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Horm Metab Res 2021; 53(02): 75-84
DOI: 10.1055/a-1298-4205
Review

Does SGLT2 Inhibition Affect Sympathetic Nerve Activity in Type 2 Diabetes?

Rumyana Dimova
1   Department of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
,
Tsvetalina Tankova
1   Department of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
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Abstract

SGLT2 inhibitors increase renal glucose excretion and thus decrease both fasting and postprandial plasma glucose levels. The effects of SGLT2 inhibition outweigh those on glycemic control and are also associated with the induction of hemodynamic changes that improve cardiovascular and renal function in people with type 2 diabetes. The exact mechanisms have not yet been completely clarified. This review is focused on the potential relationship between SGLT2 inhibition and sympathetic nerve activity. There is accumulating evidence for a suppressive effect of SGLT2 inhibitors on the sympathetic nerve tone, which might be a putative mechanism for cardiovascular protection in subjects with type 2 diabetes.

Key words

SGLT2 inhibitor - sympathetic nervous system - type 2 diabetes


Publication History

Received: 23 July 2020

Accepted after revision: 20 October 2020

Article published online:
17 November 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 De Fronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017; 13: 11-26
    CrossrefPubMedSearch in Google Scholar
  • 2 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
    Search in Google Scholar
  • 3 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986
    CrossrefPubMedSearch in Google Scholar
  • 4 Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2559
    Search in Google Scholar
  • 5 Patel A, MacMahon S, Chalmers J. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572
    Search in Google Scholar
  • 6 Duckworth AbrairaC, Thomas Moritz T. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-139
    CrossrefPubMedSearch in Google Scholar
  • 7 Look Ahead Research Group. Eight-year weight losses with an intensive lifestyle intervention: The look AHEAD study. Obesity (Silver Spring) 2014; 22: 5-13
    CrossrefPubMedSearch in Google Scholar
  • 8 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128
    CrossrefPubMedSearch in Google Scholar
  • 9 Marso SP, Daniels GH, Brown-Frandsen K. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-322
    CrossrefPubMedSearch in Google Scholar
  • 10 Inzucchi SE, Zinman B, Wanner C. et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015; 12: 90-100
    CrossrefPubMedSearch in Google Scholar
  • 11 Verma S, McMurray JJV, Cherney DZI. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: The search for the sweet spot in heart failure. JAMA Cardiol 2017; 2: 939-940
    CrossrefPubMedSearch in Google Scholar
  • 12 Sattar N, McLaren J, Kristensen SL. et al. SGLT2 inhibition and cardiovascular events: Why did EMPA-REG Outcomes surprise and what were the likely mechanisms?. Diabetologia 2016; 59: 1333-1339
    CrossrefPubMedSearch in Google Scholar
  • 13 Lytvyn Y, Bjornstad P, Udell JA. et al. Sodium glucose cotransporter-2 inhibition in heart failure: Potential mechanisms, clinical applications, and summary of clinical trials. Circulation 2017; 136: 1643-1658
    CrossrefPubMedSearch in Google Scholar
  • 14 Karg MV, Bosch A, Kannenkeril D. et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: A randomized controlled trial. Cardiovasc Diabetol 2018; 17: 5
    CrossrefPubMedSearch in Google Scholar
  • 15 Inzucchi SE, Zinman B, Fitchett D. et al. How does empagliflozin reduce cardiovascularmortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41: 356-363
    CrossrefPubMedSearch in Google Scholar
  • 16 Lambers Heerspink HJ, de Zeeuw D, Wie L. et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013; 15: 853-862
    CrossrefPubMedSearch in Google Scholar
  • 17 Hallow KM, Helmlinger G, Greasley PJ. et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018; 20: 479-487
    CrossrefPubMedSearch in Google Scholar
  • 18 Wilcox CS, Shen W, Boulton DW. et al. Interaction between the sodium-glucose-linked transporter 2 inhibitor dapagliflozin and the loop diuretic bumetanide in normal human subjects. J Am Heart Assoc 2018; 7: e007046
