Sodium glucose co-transporter inhibitors put cardiovascular medicine at a crossroads – Cardiorenal interaction and clinical implications

7th International Congress of Cardionephrology KARNEF (2025) [pp. 206-221]

AUTHOR(S) / АУТОР(И): Edoardo Gronda , Massimo Iacoviello, Arduino Arduini

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DOI: 10.46793/KARNEF25.215G

ABSTRACT / САЖЕТАК:

Heart and kidney have essential homeostatic role in circulation balance to cope with variation of body biology needs, however the two organs physiology is designed to satisfy opposing demands. The heart has to provide with oxygen and nutrition of different organs and apparatus based on intercurrent demand without any predefined schedule. In contrast, the kidneys have to adapt the body’s fluid and electrolyte content to cope with changes in the internal and external environment. The heart and kidney function confront different physiological needs, namely the energy the body requires versus the body function equilibrium.

In the specific the kidney has a role in maintaining renal glucose balance while it reabsorbs the 

99% of filtrate sodium together with other filtered substances, including all glucose molecules. The kidneys reabsorb the filtered glucose prominently through the sodium-glucose cotransporters sodium-glucose cotransporter (SGLT)2, and only a limited percentage through the SGLT1. Both SGLTs are localized on the brush border membrane of the early proximal tubule working in tandem with the structurally interlinked Na+-H+ exchanger NHE3. The reabsorption of 50 to 60% of filtered sodium occurs in this section of the tubule by breaking down adenosine triphosphate to adenosine diphosphate to provide the energy affecting the renal oxygen demand.

Any change in glomerular filtrate production directly affects the renal oxygen consumption that is the main drive of the renal sympathetic activity and regulates the SGLT2 expression.

Present paper will focus on effects of SGLT2 inhibition over renal physiology and by consequence over heart failure outcome.

KEYWORDS / КЉУЧНЕ РЕЧИ:

heart failure, glomerular filtration rate, chronic kidney disease, diabetes, type 2 sodium-glucose cotransporter

REFERENCES / ЛИТЕРАТУРА:

  • Zucker IH, Xiao L, Haack KK. The central RAS and sympathetic nerve activity in chronic heart failure. Clin Sci (Lond). 2014;126:695–706..
  • Rolfe, D.F.; Brown, G.C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev. 1997, 77, 731–758.
  • Wang, Z.; Ying, Z.; Bosy-Westphal, A.; Zhang, J.; Schautz, B.; Later, W.; Heymsfield, S.B.; Müller, M.J. Specific metabolic rates of major organs and tissues across adulthood: Evaluation by mechanistic model of resting energy expenditure. Am. J. Clin. Nutr. 2010, 92, 1369–1377.
  • Carlström, M.; Wilcox, C.S.; Arendshorst, W.J. Renal autoregulation in health and disease. Physiol. Rev. 2015, 95, 405–511.
  • Duncker, D.J.; Bache, R.J. Regulation of coronary blood flow during exercise. Physiol. Rev. 2008, 88, 1009–1086.
  • Goodwill, A.G.; Dick, G.M.; Kiel, A.M.; Tune, J.D. Regulation of Coronary Blood Compr. Physiol. 2017, 7, 321–382.
  • Gronda E, Palazzuoli A, Iacoviello M, Benevenuto M, Gabrielli D, Arduini A. Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe? Int J Mol Sci. 2023 Jun 9;24(12):9957.
  • Hansell, P.; Welch, W.J.; Blantz, R.C.; Palm, F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin. Exp. Pharmacol. Physiol. 2013, 40, 123–137.
  • Gronda E, Vanoli E, Iacoviello M, Caldarola P, Gabrielli D, Tavazzi L. The Benefit of Sodium-Glucose Co-Transporter Inhibition in Heart Failure: The Role of the Kidney. Int J Mol Sci. 2022 Oct 9;23(19):11987. doi: 10.3390/ijms231911987.
  • Heerspink, H.J.; Perkins, B.A.; Fitchett, D.H.; Husain, M.; Cherney, D.Z. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation 2016, 134, 752–772.
  • Vallon, V.; Verma, S. Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function. Annu. Rev. Physiol. 2021, 83, 503–528.
  • Gronda E, Iacoviello M, Arduini A, Benvenuto M, Gabrielli D, Bonomini M, Tavazzi L. Gliflozines use in heart failure patients. Focus on renal actions and overview of clinical experience. Eur J Intern Med. 2025 Feb;132:1-8.
  • Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, et al. Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure. J Am Coll Cardiol. 2024 Apr 16;83(15):1386-1398. doi: 10.1016/j.jacc.2024.02.020. Erratum in: J Am Coll Cardiol. 2024 Jun 25;83(25):2714.
  • Beldhuis IE, Lam CSP, Testani JM, Voors AA, Van Spall HGC, Ter Maaten JM, Damman K. Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease. Circulation. 2022 Mar;145(9):693-712.
  • Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Rocca HB, Janssens S, Tsutsui H, Zhang J, Brueckmann M, Jamal W, Cotton D, Iwata T, Schnee J, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021 Feb 11;42(6):671-680.
  • Adamson C, Docherty KF, Heerspink HJL, de Boer RA, Damman K, Inzucchi SE , et al. Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights From DAPA-HF. Circulation. 2022 Aug 9;146(6):438-449. doi: 10.1161/CIRCULATIONAHA.121.058910. Epub 2022 Apr 20. PMID: 35442064; PMCID: PMC9354593.
  • Mc Causland FR, Claggett BL, Vaduganathan M, Desai AS, Jhund P, de Boer RA, et al. Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. 2023 Jan 1;8(1):56-65.
  • Rastogi T, Ferreira JP, Butler J, Kraus BJ, Mattheus M, Brueckmann M, Filippatos G, Wanner C, Pocock SJ, Packer M, Anker SD, Zannad F. Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved. Eur J Heart Fail. 2024 Apr;26(4):885-896. doi: 10.1002/ejhf.3136. Epub 2024 Jan 21. PMID: 38247160.
  • Packer M, Butler J, Zeller C, Pocock SJ, Brueckmann M, Ferreira JP, Filippatos G, Usman MS, Zannad F, Anker SD. Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure. Circulation. 2023 Sep 26;148(13):1011-1022
  • Sharma A, Ferreira JP, Zannad F, Pocock SJ, Filippatos G, Pfarr E, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: Insights from the EMPEROR-Preserved trial. Eur J Heart Fail. 2023 Aug;25(8):1337-1348.
  • Jongs N, Greene T, Chertow GM, McMurray JJV, Langkilde AM, Correa-Rotter R, et al.; DAPA-CKD Trial Committees and Investigators. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):755-766. doi: 10.1016/S2213-8587(21)00243-6
  • Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Böhm M, et al. Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction: Results of DAPA-HF. Circulation. 2021 Jan 26;143(4):298-309.
  • The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 388(2):117-127.