Frederick Wang

Introduction.  Heart failure is a progressive disease resulting in inadequate blood flow and poor systemic nutrient exchange.  Alarmingly, the coexistence of Type 2 diabetes mellitus (T2DM) and heart failure is extremely high, affecting 30-40% of patients, and is associated with higher heart failure hospitalizations and cardiovascular-related mortality.^1,2 T2DM metabolic dysfunction exacerbates severe cardiac and aortic stiffness, and leads to subsequent cardiomyocyte triglyceride deposition, cellular damage, and inflammation.^1,2,3  Recently, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors are anti-hyperglycemic therapies for T2DM that have demonstrated significant reductions in mortality and cardiovascular events.^3,4,5,6  Originally intended to inhibit the SGLT2 channel and reduce sodium and glucose reabsorption to lower blood pressure, the drastic reductions in cardiovascular mortality were shocking.³  These beneficial cardiovascular effects cannot be adequately explained by lowering blood pressure, therefore studies have been conducted to identify additional mechanisms behind this phenomenon. Methods. Using obese mice model with SGLT2 inhibitor and vehicle treatment, ion cyclotron resonance mass spectrometry imaging visualized the distribution of SGLT2 inhibitor in the kidneys and monitored glucose metabolic products.⁷  Cytoplasmic sodium and calcium, mitochondrial calcium, and sodium-hydrogen exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and mice that were treated with or without SGLT2 inhibitor.⁸  In a separate experiment, glucose metabolism and urinary sodium excretion were monitored over 5 weeks in obese mice and non-obese mice treated with 1% NaCl and vehicle or with SGLT2 inhibitor.  Blood pressure was routinely monitored during both sleep and awake hours.⁹  Results.  The diabetic, obese mice had increased levels of citrate.  Additionally, oxidized glutathione, observed to be accumulating in the cortex of the kidneys, was eliminated by SGLT2 inhibitors.⁷  SGLT2 inhibition normalized accumulating citrate intermediates and reduced oxidative stress in the kidneys, thereby restoring renal function.⁷  SGLT2 inhibitor directly inhibited NHE flux, causing a reduction in cytoplasmic sodium and calcium, and increasing mitochondrial calcium independent of SGLT2 activity.⁸  SGLT2 inhibitor treated mice showed increased urinary glucose excretion, improved glucose metabolism, and insulin resistance. Moreover, treatment prevented development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile.⁹ Conclusions.  Studies have shown SGLT2 inhibitors act through additional mechanisms, such as normalizing the circadian rhythm of blood pressure, directly lowering cytoplasmic sodium and calcium through NHE inhibition, and normalizing accumulating citrate intermediates.  These multifactorial effects of SGLT2 inhibitors may help explain the reductions in cardiovascular events in T2DM, however further research is needed to better understand these complex mechanisms.

1. Lehrke M, Marx N. Diabetes mellitus and heart failure. Am J Cardiol. 2017;120(1):S37-S47.
2. Seferović PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: A position statement from the heart failure association of the european society of cardiology. Eur J Heart Fail. 2018;20(5):853-872.
3. 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(9):1025–1029.
4. Heerspink Hiddo JL, Perkins Bruce A, Fitchett David H, Mansoor H, Cherney David ZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation. 2016;134(10):752-772.
5. Wu JHY, Foote C, Blomster J, et al. 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 meta-analysis. The Lancet Diabetes & Endocrinology. 2016;4(5):411-419.
6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–2128.
7. Tanaka S, Sugiura Y, Saito H, et al. Sodium-glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice. Kidney Int. 2018;94(5):912–925.
8. Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–573.
9. Takeshige Y, Fujisawa Y, Rahman A, et al. 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(6):415–422.