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A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity

Open AccessPublished:February 04, 2018DOI:https://doi.org/10.1016/j.jjcc.2017.12.004

      Highlights

      • Sodium glucose cotransporter 2 (SGLT2) inhibitors protect the cardiovascular system beyond lowering blood glucose.
      • A common feature of type 2 diabetes mellitus (T2DM) is chronic activation of the sympathetic nervous system.
      • The kidney is the epicenter of sympathetic overactivity in T2DM and heart failure.
      • SGLT2 participates in activation of the sympathetic nervous system.
      • SGLT2 inhibitors reduce the elevated heart rate in T2DM.

      Abstract

      Even in the presence of excess glucose, the proximal renal tubules continue to resorb more glucose. Sodium glucose cotransporter 2 (SGLT2) inhibitors are drugs that control this “greed” (H. Ito, Keio University, Japan). Negative feedback mechanisms maintain homeostasis for various physiological functions. However, there is no negative feedback mechanism for resorption of glucose by the proximal renal tubules. When food was scarce during human evolution, not limiting nutrient reabsorption was advantageous for survival, but the opposite is true in the era of satiation. SGLT2 inhibitors were designed to apply the brakes to uncontrolled glucose resorption by the kidneys in patients with diabetes. It has become clear that SGLT2 inhibitors not only improve the blood glucose level, but also show cardiovascular and renal protective effects irrespective of the reduction of blood glucose in patients with type 2 diabetes mellitus (T2DM). The mechanisms underlying cardiovascular and renal protection by SGLT2 inhibitors in T2DM are complex, multifactorial, and not completely understood. A common, and perhaps underappreciated, feature of T2DM is chronic activation of the sympathetic nervous system. This elevation of sympathetic activity contributes to the development of hypertension. It is also associated with a poor prognosis and with increased cardiovascular and renal morbidity/mortality independently of the effect on blood pressure. This review discusses novel insights into cardiovascular protection by SGLT2 inhibitors, focusing on the interaction between SGLT2 and the sympathetic nervous system.

      Keywords

      Introduction

      The EMPA-REG OUTCOME trial [(Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients and the CANVAS trial (Canagliflozin Cardiovascular Assessment Study)] demonstrated significant reduction in hospitalization for heart failure (HF) in patients with type 2 diabetes mellitus (T2DM) at risk of HF who were treated with sodium glucose cotransporter 2 (SGLT2) inhibitors and conventional cardioprotective drugs [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ]. Since the reduction in hospitalization for HF was observed immediately after starting SGLT2 inhibitor therapy, it was considered that this effect was due to direct improvement in hemodynamics. SGLT2 inhibitors reduce preload by promoting diuresis and reduce afterload by lowering blood pressure (BP) and decreasing arterial stiffness [
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      ]. In clinical practice, SGLT2 inhibitors have already been applied as a “new HF remedy” for management of T2DM patients who have either HF with a reduced ejection fraction (HFrEF) or HF with a preserved ejection fraction (HFpEF). Improvement that could not be obtained with conventional vasodilators or diuretics has been reported, although the mechanisms involved remain incompletely understood. Various clinical trials are ongoing to verify the cardiovascular effects of SGLT2 inhibitors (Table 1), and it is possible that use of these drugs will expand to non-diabetic patients with HF.
      Table 1Clinical trials currently investigating the cardiovascular effects of SGLT2 inhibitors.
      SGLT2 inhibitorAbbreviated study titleFull study titleDiabetes statusTrial identification number
      DapagliflozinDEFINE-HFDapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients With Heart FailureAll T2DMNCT02653482
      DapagliflozinPRESERVED HFDapagliflozin in Type 2 Diabetes or Pre-diabetes, and Preserved Ejection Fraction Heart FailureT2DM or prediabetesNCT03030235
      DapagliflozinDAPA-HFStudy to Evaluate the Effect of Dapagliflozin on Incidence of Worsening Heart failure or Cardiovascular Death in Patients with CHFNondiabetic and T2DM (T1DM excluded)NCT03036124
      EmpagliflozinEMPEROR-PreservedEmpagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection FractionNondiabetic, T1DM, and T2DM eligibleNCT03057951
      EmpagliflozinEMPEROR-ReducedEmpagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection FractionNondiabetic, T1DM, and T2DM eligibleNCT03057977
      EmpagliflozinEMBRACE-FEmpagliflozin Impact on Hemodynamics in Patients With Diabetes and Heart FailureAll T2DMNCT03030222
      DapagliflozinREFORMStudy and Effectiveness of SGLT-2 Inhibitors in Patients with Heart Failure and DiabetesAll T2DMNCT02397421
      EmpagliflozinEMPAEmpagliflozin in Heart Failure: Diuretic and Cardio-Renal EffectsAll T2DMNCT03027960
      SGLT2, sodium glucose cotransporter 2; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
      Overall, treatment with SGLT2 inhibitors reduces BP in T2DM patients without a compensatory increase in the heart rate (HR). Based on this observation, it has been postulated that the moderate diuretic effect of SGLT2 inhibitors does not activate neurohumoral factors and thus is beneficial for HF. However, even the mechanism of diuresis related to SGLT2 inhibitors is not well understood. The increase in urine volume peaks during the first 24 h of SGLT2 inhibitor administration and it returns to the pretreatment level after a few days. This initial increase in urine volume has been interpreted as osmotic diuresis. Patients with diabetes tend to have fluid retention, and the body fluid volume gradually decreases over two months when an SGLT2 inhibitor is administered, subsequently being maintained at this lower level. This suggests that the “set point” for body fluid volume is altered by administration of SGLT2 inhibitors.

