Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

Abstract

SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce the risk of heart failure hospitalizations by ≈30% in large-scale trials of patients with type 2 diabetes, chronic heart failure, and chronic kidney disease, an effect that is independent of glycemic status, ejection fraction, or renal function.¹ Although myriad hypotheses have been proposed, 2 broad mechanisms are considered likely to underlie this benefit. First, SGLT2 inhibitors act on the kidney to promote changes in urinary electrolyte and water excretion. The resulting shift in the volume of circulating and noncirculating fluid compartments, in conjunction with potential modulation of renal salt sensing, reduces the likelihood of volume expansion that often precedes hospitalization for heart failure.² Second, SGLT2 inhibitors act directly on the heart to induce nutrient deprivation signaling and promote autophagy, which reduces oxidative and endoplasmic reticulum stress and enhances cellular function and viability.^3,4 This direct action on cardiomyocytes is independent of the presence, binding, or inhibition of SGLT2,^3,5 and the effects on cellular health can be negated by genetic or pharmacological interventions that silence sirtuin-1 or AMP-activated protein kinase or interfere with autophagic flux.³

Recent reviews have focused on the direct cardiac effects of SGLT2 inhibitors mediated by the modulation of nutrient transport and nutrient deprivation signaling,^3,4 whereas the current overview provides a comprehensive and critical analysis of the direct effects of SGLT2 inhibitors on the urinary handling of electrolytes and water.

EFFECTS OF SGLT2 INHIBITION IN THE PROXIMAL RENAL TUBULE AND IMPORTANCE OF COUNTERBALANCING RESPONSES IN DOWNSTREAM NEPHRON SEGMENTS

Diabetes and heart failure lead to upregulation of SGLT2 in the proximal renal tubule, enhancing its sensitivity to SGLT2 inhibition.^6–8 The expression of SGLT2 is enhanced by renal sympathetic hyperactivity;^7,9 consequently, renal denervation reduces glycosuria, and it attenuates the glycosuric effect of SGLT2 inhibitors.^7,9,10 Renal sympathetic nerve activity is heightened particularly in acutely decompensated heart failure,¹¹ potentially augmenting the glycosuric effect of SGLT2 inhibitors; accordingly, the magnitude of glycosuria appears to wane as the acuity of the episode subsides.¹²

SGLT2 in the S1 and S2 segments of the proximal tubule is responsible for the overwhelming majority of glucose reabsorption in the kidney (Figure 1).¹³ In micropuncture studies, SGLT2 inhibition produces a glycosuria-dependent osmotic diuresis, which increases tubular fluid osmolality sufficiently to dilute proximal tubular sodium and induce a back leak of sodium into the lumen by passive paracellular pathways;^13,14 thus, an osmotic diuresis yields an increase in urine volume accompanied by a modest reduction in proximal tubular sodium reabsorption.¹³ The magnitude of SGLT2 inhibitor–mediated glycosuria is reduced in chronic kidney disease.^14,15

Figure 1.

Direct and compensatory actions of SGLT2 inhibitors on the proximal renal tubule and distal nephron segments. SGLT2 (sodium glucose cotransporter 2) inhibitors directly interfere with the actions of SGLT2 and NHE3 (sodium hydrogen exchanger 3) in the S1 and S2 segments of the proximal tubule, thus inhibiting the reabsorption of sodium, glucose, bicarbonate, and water. These effects are counteracted by upregulation of electrolyte and water reabsorptive pathways in downstream nephron segments, mediated by vasopressin, aldosterone, α-ketoglurate, carbonic anhydrase, and uromodulin. The net result is a modest short-lived natriuresis and diuresis, and potentially, a change in the equilibrium set point for volume homeostasis. Segments in blue are sites of sodium, glucose, bicarbonate and water reabsorption that are attenuated by SGLT2 inhibitors; segments in red are sites of sodium, chloride, bicarbonate, and water reabsorption that are potentiated by SGLT2 inhibitors.