    CrossrefPubMedSearch in Google Scholar
  • 19 Striepe K, Jumar A, Ott C. et al. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation 2017; 136: 1167-1169
    CrossrefPubMedSearch in Google Scholar
  • 20 Chilton R, Tikkanen I, Cannon CP. et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 2015; 17: 1180-1193
    CrossrefPubMedSearch in Google Scholar
  • 21 Li H, Shin SE, Seo MS. et al. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci 2018; 197: 46-55
    CrossrefPubMedSearch in Google Scholar
  • 22 Solini A, Giannini L, Seghieri M. et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: A pilot study. Cardiovasc Diabetol 2017; 16: 138
    CrossrefPubMedSearch in Google Scholar
  • 23 Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-transporter 2 inhibitors (SGLT2is): More than osmotic diuresis. Curr Hypertens Rep 2019; 21: 12
    CrossrefPubMedSearch in Google Scholar
  • 24 Dekkers CJ, Wheeler DC, Sjöström CD. et al. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and stages 3b-4 chronic kidney disease. Nephrol Dial Transplant 2018; 33: 2005-2011
    CrossrefPubMedSearch in Google Scholar
  • 25 Sjostrom CD, Johansson P, Ptaszynska A. et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diabetes Vasc Dis Res 2015; 12: 352-358
    CrossrefPubMedSearch in Google Scholar
  • 26 Cefalu WT, Stenlöf K, Leiter LA. et al. Effects of canagliflozin on body weight and relationship toHbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia 2015; 58: 1183-1187
    CrossrefPubMedSearch in Google Scholar
  • 27 Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG Outcome Trial: A “Thrifty Substrate” hypothesis. Diabetes Care 2016; 39: 1108-1114
    CrossrefPubMedSearch in Google Scholar
  • 28 Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis: Not so soon. Cell Metab 2016; 24: 200-202
    CrossrefPubMedSearch in Google Scholar
  • 29 Santos-Gallego CG, Ibanez JAR, San Antonio R. et al. Empagliflozin induces a myocardial metabolic shift from glucose consumption to ketone metabolism that mitigates adverse cardiac remodeling and improves myocardial contractility. J Am Coll Cardiol 2018; 71: A674
    CrossrefPubMedSearch in Google Scholar
  • 30 Kappel BA, Lehrke M, Schutt K. et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation 2017; 136: 969-972
    CrossrefPubMedSearch in Google Scholar
  • 31 Chakraborty S, Galla S, Cheng X. et al. Saltresponsive metabolite, β-hydroxybutyrate, attenuates hypertension. Cell Rep 2018; 25: 677-689
    CrossrefPubMedSearch in Google Scholar
  • 32 Prattichizzo F, De Nigris V, Micheloni S. et al. Increases in Circulating Levels of Ketone Bodies and Cardiovascular Protection With SGLT2 Inhibitors: Is Low-Grade Inflammation the Neglected Component?. Diabetes Obes Metab 2018; 20: 2515-2522
    CrossrefPubMedSearch in Google Scholar
  • 33 Baker HE, Kiel AM, Luebbe ST. et al. Inhibition of sodium–glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization. Basic Res Cardiol 2019; 114: 25
    CrossrefPubMedSearch in Google Scholar
  • 34 Holman R, Paul S, Bethel M. et al. A. 10‑year follow‑up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577-1589
    CrossrefPubMedSearch in Google Scholar
  • 35 Hayward RA, Reaven PD, Emanuele NV. et al. Follow‑up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372: 2197-2206
    CrossrefPubMedSearch in Google Scholar
  • 36 Januzzi JL, Butler J, Jarolim P. et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol 2017; 70: 704-712
    CrossrefPubMedSearch in Google Scholar
  • 37 Packer M, Anker SD, Butler J. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 38 Uthman L, Baartscheer A, Bleijlevens B. et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 39 Baartscheer A, Schumacher CA, Wust RC. et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 2017; 60: 568-573
    CrossrefPubMedSearch in Google Scholar
  • 40 Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab 2018; 20: 1361-1366
    Search in Google Scholar
  • 41 Timothy Garvey W, Van Gaal L, Leiter LA. et al. Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes. Metabolism 2018; 85: 32-37
    CrossrefPubMedSearch in Google Scholar
  • 42 Sato T, Aizawa Y, Yuasa S. et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 2018; 17: 6
    CrossrefPubMedSearch in Google Scholar