      Effect of SGLT2 inhibitors on sympathetic activity

      Chronic activation of the sympathetic nervous system has been identified in numerous clinical conditions, including ischemic heart disease [
      • Graham L.N.
      • Smith P.A.
      • Huggett R.J.
      • Stoker J.B.
      • Mackintosh A.F.
      • Mary D.A.
      Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction.
      ], HF [
      • Leimbach Jr., W.N.
      • Wallin B.G.
      • Victor R.G.
      • Aylward P.E.
      • Sundlöf G.
      • Mark A.L.
      Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure.
      ], hypertension [
      • Grassi G.
      • Cattaneo B.M.
      • Seravalle G.
      • Lanfranchi A.
      • Mancia G.
      Baroreflex control of sympathetic nerve activity in essential and secondary hypertension.
      ], kidney disease [
      • Converse Jr., R.L.
      • Jacobsen T.N.
      • Toto R.D.
      • Jost C.M.
      • Cosentino F.
      • Fouad-Tarazi F.
      • et al.
      Sympathetic overactivity in patients with chronic renal failure.
      ], T2DM [
      • Huggett R.J.
      • Scott E.M.
      • Gilbey S.G.
      • Stoker J.B.
      • Mackintosh A.F.
      • Mary D.A.
      Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension.
      ], metabolic syndrome [
      • Grassi G.
      • Dell’Oro R.
      • Quarti-Trevano F.
      • Scopelliti F.
      • Seravalle G.
      • Paleari F.
      • et al.
      Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome.
      ], and obstructive sleep apnea syndrome [
      • Narkiewicz K.
      • Somers V.K.
      The sympathetic nervous system and obstructive sleep apnea: implications for hypertension.
      ]. Importantly, sympathetic overactivity is associated with a poor prognosis in patients with HF [
      • Barretto A.C.
      • Santos A.C.
      • Munhoz R.
      • Rondon M.U.
      • Franco F.G.
      • Trombetta I.C.
      • et al.
      Increased muscle sympathetic nerve activity predicts mortality in heart failure patients.
      ] or end-stage renal disease [
      • Zoccali C.
      • Mallamaci F.
      • Parlongo S.
      • Cutrupi S.
      • Benedetto F.A.
      • Tripepi G.
      • et al.
      Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.
      ], as well as in high-functioning, community-dwelling elderly persons [
      • Reuben D.B.
      • Talvi S.L.
      • Rowe J.W.
      • Seeman T.E.
      High urinary catecholamine excretion predicts mortality and functional decline in high-functioning, community-dwelling older persons: MacArthur Studies of Successful Aging.
      ].
      Chronic elevation of sympathetic activity not only triggers the development of hypertension [
      • Grassi G.
      Role of the sympathetic nervous system in human hypertension.
      ], but also has deleterious effects on the vasculature and kidneys that are independent of the increase in BP [
      • Fisher J.P.
      • Young C.N.
      • Fadel P.J.
      Central sympathetic overactivity: maladies and mechanisms.
      ]. Sympathetic overactivity increases arterial stiffness [
      • Mangoni A.A.
      • Mircoli L.
      • Giannattasio C.
      • Mancia G.
      • Ferrari A.U.
      Effect of sympathectomy on mechanical properties of common carotid and femoral arteries.
      ], causes endothelial dysfunction [
      • Hijmering M.L.
      • Stroes E.S.
      • Olijhoek J.
      • Hutten B.A.
      • Blankestijn P.J.
      • Rabelink T.J.
      Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation.
      ], and alters renal sodium and water homeostasis to promote fluid retention and edema [
      • DiBona G.F.
      Sympathetic nervous system and the kidney in hypertension.
