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SGLT2 Inhibitor: Not a Traditional Diuretic for Heart Failure

2020; Cell Press; Volume: 32; Issue: 1 Linguagem: Inglês

10.1016/j.cmet.2020.06.014

1932-7420

Ashish Verma, Ankit Patel, Sushrut S. Waikar,

Pharmacology and Obesity Treatment

Recent studies have shown impressive cardiovascular health benefits in individuals treated with SGLT2 inhibitors (SGLT2i) regardless of diabetic status. The underlying mechanisms driving these benefits are not well understood. Recently in Circulation, Griffin et al., 2020Griffin M. Rao V.S. Ivey-Miranda J. Fleming J. Mahoney D. Maulion C. Suda N. Siwakoti K. Ahmad T. Jacoby D. et al.Empagliflozin in heart failure: diuretic and cardio-renal effects.Circulation. 2020; (Published online May 15, 2020)https://doi.org/10.1161/CIRCULATIONAHA.120.045691Crossref Scopus (67) Google Scholar reported the first human study investigating the diuretic effect of empagliflozin. Recent studies have shown impressive cardiovascular health benefits in individuals treated with SGLT2 inhibitors (SGLT2i) regardless of diabetic status. The underlying mechanisms driving these benefits are not well understood. Recently in Circulation, Griffin et al., 2020Griffin M. Rao V.S. Ivey-Miranda J. Fleming J. Mahoney D. Maulion C. Suda N. Siwakoti K. Ahmad T. Jacoby D. et al.Empagliflozin in heart failure: diuretic and cardio-renal effects.Circulation. 2020; (Published online May 15, 2020)https://doi.org/10.1161/CIRCULATIONAHA.120.045691Crossref Scopus (67) Google Scholar reported the first human study investigating the diuretic effect of empagliflozin. Humans have developed the ability to regulate their internal environment through tight control of extracellular volume and fluid composition by the kidneys. Heart failure (HF) occurs from inefficiency of the heart to circulate blood from the venous to arterial circulation, ultimately leading to dysregulation of extracellular volume balance due to excess sodium and fluid retention. Traditionally, loop diuretics (diuretics that act in the ascending limb of the loop of Henle) and thiazides have been used alone or in combination for alleviating symptoms related to HF by promoting urinary sodium excretion. Despite being the cornerstone of HF management for symptom relief, the use of diuretics has not demonstrated improvement in mortality for HF patients. This is felt to be due to counter-regulatory responses through activation of the renin-angiotensin system, neurohormonal activation, development of diuretic resistance, and blunting of tubuloglomerular feedback by loop diuretics (Hoorn and Ellison, 2017Hoorn E.J. Ellison D.H. Diuretic resistance.Am. J. Kidney Dis. 2017; 69: 136-142Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). SGLT2 inhibitors (SGLT2i) lower plasma glucose by blocking glucose reabsorption in the proximal tubule, thus leading to excretion of glucose into the urine. Initially, a diuretic effect of SGLT2i was assumed to be from a mild osmotic diuresis from glycosuria. More recent data showing cardiovascular benefits in congestive HF even in individuals without diabetes mellitus raise important questions about more nuanced effects of SGLT2i on salt and water homeostasis (Bhatt et al., 2019Bhatt D.L. Verma S. Braunwald E. The DAPA-HF trial: a momentous victory in the war against heart failure.Cell Metab. 2019; 30: 847-849Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). To begin to understand the physiological impact of SGLT2i in humans, Griffin et al. conducted a randomized, double-blind, placebo-controlled, crossover study consisting of treatment with either 10 mg empagliflozin or matched placebo daily for 14 days followed by a 2-week washout period and crossover to 14 days of the alternate treatment in 20 patients with type 2 diabetes and stable, euvolemic HF patients (Griffin et al., 2020Griffin M. Rao V.S. Ivey-Miranda J. Fleming J. Mahoney D. Maulion C. Suda N. Siwakoti K. Ahmad T. Jacoby D. et al.Empagliflozin in heart failure: diuretic and cardio-renal effects.Circulation. 2020; (Published online May 15, 2020)https://doi.org/10.1161/CIRCULATIONAHA.120.045691Crossref Scopus (67) Google Scholar). By using a crossover design, they were able to garner meaningful conclusions from extensive characterization of a relatively small number of patients. The significant findings from this study include:(1)The modest natriuretic effect (excretion of salt into the urine) of empagliflozin as monotherapy was additive to natriuretic effect with loop diuretics.(2)The glucosuric effect (excretion of glucose into the urine) of empagliflozin inversely correlates with its natriuretic effect.(3)Renal dysfunction was not the limiting factor for the natriuretic effect.(4)The natriuretic effect was persistent through 14 days, resulting in a reduction in blood and plasma volume.(5)Intravascular contraction did not lead to activation of the sympathetic nervous system or renin-angiotensin system (RAAS).