  • 43 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 2018; 104: 298-310
    CrossrefPubMedSearch in Google Scholar
  • 44 Kang S, Verma S, Teng G. et al. Direct effects of empagliflozin on extracellular matrix remodeling in human cardiac fibroblasts: Novel translational clues to EMPA-REG Outcome. Can J Cardiol 2017; 33: S169
    CrossrefPubMedSearch in Google Scholar
  • 45 Fukuda T, Bouchi R, Terashima M. et al. Ipragliflozin reduces epicardial fat accumulation in non-obese type 2 diabetic patients with visceral obesity: a pilot study. Diabetes Ther 2017; 8: 851-861
    CrossrefPubMedSearch in Google Scholar
  • 46 Wilcox C. Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors. Hypertension 2020; 75: 894-901
    CrossrefPubMedSearch in Google Scholar
  • 47 Pop-Busui R, Boulton A, Feldman E. et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017; 40: 136-154
    Search in Google Scholar
  • 48 Gaede P, Vedel P, Larsen N. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-393
    CrossrefPubMedSearch in Google Scholar
  • 49 Maser RE, Mitchell BD, Vinik AI. et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: A meta-analysis. Diabetes Care 2003; 26: 1895-1901
    CrossrefPubMedSearch in Google Scholar
  • 50 Pop-Busui R, Evans GW, Gerstein HC. et al. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010; 33: 1578-1584
    CrossrefPubMedSearch in Google Scholar
  • 51 Lonn EM, Rambihar S, Gao P. et al. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and allcause death in patients with stable chronic cardiovascular disease: An analysis of ONTARGET/ TRANSCEND. Clin Res Cardiol 2014; 103: 149-159
    CrossrefPubMedSearch in Google Scholar
  • 52 Vinik A, Casellini C, Parson H. et al. Cardiac autonomic neuropathy in diabetes: A predictor of cardiometabolic events. Front Neurosci 2018; 12: 591
    CrossrefPubMedSearch in Google Scholar
  • 53 Tikkanen I, Narko K, Zeller C. et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 2015; 38: 420-428
    CrossrefPubMedSearch in Google Scholar
  • 54 Baker WL, Smyth LR, Riche DM. et al. Effects of sodium-glucose cotransporter 2 inhibitors on blood pressure: A systematic review and meta-analysis. J Am Soc Hypertens 2014; 8: 262-275
    CrossrefPubMedSearch in Google Scholar
  • 55 Abdul-Ghani M, Del Prato S, Chilton R. et al. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPAREG OUTCOME study. Diabetes Care 2016; 39: 717-725
    CrossrefPubMedSearch in Google Scholar
  • 56 Wan N, Rahman A, Hitomi H. et al. The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol 2018; 9: 421
    CrossrefPubMedSearch in Google Scholar
  • 57 Cherney DZ, Perkins BA, Soleymanlou N. et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014; 13: 28
    CrossrefPubMedSearch in Google Scholar
  • 58 Haring HU, Merker L, Seewaldt-Becker E. et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2013; 36: 3396-3404
    CrossrefPubMedSearch in Google Scholar
  • 59 Kovacs CS, Seshiah V, Swallow R. et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial. Diabetes Obesity Metab 2014; 16: 147-158
    CrossrefPubMedSearch in Google Scholar
  • 60 Nishimura R, Tanaka Y, Koiwai K. et al. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol 2015; 14: 11
    CrossrefPubMedSearch in Google Scholar
  • 61 Haring HU, Merker L, Seewaldt-Becker E. et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014; 37: 1650-1659
    CrossrefPubMedSearch in Google Scholar
  • 62 Rosenstock J, Jelaska A, Zeller C. et al. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: A 78-week randomized, doubleblind, placebo-controlled trial. Diabetes Obesity Metab 2015; 17: 936-948
    CrossrefPubMedSearch in Google Scholar
  • 63 Rosenstock J, Jelaska A, Frappin G. et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 2014; 37: 1815-1823
    CrossrefPubMedSearch in Google Scholar
  • 64 Ferrannini E, Berk A, Hantel S. et al. Longterm safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 2013; 36: 4015-4021
    CrossrefPubMedSearch in Google Scholar
  • 65 Wilding JP, Woo V, Rohwedder K. et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: Efficacy and safety over 2 years. Diabetes Obesity Metab 2014; 16: 124-136
    CrossrefPubMedSearch in Google Scholar
  • 66 Nauck MA, Del Prato S, Meier JJ. et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34: 2015-2022