Two-thirds of the filtered sodium is absorbed in the proximal tubule,¹⁶ primarily through the action of NHE3 (sodium-hydrogen exchanger 3). NHE3 is colocalized with and structurally interlinked with SGLT2 in the brush border.^17,18 As a result, SGLT2 inhibitors modulate the functionality of NHE3 (even in the absence of luminal glucose), and this action likely underlies the effects of these drugs on renal sodium handling. Experimental silencing of NHE3 abrogates the effects of SGLT2 inhibition on proximal tubular sodium reabsorption.^8,17,19 Inhibition of NHE3 also promotes bicarbonate excretion,^{8,16,17,19–21} contributing to the small decrease in serum bicarbonate observed in clinical trials.^22,23

Activation of Counterbalancing Renal Tubular Mechanisms

If the effects of SGLT2 inhibitors were determined entirely by their actions on SGLT2 and NHE3 in the proximal renal tubule, their administration would result in a massive loss of sodium, water, and bicarbonate, leading to intravascular and extracellular volume depletion and marked acidosis.²⁴ Although hypovolemic euglycemic acidosis can occur in patients receiving SGLT2 inhibitors, it is typically associated with ketosis resulting from calorie restriction or insulinopenia.²⁵ In most circumstances, the lack of hypovolemia and acidosis is related to compensatory nephron mechanisms that counteract the effects of SGLT2 and NHE3 inhibition.

Specifically, SGLT2 inhibition is followed by marked enhancement of sodium reabsorption in downstream nephron segments, including the S3 segment of the proximal tubule, the loop of Henle, and the distal nephron (Figure 1).^13,26,27 Clinical trial proteomic analyses suggest that SGLT2 inhibition is accompanied by upregulation of carbonic anhydrase and uromodulin.²⁸ Activation of carbonic anhydrase promotes sodium and bicarbonate reabsorption in the proximal tubule and in the cortical collecting duct,^29,30 and uromodulin activates the Na⁺,K⁺,2Cl^– cotransporter in the loop of Henle.³¹ SGLT2 inhibition elevates circulating levels of aldosterone in some studies,³² and increased glucose delivery to the distal convoluted tubule activates sodium reabsorption by the Na-Cl cotransporter.³³ In addition, SGLT2 inhibitors increase the proximal tubular levels of α-ketoglutarate,¹⁹ which promotes sodium and chloride reabsorption by facilitating chloride-bicarbonate exchanger–related reabsorption pathways, while enhancing ammoniagenesis to achieve renal acid excretion.^19,34,35 These compensatory mechanisms, acting in concert, enhance sodium chloride reabsorption in the loop of Henle and more distal segments of the nephron, while simultaneously preventing the development of severe metabolic acidosis.

The mild osmotic diuresis that occurs with the tubular glucose load induced by SGLT2 inhibitors is easily compensated for by normal osmoregulatory mechanisms, primarily vasopressin.^36–39 The magnitude of the reactive antiaquaretic effect can be sufficiently marked to paradoxically cause a decrease in free water clearance in clinical studies of SGLT2 inhibitors,^37,40 explaining why plasma osmolarity increases only slightly during the water diuresis induced by glycosuria^18,39,40 and why serum sodium concentration can decline after initiation of treatment.⁴¹ An increase in electrolyte-free water clearance becomes apparent if vasopressin is suppressed by water loading.⁴² Vasopressin also increases sodium reabsorption in the loop of Henle and distal segments.⁴³

Consequences of SGLT2 Inhibitor–Mediated Increases in Distal Chloride Delivery

In micropuncture studies, inhibition of SGLT2 and NHE3 in the proximal tubule enhances the delivery of chloride to downstream segments,²⁰ with several potential consequences.

Activation of Downstream Sodium Avidity and Mitigation of Hyperkalemia

As noted earlier, after SGLT2 inhibition, the reabsorption of sodium and chloride is enhanced in downstream nephron sites^20,33 as a result of upregulation of vasopressin, uromodulin, aldosterone, and α-ketoglutarate.^{20,28,32,36–38,44–46} Increases in aldosterone may in part explain the effect of SGLT2 inhibitors to mitigate the risk of hyperkalemia (without inducing hypokalemia) in patients with diabetes or heart failure.^47,48