(6)Empagliflozin decreased renal magnesium excretion and increased uric acid excretion and did not worsen renal potassium excretion like a traditional diuretic. This study demonstrates that SGLT2i are natriuretic and that this effect is synergistic with loop diuretics. Loop diuretics inhibit the sodium-potassium-chloride cotransporter 2 at the apical membrane of the thick ascending limb (TAL) inhibiting reabsorption of about 25% of the filtered sodium. Loop diuretics also inhibit NKCC2 (Na-K-2Cl cotransporter) at the macula densa, the distal most aspect of the TAL, which acts as a sensor for intravascular volume. NKCC2 inhibition at the macula densa leads to increased renin secretion and increase in intraglomerular pressures by preventing tubuloglomerular feedback (TGF) having potentially detrimental effects on cardiac and renal function. Though loop diuretics are effective in natriuresis in the acute setting, chronic use can lead to compensatory increase in sodium reabsorption distally mitigating the natriuretic effect, known as the breaking phenomenon (Felker et al., 2020Felker G.M. Ellison D.H. Mullens W. Cox Z.L. Testani J.M. Diuretic therapy for patients with heart failure: JACC state-of-the-art review.J. Am. Coll. Cardiol. 2020; 75: 1178-1195Crossref PubMed Scopus (29) Google Scholar). SGLT2i do not inhibit macula densa sensing and thus appear to not further increase renin secretion. By not providing a stimulus for RAAS activation, SGLT2i can decrease some of the compensatory mechanisms for sodium reabsorption and limit the braking phenomenon observed with loop diuretics. Griffin et al. demonstrate a sustained decrease in blood and plasma volume with empagliflozin consistent with mitigation of the breaking phenomenon. Empagliflozin has other favorable effects on tubular transport, including decreasing urinary magnesium and potassium excretion while increasing uric acid excretion. These findings were further validated by Griffin et al. and help lend support to animal studies that show decreased URAT1 (uric acid transporter 1) activity leading to increased uric acid excretion in response to SGLT2 (Vallon and Thomson, 2020Vallon V. Thomson S.C. The tubular hypothesis of nephron filtration and diabetic kidney disease.Nat. Rev. Nephrol. 2020; 16: 317-336Crossref PubMed Scopus (45) Google Scholar). There is limited mechanistic understanding for the decreased urinary magnesium and potassium excretion with SGLT2i, and further studies will be required to be understand these mechanisms. These effects are in direct contrast to loop and thiazide diuretics, which often lead to significant hypokalemia (low potassium levels in the blood), magnesium wasting, and hyperuricemia (high uric acid in the blood), pointing out a crucial difference in the side effect profile of this novel class of diuretics. SGLT2i are increasingly understood to be a unique class of diuretics. The natriuretic effect has been proposed to result from a decrease in Na+/H+ exchanger 3 (NHE3) and bicarbonate flux in the proximal tubule, which is responsible for reabsorption of about 40% of filtered sodium (Borges et al., 2018Borges Jr., F.A. Silva C.A. Crajoinas R.O. Castelo-Branco R.C. Luchi W.M. Girardi A.C.C. Empagliflozin inhibits NHE3 activity in the proximal tubule of normotensive and hypertensive rats.FASEB J. 2018; 32: lb355Google Scholar). Acetazolamide is another diuretic that similarly decreases sodium reabsorption by NHE3 through inhibition of carbonic anhydrase. Similar to SGLT2i, acetazolamide has a synergistic effect with a number of diuretics including loop diuretics and thiazides in increasing natriuresis (Zahedi et al., 2013Zahedi K. Barone S. Xu J. Soleimani M. Potentiation of the effect of thiazide derivatives by carbonic anhydrase inhibitors: molecular mechanisms and potential clinical implications.PLoS One. 2013; 8: e79327Crossref PubMed Scopus (27) Google Scholar). Though acetazolamide has been found to decrease urinary magnesium excretion (Nijenhuis et al., 2006Nijenhuis T. Renkema K.Y. Hoenderop J.G.J. Bindels R.J.M. Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins.J. Am. Soc. Nephrol. 2006; 17: 617-626Crossref PubMed Scopus (105) Google Scholar) similar to SGLT2i, it leads to increased urinary potassium excretion with unclear effect on uric acid excretion. Additionally, acetazolamide causes a non-gap metabolic acidosis, making it a less favorable diuretic choice (Imiela and Budaj, 2017Imiela T. Budaj A. Acetazolamide as add-on diuretic therapy in exacerbations of chronic heart failure: a pilot study.Clin. Drug Invest. 2017; 37: 1175-1181Crossref PubMed Scopus (19) Google Scholar). Figure 1 shows the individual and synergistic effect of the loop diuretic bumetanide and empagliflozin on urine electrolytes and tubuloglomerular feedback. Previous studies by Wilcox et al. were also able to delineate the synergistic natriuretic effects of a loop diuretic with the SGLT2 inhibitor dapagliflozin, with similar effects on urinary magnesium, potassium, and uric acid excretion in humans (Wilcox et al., 2018Wilcox C.S. Shen W. Boulton D.W. Leslie B.R. Griffen S.C. 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: e007046Crossref PubMed Scopus (57) Google Scholar); however, Griffin et al. further validated these conclusions by showing sustained decrease in blood and plasma volume measurements. This study provides a blueprint for evaluation of SGLT2i with other diuretics to evaluate for synergistic effects on natriuresis and blood volume reduction, urinary excretion patterns for electrolytes, and impact on neurohormonal regulation. The studies by Griffin et al. should pave the way for more expanded and physiologically grounded use of SGLT2i for the management of volume overload in congestive HF. Loop diuretics have the benefit of legacy, but SGLT2i increasingly seem to be more aligned to HF pathophysiology.