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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.
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.
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 [
]. 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 [
]. 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.
Abbreviated study title
Full study title
Trial identification number
Dapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients With Heart Failure
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 [
]. 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 [
]. 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 [
]. 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 [
] 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 [
]. 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 [
]. 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 [
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 [
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 [
], 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 [
]. 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.
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 [
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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
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.
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.
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.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.