Activation of Tubuloglomerular Feedback

Increased delivery of chloride to the macula densa after SGLT2 inhibition activates tubuloglomerular feedback, leading to afferent arteriolar vasoconstriction or efferent arteriolar vasodilation and a decline in glomerular filtration pressure.^20,49–51 Tubuloglomerular feedback becomes saturated, and single-nephron glomerular filtration falls dramatically, but with time, there is partial adaptation caused by increased sodium reabsorption in the loop of Henle, in conjunction with resetting of tubuloglomerular feedback.²⁰ Tubuloglomerular feedback has been hypothesized to contribute to the early dip in glomerular filtration rate after initiation of SGLT2 inhibitors, although this link has been challenged.⁵²

Alleviation of Resistance to Loop Diuretics

Hypochloremia is a hallmark of diuretic resistance.^53,54 A reduction in filtered chloride combined with cellular chloride depletion activates WNK4 (with no lysine 4), thus increasing the activity of the Na⁺,K⁺,2Cl^- cotransporter,⁵⁵ the site of action of loop diuretics. Efforts to enhance chloride delivery (by dietary chloride⁵³ or acetazolamide⁵⁶) may inhibit WNK4 and restore responsiveness to loop diuretics.^53,57 SGLT2 inhibitors can increase serum chloride^58–60 and enhance the effects of loop diuretics,⁶¹ presumably because the increased delivery of sodium chloride to the loop of Henle enlarges the drug target.⁶²

Therefore, the net effect of SGLT2 inhibitors on the urinary sodium and water excretion may depend on (1) the activation of SGLT2 and NHE3; (2) the magnitude of glycosuria, which is limited in patients with impaired renal function; (3) the effect to promote downstream chloride delivery; and (4) the degree of upregulation of counterregulatory antinatriuretic and antiaquaretic mechanisms at downstream nephron sites.

EVALUATION OF SODIUM AND WATER EXCRETION IN CLINICAL STUDIES OF SGLT2 INHIBITORS

From our comprehensive review, we identified 27 studies that evaluated the effects of SGLT2 inhibitors on urinary sodium and water excretion in healthy volunteers or patients with type 2 diabetes, heart failure, or chronic kidney disease, for periods ranging from 3 days to 3 months (Table 1).^{12,32,37,39,40,42,44,46,58,61,63–81} Typically, dietary sodium and use of diuretics were not controlled; sodium balance was not achieved; and some studies analyzed spot (rather than 24-hour) urine collections.^12,46,67,81 Trials that were double-blind and placebo-controlled are less subject to these confounding factors.

Table 1.

Studies Reporting Effect of SGLT2 Inhibitors on Urinary Sodium and Water Excretion

Body weight was reported in many studies, but decreases in body weight during SGLT2 inhibition can be caused by the excretion of fluid or the loss of calories due to glycosuria.⁸² It is noteworthy that Zanchi et al³² and Sha et al⁶⁴ (who studied healthy volunteers and patients with diabetes) reported a reduction in body weight in the absence of a diuresis, but paradoxically, Mordi et al,⁴² Kolwelter et al,⁷⁹ Boorsma et al,^12,77 Tamaki et al,⁷⁸ and Schulze et al⁸⁰ (who studied patients with heart failure) did not observe decreases in weight, despite increased urine volume. These observations suggest that changes in body weight after SGLT2 inhibitors do not reliably reflect pretreatment fluid retention or the diuretic response to these drugs.

As shown in Table 1, the effect of SGLT2 inhibitors on sodium and water excretion varies with the clinical setting or study design (Figure 2).

Figure 2.

Effects of SGLT2 inhibitors on urinary sodium and water excretion in chronic heart failure and acutely decompensated heart failure. The administration of an SGLT2 (sodium glucose cotransporter 2) inhibitor to patients with acutely decompensated heart failure is often accompanied by a short-term water diuresis, but clinical improvement may be related primarily to a rapid and direct cardioprotective effect similar to that seen during the first 2 to 4 weeks of treatment in clinical trials of patients with chronic heart failure. The administration of an SGLT2 inhibitor to patients with chronic heart failure who are receiving loop diuretics can be accompanied by potentiation of the effect of the loop diuretic, resulting in a modest diuresis and a reduction in plasma volume. However, because of their erythropoietic effect, these drugs produce minimal changes in total blood volume or decreases in circulating natriuretic peptides, and thus, short-term changes in urinary sodium or water excretion do not explain the short- and long-term decrease in the risk of heart failure events. Intriguingly, these events are not reduced in randomized controlled trials of short-term intensification of other diuretic drugs. NHE3 indicates sodium hydrogen exchanger 3.

