Effect of SGLT2 Inhibitors on the Sympathetic Nervous System and Blood Pressure

Current Cardiology Reports

Volumn 21, Issue 8, 2019, Pages

  Scheen, André J ^a  

^a UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Blood pressure; Diuretic; Hypertension; SGLT2 inhibitor; Sympathetic nervous system; Type 2 diabetes

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; DIURETIC AGENT; EMPAGLIFLOZIN; ERTUGLIFLOZIN; IPRAGLIFLOZIN; PLACEBO; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; THIAZIDE DIURETIC AGENT; ANTIDIABETIC AGENT; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

ADRENERGIC ACTIVITY; ADRENERGIC SYSTEM; ARTERIAL PRESSURE; ARTERIAL STIFFNESS; BLOOD GLUCOSE MONITORING; BLOOD PRESSURE; BLOOD PRESSURE MEASUREMENT; BLOOD PRESSURE MONITORING; BODY WEIGHT LOSS; CHRONIC KIDNEY FAILURE; DIASTOLIC BLOOD PRESSURE; DIURESIS; DOSE RESPONSE; DRUG EFFECT; ETHNIC GROUP; GLUCOSURIA; HEART FAILURE; HEART RATE; HOSPITALIZATION; HUMAN; HYPERTENSION; MICROANGIOPATHY; NATRIURESIS; NON INSULIN DEPENDENT DIABETES MELLITUS; OSMOTIC DIURESIS; PLASMA VOLUME; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK REDUCTION; SUDDEN DEATH; SYSTOLIC BLOOD PRESSURE; COMPLICATION; PATHOPHYSIOLOGY; PHARMACOLOGY; TREATMENT OUTCOME;

BLOOD PRESSURE; DIABETES MELLITUS, TYPE 2; HUMANS; HYPERTENSION; HYPOGLYCEMIC AGENTS; SODIUM-GLUCOSE TRANSPORTER 2; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; SYMPATHETIC NERVOUS SYSTEM; TREATMENT OUTCOME;

EID: 85067840960     PISSN: 15233782     EISSN: 15343170     Source Type: Journal    
DOI: 10.1007/s11886-019-1165-1     Document Type: Review

References (101)