      ]. The kidney is the epicenter of sympathetic overactivity in patients with high BP and HF. Renal stress results in signaling to the brain, which stimulates the sympathetic center and enhances sympathetic outflow to the whole body. We hypothesized that SGLT2 participates in activation of the sympathetic nervous system and that inhibition of SGLT2 may have a cardiovascular protective effect by reducing renal afferent nervous activity and suppressing central reflex mechanisms that contribute to generalized sympathetic activation. In agreement with this hypothesis, SGLT2 inhibitors have been shown to improve the circadian rhythm of sympathetic activity in rats with metabolic syndrome [
      • Rahman A.
      • Fujisawa Y.
      • Nakano D.
      • Hitomi H.
      • Nishiyama A.
      Effect of a selective SGLT2 inhibitor, luseogliflozin, on circadian rhythm of sympathetic nervous function and locomotor activities in metabolic syndrome rats.
      ] and to reduce high fat diet-induced elevation of tyrosine hydroxylase and noradrenaline in the kidneys and hearts of mice [
      • Matthews V.B.
      • Elliot R.H.
      • Rudnicka C.
      • Hricova J.
      • Herat L.
      • Schlaich M.P.
      Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2.
      ].
      In patients with T2DM, a higher HR is associated with an increased risk of death and cardiovascular complications [
      • Hillis G.S.
      • Hata J.
      • Woodward M.
      • Perkovic V.
      • Arima H.
      • Chow C.K.
      • et al.
      Resting heart rate and the risk of microvascular complications in patients with type 2 diabetes mellitus.
      ]. The baseline resting HR and the change in HR over time have been reported to predict outcomes for patients with HFpEF [
      • Vazir A.
      • Claggett B.
      • Pitt B.
      • Anand I.
      • Sweitzer N.
      • Fang J.
      • et al.
      Prognostic importance of temporal changes in resting heart rate in heart failure and preserved ejection fraction: from the TOPCAT Study.
      ]. When an SGLT2 inhibitor was administered to T2DM patients with an early morning surge for BP control, I noticed that HR declined in the patients with a high resting HR. In placebo-controlled clinical trials of the SGLT2 inhibitor luseogliflozin for T2DM patients not receiving other hypoglycemic medications, the relationship between pretreatment resting HR and the change in resting HR after 12 weeks of treatment was analyzed [
      • Sano M.
      Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors.
      ,
      • Sano M.
      • Chen S.
      • Imazeki H.
      • Ochiai H.
      • Seino Y.
      Changes in heart rate in patients with type 2 diabetes mellitus after treatment with luseogliflozin: Sub-analysis of placebo controlled, double-blind clinical trials.
      ]. When the resting HR was ≤70 beats per minute (bpm), it showed no change after starting luseogliflozin. However, among patients with a resting HR >70 bpm, a higher HR was associated with a larger decrease after starting luseogliflozin treatment. Given that resting HR is one of the indicators of sympathetic outflow to the heart, this clinical observation suggests that luseogliflozin reduced the HR in T2DM patients with central sympathetic overactivity. In the same manner, correction of systemic fluid retention by SGLT2 inhibitors following transient osmotic diuresis can be explained as being due to reduction of sympathetic outflow to the kidneys. That is, the renal pressure–natriuresis curve may be shifted to the left (i.e. the kidneys excrete more sodium and water at a given pressure) over a 2-month period, thereby normalizing fluid retention in T2DM patients on treatment with SGLT2 inhibitors.