Healthy Volunteers and Patients With Type 2 Diabetes

In 18 studies of healthy individuals or patients with type 2 diabetes (none of whom were reportedly receiving diuretics), SGLT2 inhibition was typically (but not invariably) accompanied by immediate increases in the fractional excretion of lithium (indicative of inhibited proximal tubular sodium reabsorption), total urinary sodium excretion, and urinary volume (Table 1). However, after 5 to 7 days, although fractional lithium excretion was maintained and glycosuria persisted, the drugs had no significant effect on total urinary sodium excretion or volume. Several studies^{37,39,40,44,46,72} have noted a decrease in free water clearance, accompanied by vasopressin activation; such an antiaquaretic counterregulatory response may be particularly likely in patients with diabetes.⁸³

Heart Failure With and Without Recent Acute Decompensation

In patients with chronic heart failure receiving low doses of loop diuretics, the response to SGLT2 inhibition was characterized primarily by an increase in electrolyte-free water clearance. Four double-blind, placebo-controlled trials reported on the effects of SGLT2 inhibitors in patients who were treated with and responsive to furosemide equivalent doses <40 to 80 mg/d;^12,42,79,80 2 of the 4 trials evaluated patients with acutely decompensated heart failure. In all 4 trials, SGLT2 inhibition produced an immediate and persistent increase in urinary volume, which was not accompanied by significant changes in urinary sodium excretion and was attributed to an osmotic diuresis produced by glycosuria. Counterregulatory downstream sodium reabsorptive mechanisms may be particularly active in the sodium-avid state of heart failure. A water diuretic effect may be especially evident in patients with acutely decompensated heart failure, possibly because renal sympathetic nerve hyperactivity in this setting enhances the glycosuric effect of SGLT2 inhibitors.^7–12 However, any water diuresis that follows a tubular glucose load would be rapidly opposed by normal osmoregulatory mechanisms, such as thirst and the release of vasopressin, thus minimizing the durability and clinical importance of an osmotic effect.

Chronic Heart Failure With Diuretic Resistance

Two studies evaluated in the effect of SGLT2 inhibition in patients with heart failure who were diuretic-resistant. Yeoh et al⁸¹ evaluated 61 patients with heart failure who had fluid retention while receiving mean furosemide equivalent doses of ≈250 mg/d, who were randomized to dapagliflozin 10 mg/d or metolazone 5 to 10 mg/d; metolazone (but not dapagliflozin) potentiated the natriuretic effect of loop diuretics. Griffin et al⁷⁴ randomized 20 patients with diabetes and chronic heart failure who were clinically euvolemic while receiving mean furosemide equivalent doses of 244 mg/d. Patients received empagliflozin 10 mg/d or placebo (double blind), each for 14 days, followed by crossover to the alternative treatment. SGLT2 inhibition produced an immediate increase in the fractional sodium excretion, which was still discerned after 14 days, and the natriuresis was enhanced by bumetanide but was unrelated to the magnitude of glycosuria. Wilcox et al⁶¹ and Heise et al⁶⁶ also observed that SGLT2 inhibitors could potentiate the natriuretic effects of loop diuretics. Such potentiation may be related to the action of SGLT2 inhibitors to increase distal chloride delivery, thus sensitizing the Na⁺,K⁺,2Cl^- cotransporter to pharmacological antagonism,⁸⁴ yet potentiation of natriuresis was not observed in the patients with diuretic resistance and fluid retention who were studied by Yeoh et al.⁸¹

It is understood that the initial natriuretic response to any diuretic is typically attenuated as euvolemia is achieved as a result of the activation of counterregulatory mechanisms. The finding that fractional lithium clearance and glucose excretion persists during long-term SGLT2 inhibition indicates that pharmacological tolerance to the effects of these drugs on the proximal tubule does not develop.