1. Vecchione C, Argenziano L, Fratta L, et al. Sympathetic nervous system and hypertension in diabetic patients. Diabetes Nutr Metab. 2000;13:327–31.
2. Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116:976–90.
3. Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur Heart J. 2012;33:1058–66.
4. Toschi-Dias E, Rondon M, Cogliati C, et al. Contribution of autonomic reflexes to the hyperadrenergic state in heart failure. Front Neurosci. 2017;11:162.
5. van Bilsen M, Patel HC, Bauersachs J, Böhm M, Borggrefe M, Brutsaert D, et al. The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the translational research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2017;19:1361–78.
6. Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet. 2012;380:601–10.
7. Ofstad AP, Atar D, Gullestad L, Langslet G, Johansen OE. The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions. Heart Fail Rev. 2018;23:303–23.
8. Ortega-Loubon C, Fernandez-Molina M, Singh G, et al. Obesity and its cardiovascular effects. Diabetes Metab Res Rev. 2019;35:e3135.
9. Lim K, Jackson KL, Sata Y, Head GA. Factors responsible for obesity-related hypertension. Curr Hypertens Rep. 2017;19:53.
10. Schlaich M, Straznicky N, Lambert E, Lambert G. Metabolic syndrome: a sympathetic disease? Lancet Diabetes Endocrinol. 2015;3:148–57.
11. Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DASG. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation. 2003;108:3097–101.
12. Masuo K, Rakugi H, Ogihara T, Esler M, Lambert G. Cardiovascular and renal complications of type 2 diabetes in obesity: role of sympathetic nerve activity and insulin resistance. Curr Diabetes Rev. 2010;6:58–67.
13. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.
14. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–75 e9.
15. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18:783–94.
16. • Mazidi M, Rezaie P, Gao HK, Kengne AP. 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. 2017;6:e004007 This systematic review of prospective studies shows that treatment with SGLT2 inhibitors has beneficial off-target effects on blood pressure in patients with type 2 diabetes mellitus.
17. • Baker WL, Buckley LF, Kelly MS, 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. 2017;6:e005686 According to this meta-analysis, the diurnal effect of SGLT2 inhibitors on 24-hour ambulatory blood pressure is a class effect and may contribute to their favorable effects on cardiovascular outcomes.
18. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136:1643–58.
19. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.
20. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
21. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.
22. •• Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, 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. 2019;393:31–9 SGLT2i-associated moderate benefits on atherosclerotic major adverse cardiovascular events in patients with established atherosclerotic disease, but robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic disease or a history of heart failure.
23. Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42:71–6.
24. Ferrannini E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017;26:27–38.
25. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60:215–25.
26. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–17.
27. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018;94:26–39.
28. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in EMPA-REG OUTCOME: comparison with classic diuretics. Diabetes Metab. 2016;42:224–33.
29. Grassi G. Sympathetic and baroreflex function in hypertension: implications for current and new drugs. Curr Pharm Des. 2004;10:3579–89.
30. Rabbia F, Martini G, Cat Genova G, et al. Antihypertensive drugs and sympathetic nervous system. Clin Exp Hypertens. 2001;23:101–11.
31. Wan N, Rahman A, Hitomi H, Nishiyama A. The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol (Lausanne). 2018;9:421.
32. Perret-Guillaume C, Joly L, Benetos A. Heart rate as a risk factor for cardiovascular disease. Prog Cardiovasc Dis. 2009;52:6–10.
33. Hillis GS, Woodward M, Rodgers A, Chow CK, Li Q, Zoungas S, et al. Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus. Diabetologia. 2012;55:1283–90.
34. Scheen AJ. Cardiovascular outcome studies in type 2 diabetes: comparison between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract. 2018;143:88–100.
35. Lorenz M, Lawson F, Owens D, Raccah D, Roy-Duval C, Lehmann A, et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16:6.
36. Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Res Clin Pract. 2016;121:204–14.
37. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–9.
38. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9:48–53.
39. Imprialos KP, Sarafidis PA, Karagiannis AI. Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class? J Hypertens. 2015;33:2185–97.
40. Townsend RR, Machin I, Ren J, Trujillo A, Kawaguchi M, Vijapurkar U, et al. Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich). 2016;18:43–52.
41. Weir MR, Januszewicz A, Gilbert RE, Vijapurkar U, Kline I, Fung A, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2014;16:875–82.
42. Lambers Heerspink HJ, 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 Metab. 2013;15:853–62.
43. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4:211–20.
44. Sjostrom CD, Johansson P, Ptaszynska A, et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015;12:352–8.
45. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–8.
46. Zhao D, Liu H, Dong P. Empagliflozin reduces blood pressure and uric acid in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Hum Hypertens. 2019;33:327–39.
47. Amin NB, Wang X, Mitchell JR, Lee DS, Nucci G, Rusnak JM. Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension. Diabetes Obes Metab. 2015;17:805–8.
48. Kashiwagi A, Yoshida S, Kawamuki K, Nakamura I, Kazuta K, Ueyama E, et al. Effects of ipragliflozin, a selective sodium-glucose co-transporter 2 inhibitor, on blood pressure in Japanese patients with type 2 diabetes mellitus: a pooled analysis of six randomized, placebo-controlled clinical trials. Diabetol Int. 2017;8:76–86.
49. Scheen AJ, Delanaye P. Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab. 2017;43:99–109.
50. Takenaka T, Ohno Y, Suzuki H. Impacts of sodium-glucose co-transporter type 2 inhibitors on central blood pressure. Diab Vasc Dis Res. 2018;15:154–7.
51. Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16:26.
52. 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;published on line;139:2089–97. 10.1161/CIRCULATIONAHA.118.037076.
53. Tamura K, Wakui H, Azushima K, Uneda K, Umemura S. Circadian blood pressure rhythm as a possible key target of SGLT2 inhibitors used for the treatment of type 2 diabetes. Hypertens Res. 2016;39:396–8.
54. Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, 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;17:1180–93.
55. Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18:590–7.