    CrossrefPubMedSearch in Google Scholar
  • 67 List JF, Woo V, Morales E. et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32: 650-657
    CrossrefPubMedSearch in Google Scholar
  • 68 Wilding JP, Woo V, Soler NG. et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: A randomized trial. Ann Internal Med 2012; 156: 405-415
    CrossrefPubMedSearch in Google Scholar
  • 69 Cefalu WT, Leiter LA, Yoon KH. et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013; 382: 941-950
    CrossrefPubMedSearch in Google Scholar
  • 70 Devineni D, Morrow L, Hompesch M. et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obesity Metab 2012; 14: 539-545
    CrossrefPubMedSearch in Google Scholar
  • 71 Rosenstock J, Aggarwal N, Polidori D. et al. Doseranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012; 35: 1232-1238
    CrossrefPubMedSearch in Google Scholar
  • 72 Leiter LA, Yoon KH, Arias P. et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: A randomized, double-blind, phase 3 study. Diabetes Care 2015; 38: 355-364
    CrossrefPubMedSearch in Google Scholar
  • 73 Sha S, Devineni D, Ghosh A. et al. Pharmacodynamic effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PLoS One 2014; 9: e105638
    CrossrefPubMedSearch in Google Scholar
  • 74 Lavalle-Gonzalez FJ, Januszewicz A, Davidson J. et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: A randomised trial. Diabetologia 2013; 56: 2582-2592
    CrossrefPubMedSearch in Google Scholar
  • 75 Stenlof K, Cefalu WT, Kim KA. et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitusinadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15: 372-382
    CrossrefPubMedSearch in Google Scholar
  • 76 Wilding JP, Charpentier G, Hollander P. et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: A randomised trial. Int J Clin Pract 2013; 67: 1267-1282
    CrossrefPubMedSearch in Google Scholar
  • 77 Schernthaner G, Gross JL, Rosenstock J. et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 2013; 36: 2508-2515
    CrossrefPubMedSearch in Google Scholar
  • 78 Forst T, Guthrie R, Goldenberg R. et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes ObesityMetab 2014; 16: 467-477
    PubMedSearch in Google Scholar
  • 79 Yale JF, Bakris G, Cariou B. et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013; 15: 463-473
    CrossrefPubMedSearch in Google Scholar
  • 80 Maegawa H, Tobe K, Tabuchi H. et al. Baseline characteristics and interim (3-month) efficacy and safety data from STELLA-LONG TERM, a long-term post-marketing surveillance study of ipragliflozin in Japanese patients with type 2 diabetes in real-world clinical practice. Expert Opin Pharmacother 2016; 17: 1985-1994
    CrossrefPubMedSearch in Google Scholar
  • 81 Sano M, Chen S, Imazeki H. et al. Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Sub-analysis of placebo controlled, double-blind clinical trials. J Diabetes Investig 2018; 9: 638-641
    CrossrefPubMedSearch in Google Scholar
  • 82 Sano M. Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors. J Clin Med Res 2017; 9: 457-460
    CrossrefPubMedSearch in Google Scholar
  • 83 Rahman A, Fujisawa Y, Nakano D. et al. Effect of a selective SGLT2 inhibitor, luseogliflozin, on circadian rhythm of sympathetic nervous function and locomotor activities in metabolic syndrome rats. J Clin Exp Pharmacol Physiol 2017; 44: 522-525
    CrossrefPubMedSearch in Google Scholar
  • 84 Chilton R, Tikkanen I, Hehnke U. et al. Impact of empagliflozin on blood pressure in dipper and non-dipperpatients with type 2 diabetes mellitus and hypertension. Diabetes Obesity Metab 2017; 19: 1620-1624
    CrossrefPubMedSearch in Google Scholar
  • 85 Yoshikawa T, Kishi T, Shinohara K. et al. Arterial pressure lability is improved by sodium-glucose cotransporter 2 inhibitor in streptozotocin-induced diabetic rats. Hypertens Res 2017; 40: 646-651
    CrossrefPubMedSearch in Google Scholar
  • 86 Chiba Y, Yamada T, Tsukita S. et al. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PLoS ONE 2016; 11: e0150756
    CrossrefPubMedSearch in Google Scholar
  • 87 Matthews VB, Elliot RH, Rudnicka C. et al. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens 2017; 35: 2059-2068
    CrossrefPubMedSearch in Google Scholar