      SGLT2 inhibitors reduce the burden on the proximal renal tubules in diabetic kidney disease

      SGLT2 is almost exclusively expressed in the proximal tubular epithelial cells of the kidneys and selective SGLT2 inhibitors block resorption of glucose by the proximal renal tubules. What is responsible for SGLT2 inhibitors reducing renal afferent sympathetic tone in T2DM patients? Clearly, it cannot be explained by the increase in urinary glucose excretion and associated osmotic diuresis that are well-known effects of these drugs. In order to solve this mystery, it is necessary to elucidate the mechanism responsible for the renoprotective effect of SGLT2 inhibitors. A pre-specified secondary analysis of renal outcomes from the EMPA-REG OUTCOME trial revealed that adding empagliflozin to standard care for T2DM patients (80% of them were treated with renin–angiotensin system blockers) was associated with a significant reduction in the progression of kidney disease, including the rate of decline in the estimated glomerular filtration rate (eGFR), progression of albuminuria, and initiation of renal replacement therapy [
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • Fitchett D.
      • von Eynatten M.
      • Mattheus M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      ]. In addition, a favorable effect of canagliflozin on renal outcomes was observed in the CANVAS trial [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ] and cardiovascular death was decreased by 40% in the EMPA-REG OUTCOME trial. While empagliflozin therapy was associated with changes in various clinical parameters, the change in hematocrit (Hct) was most closely related to the decrease in cardiovascular death. The key to elucidating the effect of SGLT2 inhibitors on the diabetic kidney is related to the characteristic increase in Hct observed when these drugs are administered. Although Hct increases, the blood urea nitrogen (BUN) level and BUN/creatinine ratio usually show no changes. When thiazide diuretics are administered, elevation of Hct is not considered to increase the risk of cerebral infarction. With SGLT2 inhibitor therapy, Hct increases slowly over 2 months and the higher level is subsequently maintained for as long as administration continues. This change in Hct does not correspond with the time course of the increase in urine volume. As mentioned above, urine volume peaks on the first day of SGLT2 inhibitor administration and then returns to the basal level within a few days. Therefore, the increase in Hct is unlikely to be due to reduction of the circulating blood volume because of hypovolemia accompanying dehydration. If the increase in Hct is not ascribable to hypovolemia, another possibility is an increase in circulating red blood cells. In support of this possibility, when the SGLT2 inhibitor dapagliflozin was administered to T2DM patients, the blood level of erythropoietin (EPO) increased after 1 week and peaked at 2 weeks, before returning to the pretreatment level after 2 months [
      • Lambers Heerspink H.J.
      • de Zeeuw D.
      • Wie L.
      • Leslie B.
      • List J.
      Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.
      ]. The reticulocyte count also increased along with the increase in EPO, followed by elevation of both hemoglobin and Hct. These changes were not observed in the patients treated with placebo or hydrochlorothiazide.
      As chronic kidney disease (CKD) progresses, fibrosis occurs, and EPO production is impaired. In the kidneys, interstitial fibroblasts exist in contact with the renal tubules. In addition to maintaining tissue architecture, fibroblasts act as endocrine cells, producing EPO in the renal cortex and prostaglandins in the renal medulla. Under normal conditions, several percent of cortical fibroblasts are involved in EPO production.
      Yanagida's research group at Kyoto University reported that targeted proximal tubule injury triggers the transformation of fibroblasts to myofibroblasts, after which the transformed cells promoted interstitial fibrosis and lost the ability to produce EPO [
      • Asada N.
      • Takase M.
      • Nakamura J.
      • Oguchi A.
      • Asada M.
      • Suzuki N.
      • et al.
      Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.
      ]. If proximal renal tubular injury is mild, transformation of fibroblasts is reversible and EPO production can recover [
      • Takaori K.
      • Nakamura J.
      • Yamamoto S.
      • Nakata H.
      • Sato Y.
      • Takase M.
      • et al.
      Severity and frequency of proximal tubule injury determines renal prognosis.
      ]. Repeated injury to the proximal tubules has been shown to reproduce various characteristic features of CKD, such as interstitial fibrosis, atubular glomeruli, loss of microvessels, distal tubular injury, and glomerulosclerosis [
      • Takaori K.
      • Nakamura J.
      • Yamamoto S.
      • Nakata H.
      • Sato Y.
      • Takase M.
      • et al.