EVALUATION OF PLASMA AND BLOOD VOLUME IN CLINICAL STUDIES OF SGLT2 INHIBITORS

Loop diuretics produce pulmonary decongestion in patients with heart failure by decreasing circulating plasma and blood volume, thus reducing cardiac filling pressures. Therefore, in characterizing the diuretic properties of SGLT2 inhibitors, studies of their effects on plasma volume are relevant.

Challenges in the Assessment of Plasma Volume During SGLT2 Inhibition

Plasma volumes can be measured using indicator dilution methods based on agents that bind to albumin. However, in most reports, plasma volume has been estimated indirectly, relying on formulae developed by Kaplan and Hakim for single assessments and by Strauss et al for paired assessments.⁸⁵ The Kaplan formula is based on hematocrit and body weight, whereas the Strauss formula focuses on the ratios of hemoglobin and hematocrit. These formulas yield poor estimates of directly measured values⁸⁶—often deviating by >1 liter⁸⁷—and provide unreliable metrics of clinical congestion⁸⁸ or decongestion.⁸⁹ Furthermore, the Strauss formula assumes that red blood cell mass in the central circulation does not change between paired assessments.^86,87 Because SGLT2 inhibitors stimulate erythropoietin and reticulocytosis within 7 days,^90–92 the Strauss formula cannot be applied for the estimation of changes in plasma volume with these drugs. Even if there were no erythropoiesis, estimation of plasma volume by the Strauss formula can be distorted by shifts in the distribution of red blood cells from intravascular pools, as is commonly seen during the clinical course of patients with acutely decompensated heart failure.^86–88,93

Even if measured accurately, decreases in plasma volume do not reliably reflect intravascular or total body decongestion. Diuretics may have little effect on or even increase plasma volume in heart failure, if they mobilize fluid from the interstitial space.^89,93–95 Furthermore, any expansion of red blood cell mass triggers an adaptive reduction in plasma volume, because if plasma volume were to remain constant, erythrocytosis would result in intolerable hypervolemia. This principle explains why physiological or pharmacologically induced increases in hematocrit (regardless of cause) lead to decreases in plasma volume.^96,97

Effect of SGLT2 Inhibitors on Plasma and Blood Volume in Clinical Studies

On the basis of a comprehensive review, we identified 15 studies that evaluated the effect of SGLT2 inhibitors on plasma volume (Table 2).^{64,72–74,78,98–109} Unfortunately, most studies estimated changes in plasma volume using the Kaplan-Hakim and Strauss formulae, which cannot be applied to the evaluation of changes produced by SGLT2 inhibitors. Four reports^64,72,74,109 used indicator dilution methods, and of these, 3 were double blind and placebo controlled. In patients with type 2 diabetes, SGLT2 inhibition for 12 weeks reduced plasma volume in 1 trial,¹⁰⁹ but not in another.⁶⁴ In the third trial,⁷⁴ SGLT2 inhibition decreased plasma volume in diuretic-resistant patients with heart failure after 2 weeks.

Table 2.

Studies Reporting Effect of SGLT2 Inhibitors on Plasma Volume

Decreases in the serum albumin concentration may reflect a dilution that occurs when plasma volume expands during sodium-avid states.¹¹⁰ SGLT2 inhibitors increase serum albumin in mechanistic studies and large-scale trials; the effects are seen after a few weeks and persist for the duration of treatment.^{23,103,108,110} When SGLT2 inhibitors are discontinued after long-term therapy, serum albumin falls within 7 days.¹¹¹

These observations indicate that SGLT2 inhibitors likely lead to a short- and long-term decrease in plasma volume (Figure 2). However, it is not clear whether this effect is related to the action of these drugs to promote a diuresis or an erythrocytosis. Regardless, as a result of SGLT2 inhibitor–stimulated erythropoiesis, the increase in red blood cell mass offsets any ability of a decrease in plasma volume to be translated into a change in total circulating blood volume during long-term therapy. SGLT2 inhibition reduced estimated total blood volume by only 1% in the only study in which it was evaluated.¹¹²

