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

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

Publikationsverlauf

Eingereicht: 23. Juli 2020

Angenommen nach Revision: 20. Oktober 2020

Artikel online veröffentlicht:
17. November 2020

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 28 Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis: Not so soon. Cell Metab 2016; 24: 200-202
• 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
• 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
• 31 Chakraborty S, Galla S, Cheng X. et al. Saltresponsive metabolite, β-hydroxybutyrate, attenuates hypertension. Cell Rep 2018; 25: 677-689
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 42 Sato T, Aizawa Y, Yuasa S. et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 2018; 17: 6
• 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
• 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
• 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
• 46 Wilcox C. Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors. Hypertension 2020; 75: 894-901
• 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
• 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
• 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
• 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
• 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
• 52 Vinik A, Casellini C, Parson H. et al. Cardiac autonomic neuropathy in diabetes: A predictor of cardiometabolic events. Front Neurosci 2018; 12: 591
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 82 Sano M. Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors. J Clin Med Res 2017; 9: 457-460
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 90 Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci 2017; 18: E1682
• 91 Campese VM, Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension 1995; 25: 878-882
• 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
• 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
• 94 Hausberg M, Kosch M, Harmelink P. et al. Sympathetic nerve activity in end-stage renal disease. Circulation 2002; 106: 1974-1979
• 95 Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol 2018; 71: 471-476
• 96 Schlaich MP, Bakris GL. Renal denervation: One step backwards, three steps forward. Nat Rev Nephrol 2018; 14: 602-604
• 97 Rahmouni K. Leptin-induced sympathetic nerve activation: Signaling mechanisms and cardiovascular consequences in obesity. Curr Hypertens Rev 2010; 6: 104-209
• 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
• 99 Conde SV, Sacramento JF, Guarino MP. et al. Carotid body, insulin, and metabolic diseases: Unraveling the links. Front Physiol 2014; 5: 418
• 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
• 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
• 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
• 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
• 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
• 105 Thomas M, Cherney D. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 2018; 61: 2098-2107
• 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
• 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
• 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
• 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
• 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
• 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