      Severity and frequency of proximal tubule injury determines renal prognosis.
      ,
      • Bonventre J.V.
      Can we target tubular damage to prevent renal function decline in diabetes?.
      ].
      For resorption of glucose by proximal tubular epithelial cells to occur, SGLT2 localized to the apical side (adjacent to the tubular lumen) acts together with GLUT2 and Na+/K+ ATPase (Na+/K+ pump) localized to the basolateral side (adjacent to the blood vessel). The Na+/K+ pump consumes energy (ATP) to actively export intracellular Na+ (into the blood vessel) against a concentration gradient. As a result, the intracellular Na+ concentration remains low and this promotes influx of Na+ across the apical membrane via SGLT 2 simultaneously with glucose. Under physiological conditions, ATP is mainly produced from pyruvic acid or glutamine by mitochondrial respiration in the proximal nephron and glucose is rarely utilized. In the diabetic state, the proximal tubular epithelial cells consume more ATP and resorb a greater amount of glucose than in the non-diabetic state. Oxygen consumption is increased in the renal cortex of diabetic rats compared to healthy rats, resulting in a decrease in the local tissue partial pressure of oxygen, while administration of phlorizin to inhibit SGLT2 relieves proximal tubular epithelial cells from the burden of resorbing large amounts of glucose and alleviates renal cortical hypoxia [
      • Körner A.
      • Eklöf A.C.
      • Celsi G.
      • Aperia A.
      Increased renal metabolism in diabetes. Mechanism and functional implications.
      ,
      • O’Neill J.
      • Fasching A.
      • Pihl L.
      • Patinha D.
      • Franzén S.
      • Palm F.
      Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.
      ].
      The results of the above animal experiments suggest the following hypothesis (Fig. 1). In patients with diabetes, proximal renal tubular epithelial cells are overloaded by excessive energy-dependent resorption of glucose and the exhausted proximal tubular cells secrete inflammatory cytokines [
      • Gewin L.
      • Zent R.
      • Pozzi A.
      Progression of chronic kidney disease: too much cellular talk causes damage.
      ], leading to changes in the tubulointerstitial microenvironment that induce transformation of fibroblasts into myofibroblasts. Subsequently, the myofibroblasts proliferate and produce a collagen-rich extracellular matrix, while losing the ability to produce EPO. As a result of these changes, interstitial fibrosis progresses and EPO production declines. In fact, it has been reported that relative anemia associated with EPO deficiency can occur early in diabetic kidney disease before the development of advanced renal failure [
      • Bosman D.R.
      • Winkler A.S.
      • Marsden J.T.
      • Macdougall I.C.
      • Watkins P.J.
      Anemia with erythropoietin deficiency occurs early in diabetic nephropathy.
      ]. When SGLT2 inhibitors are administered to patients with diabetes, the burden of excessive glucose resorption is removed from the proximal tubular epithelial cells. This allows the damaged proximal tubular epithelial cells to undergo repair and tubulointerstitial changes in the renal cortex to recover, with EPO production by fibroblasts being restored. As the blood level of EPO increases, hematopoiesis is enhanced and Hct improves.
      Figure thumbnail gr1
      Fig. 1Proposed mechanism of cardiovascular protection by SGLT2 inhibitors. SGLT2, sodium glucose cotransporter 2.
      Thus, treatment with an SGLT2 inhibitor rests the exhausted proximal tubular epithelial cells (by reducing energy-dependent glucose resorption), resulting in amelioration of the structural and functional manifestations of diabetic kidney disease. Moreover, the increase in Hct (due to improvement of relative anemia associated with EPO deficiency) in T2DM patients receiving SGLT 2 inhibitors should be regarded as a surrogate marker of renal recovery from tubulointerstitial injury.
      In patients with HF damaged cardiomyocytes are rested by β-blocker therapy, resulting in reverse remodeling and restoration of myocardial contractility. Analogous to the action of β-blockers on damaged cardiomyocytes, SGLT2 inhibitors provide relief to the exhausted proximal tubular epithelial cells in patients with diabetes, which may allow reverse remodeling of the kidney and restoration of renal function [
      • Gilbert R.E.
      SGLT2 inhibitors: β blockers for the kidney?.
      ,
      • Sano M.
      • Takei M.
      • Shiraishi Y.
      • Suzuki Y.
      Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys.
      ].
      Since the majority of patients enrolled in the EMPA-REG OUTCOME trial and the CANVAS trial did not have any evidence of diabetic kidney disease as assessed by eGFR or albuminuria, whether SGLT2 inhibitors are effective for established diabetic kidney disease cannot be determined until the results of the CREDENCE trial (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) are reported.