56. Mancia G, Cannon CP, Tikkanen I, Zeller C, Ley L, Woerle HJ, et al. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension. 2016;68:1355–64.
57. Scheen AJ. Type 2 diabetes and thiazide diuretics. Curr Diab Rep. 2018;18:6.
58. Kimura T, Sanada J, Shimoda M, Hirukawa H, Fushimi Y, Nishioka M, et al. Switching from low-dose thiazide diuretics to sodium-glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension. J Diabetes Investig. 2018;9:875–81.
59. Komici K, Femminella GD, de Lucia C, Cannavo A, Bencivenga L, Corbi G, et al. Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity. Aging Clin Exp Res. 2019;31:321–30.
60. Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Clin Pharmacokinet. 2015;54:691–708.
61. Kohan DE, Fioretto P, Tang W, List JF. 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. 2014;85:962–71.
62. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. CREDENCE trial investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.
63. Ferdinand KC, Izzo JL, Lee J, Meng L, George J, Salsali A, et al. Antihyperglycemic and blood pressure effects of empagliflozin in African Americans with type 2 diabetes and hypertension. Circulation. 2019;139:2098–109.
64. Cai X, Gao X, Yang W, Chen Y, Zhang S, Zhou L, et al. No disparity of the efficacy and all-cause mortality between Asian and non-Asian type 2 diabetes patients with sodium-glucose cotransporter 2 inhibitors treatment: a meta-analysis. J Diabetes Investig. 2018;9:850–61.
65. Reed JW. Impact of sodium-glucose cotransporter 2 inhibitors on blood pressure. Vasc Health Risk Manag. 2016;12:393–405.
66. Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 inhibitors and mechanisms of hypertension. Curr Cardiol Rep. 2018;20(1):1.
67. 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. 2017;18:23.
68. Lee PC, Ganguly S, Goh SY. Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms. Obes Rev. 2018;19:1630–41.
69. Zomer E, Gurusamy K, Leach R, Trimmer C, Lobstein T, Morris S, et al. Interventions that cause weight loss and the impact on cardiovascular risk factors: a systematic review and meta-analysis. Obes Rev. 2016;17:1001–11.
70. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42:878–84.
71. Sjostrom CD, Hashemi M, Sugg J, et al. Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab. 2015;17:809–12.
72. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89:524–6.
73. McMurray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complicat. 2016;30:3–4.
74. Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, et al. Acute pharmacodynamic effects of empagliflozin with and without diuretic agents in patients with type 2 diabetes mellitus. Clin Ther. 2016;38:2248–64 e5.
75. Yasui A, Lee G, Hirase T, Kaneko T, Kaspers S, von Eynatten M, et al. Empagliflozin induces transient diuresis without changing long-term overall fluid balance in Japanese patients with type 2 diabetes. Diabetes Ther. 2018;9:863–71.
76. 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. 2017;34:436–51.
77. Thomas MC, Cherney DZI. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia. 2018;61:2098–107.
78. Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, 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.
79. Ramirez AJ, Sanchez MJ, Sanchez RA. Diabetic patients with essential hypertension treated with amlodipine: blood pressure and arterial stiffness effects of canagliflozin or perindopril. J Hypertens. 2019;37:636–42.
80. van Ittersum FJ, Schram MT. Van der Heijden-Spek JJ, et al. autonomic nervous function, arterial stiffness and blood pressure in patients with type I diabetes mellitus and normal urinary albumin excretion. J Hum Hypertens. 2004;18:761–8.
81. 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.
82. Ansary TM, 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:pii: E629.
83. • Jordan J, Tank J, Heusser K, Heise T, Wanner C, Heer M, et al. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J Am Soc Hypertens. 2017;11:604–12 This experimental study showed that empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies.
84. •• Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059–68 In-vitro and in-vivo studies showed an important cross-talk between the sympathetic nervous system and SGLT2 regulation that may potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.
85. Elliott RH, Matthews VB, Rudnicka C, Schlaich MP. Is it time to think about the sodium glucose co-transporter 2 sympathetically? Nephrology. 2016;21:286–94.
86. •• Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–6 This review discusses novel insights into cardiovascular protection by SGLT2is, focusing on the interaction between SGLT2 and the sympathetic nervous system in diabetic patients with hypertension or heart failure.
87. Kiuchi S, Hisatake S, Kabuki T, Fujii T, Oka T, Dobashi S, et al. Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in a patient with heart failure: a case report. Drug Discov Ther. 2018;12:51–4.
88. Vasiliadis I, Kolovou G, Mavrogeni S, Nair DR, Mikhailidis DP. Sudden cardiac death and diabetes mellitus. J Diabetes Complicat. 2014;28:573–9.
89. Fukuda K, Kanazawa H, Aizawa Y, Ardell JL, Shivkumar K. Cardiac innervation and sudden cardiac death. Circ Res. 2015;116:2005–19.
90. Kubota Y, Yamamoto T, Tara S, Tokita Y, Yodogawa K, Iwasaki Y, 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;9:2107–16.
91. Avogaro A, Fadini GP. Microvascular complications in diabetes: a growing concern for cardiologists. Int J Cardiol. 2019;published on line. 10.1016/j.ijcard.2019.02.030.
92. Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci. 2017;18:E1682.
93. Masi S, Uliana M, Virdis A. Angiotensin II and vascular damage in hypertension: role of oxidative stress and sympathetic activation. Vasc Pharmacol. 2019;115:13–7.
94. Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J, Larkin D, et al. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol. 2004;44:2368–74.
95. Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev. 2011;7:291–304.
96. Valensi P, Smagghue O, Paries J, et al. Peripheral vasoconstrictor responses to sympathetic activation in diabetic patients: relationship with rheological disorders. Metabolism. 1997;46:235–41.
97. Herat LY, Matthews VB, Rakoczy PE, et al. Focusing on sodium glucose cotransporter-2 and the sympathetic nervous system: potential impact in diabetic retinopathy. Int J Endocrinol. 2018;2018:9254126.
98. Lambert EA, Rice T, Eikelis N, Straznicky NE, Lambert GW, Head GA, et al. Sympathetic activity and markers of cardiovascular risk in nondiabetic severely obese patients: the effect of the initial 10% weight loss. Am J Hypertens. 2014;27:1308–15.
99. Costa J, Moreira A, Moreira P, Delgado L, Silva D. Effects of weight changes in the autonomic nervous system: a systematic review and meta-analysis. Clin Nutr. 2019;38:110–26.
100. Nicoll R, Henein MY. Caloric restriction and its effect on blood pressure, heart rate variability and arterial stiffness and dilatation: a review of the evidence. Int J Mol Sci. 2018;19:E751.
101. Landsberg L. Insulin resistance, energy balance and sympathetic nervous system activity. Clin Exp Hypertens A. 1990;12:817–30.