018, date last accessed).
70. Kosiborod M. Dapagliflozin Effect on Symptoms and Biomarkers in Patients With Heart Failure (DEFINE-HF). https: //clinicaltrials. gov/ct2/show/NCT02653482? term=SGLT2&draw=3&rank=127 (9 April 2018, date last accessed).
71. Struthers A. Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes? (DAPA-LVH). https: //clinicaltrials. gov/ct2/show/ NCT02956811?term=SGLT2&draw=3&rank=112 (9 April 2018, date last accessed).
72. Schmieder RE. Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI). https: //clinicaltrials. gov/ct2/ show/NCT03128528?term=SGLT2&draw=2&rank=61 (9 April 2018, date last accessed).
73. Marx N. Empagliflozin as a Modulator of Systemic Vascular Resistance and Cardiac Output in Patients With Type 2 Diabetes (EMPA). https: //clinicaltrials. gov/ct2/ show/NCT03132181?term=SGLT2&draw=2&rank=85 (9 April 2018, date last accessed).