      Future perspective – what stresses are sensed by the kidneys and transmitted to the brain?

      Chronic activation of the sympathetic nervous system increases the risk of cardiovascular disease [
      • Thorp A.A.
      • Schlaich M.P.
      Relevance of sympathetic nervous system activation in obesity and metabolic syndrome.
      ]. Many factors have been proposed to contribute to chronic sympathetic activation inT2DM patients, including hyperinsulinemia related to overeating [
      • Muntzel M.S.
      • Anderson E.A.
      • Johnson A.K.
      • Mark A.L.
      Mechanisms of insulin action on sympathetic nerve activity.
      ,
      • Cassaglia P.A.
      • Hermes S.M.
      • Aicher S.A.
      • Brooks V.L.
      Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats.
      ,
      • Lembo G.
      • Napoli R.
      • Capaldo B.
      • Rendina V.
      • Iaccarino G.
      • Volpe M.
      • et al.
      Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension.
      ] and selective leptin resistance due to visceral adiposity [
      • Mark A.L.
      Selective leptin resistance revisited.
      ]. However, sympathetic activity appears to be primarily modulated by afferent signals from the kidneys, which are richly innervated by chemoreceptors and baroreceptors that send information to the brain [
      • Kaur J.
      • Young B.E.
      • Fadel P.J.
      Sympathetic overactivity in chronic kidney disease: consequences and mechanisms.
      ]. It is possible that excessive resorption of glucose in the proximal tubules participates in the activation of renal afferent nerves and results in central sympathetic overactivity, leading to increased efferent sympathetic outflow to the heart, vessels, and kidneys [
      • Campese V.M.
      • Kogosov E.
      Renal afferent denervation prevents hypertension in rats with chronic renal failure.
      ,
      • Ye S.
      • Zhong H.
      • Yanamadala V.
      • Campese V.M.
      Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity.
      ,
      • Katholi R.E.
      • Whitlow P.L.
      • Hageman G.R.
      • Woods W.T.
      Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog.
      ,
      • Hausberg M.
      • Kosch M.
      • Harmelink P.
      • Barenbrock M.
      • Hohage H.
      • Kisters K.
      • et al.
      Sympathetic nerve activity in end-stage renal disease.
      ].
      Is renal stress and increased afferent signaling to the brain mediated by the peritubular microenvironment (hypoxia, inflammation, etc.), intraglomerular hypertension, or other factors? By modulating the tubuloglomerular feedback mechanism, SGLT2 inhibitors cause constriction of the afferent arterioles that reduces the intraglomerular pressure and single nephron GFR [
      • Cherney D.Z.
      • Perkins B.A.
      • Soleymanlou N.
      • Maione M.
      • Lai V.
      • Lee A.
      • et al.
      Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.
      ]. This nicely explains the initial decrease in eGFR after initiation of SGLT2 inhibitor therapy. However, it is unknown whether reduction of single nephron hyperfiltration is involved in the improvement in renal outcomes by SGLT 2 inhibitors. In this context, the reduction of albuminuria in patients with T2DM by dapagliflozin after 12 weeks of treatment was largely independent of changes in eGFR [