  • 88 Herat LY, Magno AL, Rudnickaet C. et al. SGLT2 inhibitor–induced sympathoinhibition. A novel mechanism for cardiorenal protection. J Am Coll Cardiol Basic Trans Science 2020; 5: 169-179
    PubMedSearch in Google Scholar
  • 89 Ansary TM, Fujisawa Y, Rahman A. et al. Responses of renal hemodynamics and tubular functions to acute sodium-glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats. Sci Rep 2017; 7: 9555
    CrossrefPubMedSearch in Google Scholar
  • 90 Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci 2017; 18: E1682
    CrossrefPubMedSearch in Google Scholar
  • 91 Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension 1995; 25: 878-882
    CrossrefPubMedSearch in Google Scholar
  • 92 Ye S, Zhong H, Yanamadala V. et al. Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens 2002; 15: 717-724
    CrossrefPubMedSearch in Google Scholar
  • 93 Katholi RE, Whitlow PL, Hageman GR. et al. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J Hypertens 1984; 2: 349-359
    CrossrefPubMedSearch in Google Scholar
  • 94 Hausberg M, Kosch M, Harmelink P. et al. Sympathetic nerve activity in end-stage renal disease. Circulation 2002; 106: 1974-1979
    CrossrefPubMedSearch in Google Scholar
  • 95 Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol 2018; 71: 471-476
    CrossrefPubMedSearch in Google Scholar
  • 96 Schlaich MP, Bakris GL. Renal denervation: One step backwards, three steps forward. Nat Rev Nephrol 2018; 14: 602-604
    CrossrefPubMedSearch in Google Scholar
  • 97 Rahmouni K. Leptin-induced sympathetic nerve activation: Signaling mechanisms and cardiovascular consequences in obesity. Curr Hypertens Rev 2010; 6: 104-209
    CrossrefPubMedSearch in Google Scholar
  • 98 Yamada T, Oka Y, Katagiri H. Inter-organ metabolic communication involved in energy homeostasis: Potential therapeutic targets for obesity and metabolic syndrome. Pharmacol Ther 2008; 117: 188-198
    CrossrefPubMedSearch in Google Scholar
  • 99 Conde SV, Sacramento JF, Guarino MP. et al. Carotid body, insulin, and metabolic diseases: Unraveling the links. Front Physiol 2014; 5: 418
    CrossrefPubMedSearch in Google Scholar
  • 100 Guyenet PG. Putative mechanism of salt-dependent neurogenic hypertension: cell-autonomous activation of organum vasculosum laminae terminalis neurons by hypernatremia. Hypertension 2017; 69: 20-22
    CrossrefPubMedSearch in Google Scholar
  • 101 Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J 2016; 37: 3192-3200
    CrossrefPubMedSearch in Google Scholar
  • 102 Cherney DZ, Perkins BA, Soleymanlou N. et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587-597
    CrossrefPubMedSearch in Google Scholar
  • 103 Ansary T, Nakano D, Nishiyama A. Diuretic effects of sodium glucose cotransporter 2 inhibitors and their influence on the renin-angiotensin system. Int J Mol Sci 2019; 20: 629
    CrossrefPubMedSearch in Google Scholar
  • 104 Rajasekeran H, Kim SJ, Cardella CJ. et al. Use of canagliflozin in kidney transplant recipients for the treatment of type 2 diabetes: a case series. Diabetes Care 2017; 40: e75-e76
    CrossrefPubMedSearch in Google Scholar
  • 105 Thomas M, Cherney D. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 2018; 61: 2098-2107
    CrossrefPubMedSearch in Google Scholar
  • 106 Bonner C, Kerr-Conte J, Gmyr V. et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 2015; 21: 512-517
    CrossrefPubMedSearch in Google Scholar
  • 107 Merovci A, Solis-Herrera C, Daniele G. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124: 509-514
    CrossrefPubMedSearch in Google Scholar
  • 108 DeFronzo R, Lewin A, Patel S. et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 2015; 38: 384-393
    CrossrefPubMedSearch in Google Scholar
  • 109 Rosenstock J, Hansen L, Zee P. et al. Dual add on therapy in type 2 diabetes poorly controlled with metformin monotherapy: A randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2015; 38: 376-383
    CrossrefPubMedSearch in Google Scholar
  • 110 Jordan J, Tank J, Heusser K. et al. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J Am Soc Hypertens 2017; 11: 604-612
    CrossrefPubMedSearch in Google Scholar
  • 111 Kubota Y, Yamamoto T, Tara S. et al. Effect of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: Rationale. Diabetes Ther 2018; 9: 2107-2121
    CrossrefPubMedSearch in Google Scholar