      • Heerspink H.J.
      • Johnsson E.
      • Gause-Nilsson I.
      • Cain V.A.
      • Sjöström C.D.
      Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin–angiotensin blockers.
      ]. This finding argues against the concept that reducing intraglomerular pressure is the mechanism underlying improvement in renal outcomes by SGLT 2 inhibitors. Rats with 5/6 nephrectomy represent a model of CKD associated with single nephron hyperfiltration and intraglomerular hypertension, and these animals display hypertension, heavy proteinuria, and a declining GFR which are not ameliorated by administration of dapagliflozin [
      • Zhang Y.
      • Thai K.
      • Kepecs D.M.
      • Gilbert R.E.
      Sodium-glucose linked cotransporter-2 inhibition does not attenuate disease progression in the rat remnant kidney model of chronic kidney disease.
      ,
      • Ansary T.M.
      • Fujisawa Y.
      • Rahman A.
      • Nakano D.
      • Hitomi H.
      • Kobara H.
      • et al.
      Responses of renal hemodynamics and tubular functions to acute sodium-glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats.
      ].
      In conclusion, a proposed mechanism for cardiovascular protection by SGLT2 inhibitors is summarized in Fig. 2. Further investigation is required to better understand the potential of SGLT2 inhibitors for managing HF. SGLT2 inhibitor priming prior to administration of furosemide could be worth trying as a treatment strategy for HF patients with cardiorenal syndrome.
      Figure thumbnail gr2
      Fig. 2SGLT2 inhibitors reduce the burden on the proximal renal tubules. SGLT2 inhibitors reduce central sympathetic overactivity, probably by suppressing renal afferent signaling to the brain. A mild state of ketosis also contributes to reduction of sympathetic tone. Decreased sympathetic outflow from the brain to the kidney alters the pressure–natriuresis relationship so that the kidneys excrete more sodium and water at a given pressure, thereby improving fluid retention. It may also suppress the renal renin–angiotensin system (RAS) and augment circulating natriuretic peptide levels by attenuating renal neprilysin activity
      [
      • Polhemus D.J.
      • Trivedi R.K.
      • Gao J.
      • Li Z.
      • Scarborough A.L.
      • Goodchild T.T.
      • et al.
      Renal sympathetic denervation protects the failing heart via inhibition of neprilysin activity in the kidney.
      ]
      , thereby correcting the imbalance between the natriuretic peptide/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway and the RAS pathway, leading to cardiovascular and renal protection. EPO, erythropoietin; SGLT2, sodium glucose cotransporter 2; T2DM, type 2 diabetes mellitus.

      Funding

      This research was supported by JSPS KAKENHI grants 15H04825 (2015–2017) (to Dr. Sano).

      Conflict of interest

      The author (M.S.) has received scholarships from Boehringer Ingelheim and Taisho Toyama Pharmaceutical Co., Ltd., and lecture fees from Boehringer Ingelheim, Taisho Toyama Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Corporation.

      Acknowledgments

      The author wishes to express his gratitude to H. Ito (Keio University, Japan), M. Yanagida (Kyoto University, Japan), and A. Nishiyama (Kagawa University, Japan) for their inspiring lectures.

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