The lack of a meaningful effect on total blood volume may explain why SGLT2 inhibition did not reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels in the 5 placebo-controlled trials in patients with heart failure summarized in Table 1, whereas NT-proBNP levels are reduced by loop diuretics.^113,114 In large-scale heart failure trials, SGLT2 inhibition for 3 months produces only modest changes in natriuretic peptides and left ventricular filling pressures (even in patients with volume overload), with little correlation between changes in natriuretic peptides and metrics of decongestion.^{105,115–117} Even in acutely decompensated heart failure, changes in NT-proBNP are not apparent⁷⁹ or are modest and not sustained.¹¹⁸

EVALUATION OF EXTRACELLULAR FLUID IN CLINICAL STUDIES OF SGLT2 INHIBITORS

Most of the excess fluid in sodium-avid states is retained in the interstitial compartment, where it is manifested as edema.¹¹⁹ Diuretics alleviate fluid retention by reducing intravascular volume, which promotes the movement of sodium and water from the interstitial space into the circulation, followed by excretion through the kidneys. Interstitial fluid is mobilized through both plasma transcapillary refill and the action of lymphatics, which drain the interstitial space, moving fluid into the great veins.¹²⁰ Lymphatic mobilization is gradient-dependent, and increases in right-sided filling pressures can impair both plasma transcapillary refill and lymphatic fluid uptake and duct flow;^120,121 lymphatic congestion within the kidney may also impair sodium excretion.¹²² Therefore, by reducing right-sided filling pressures, loop diuretics not only enhance plasma transcapillary refill but also markedly increase lymphatic flows and drainage of the interstitial space,¹²³ allowing a reduction in total body extracellular water and edema.⁸⁹

Effect of SGLT2 Inhibitors on Extracellular Fluid in Clinical Studies

On the basis of a comprehensive review, we identified 13 studies that evaluated the effects of SGLT2 inhibitors on extracellular water (Table 3).^{44,46,67,72,73,79,99,103,108,124–128} These reports performed measurements using diverse methods, typically without a control group, making it difficult to reliably discern a treatment effect. In 5 trials that were double blind and placebo controlled, SGLT2 inhibition modestly decreased extracellular fluid in patients with diabetes or heart failure after 1 to 2 weeks, but with little effect after 1 to 3 months. Meaningful responses were noted only in patients with pretreatment fluid retention,^46,127,128 but these reports were not double blind or placebo controlled.

Table 3.

Studies Reporting Effect of SGLT2 Inhibitors on Extracellular Water

Some investigators have used computer modeling to project the effect of SGLT2 inhibitors on interstitial fluid and concluded that these drugs deplete extracellular water more profoundly than conventional diuretics.² These models assumed that SGLT2 inhibitors act primarily as aquaretics to increase serum osmolarity, a finding not confirmed by clinical studies,^2,129 and the models also did not consider the effect of enhanced erythropoiesis to maintain total blood volume. The conclusions of these models are inconsistent with the efficacy of conventional diuretics in edematous states.^89,130

It has been hypothesized that the interstitium contains nonosmotically active sodium, which has adverse effects on vascular function.¹³¹ SGLT2 inhibitors may reduce skin (but not muscle) sodium content after 1 and 3 months of treatment,^79,124 but it is not clear that these measurements reflect nonosmotic stores of the ion.¹³² Nonosmotic stores of sodium might be a determinant of vascular resistance, but not of edema.^132,133

EFFECT OF SGLT2 INHIBITORS ON EDEMA AND CONGESTION

The primary end point for the regulatory approval of diuretics is the alleviation of edema in sodium-avid states. Thiazide and loop diuretics, mineralocorticoid receptor antagonists, and vasopressin antagonists ameliorate fluid retention in heart failure, hepatic cirrhosis, and nephrotic syndrome.^134–137 In contrast, there are no reports of a favorable effect of SGLT2 inhibitors to reduce the edema of heart failure or the ascites of hepatic cirrhosis. Observations about decongestion are difficult to interpret when patients are being concurrently treated with an intensified regimen of loop diuretics.⁸¹

It is interesting that in patients hospitalized for heart failure, there may be little relationship between the magnitude of natriuresis and the relief of symptoms. Intensive intravenous loop diuretics produce a greater diuresis but not greater effects on pulmonary congestion.¹³⁸ The addition of hydrochlorothiazide to a loop diuretic yields a modest diuretic effect, but no incremental benefit on dyspnea.¹³⁹ Acetazolamide potentiates the natriuretic response to loop diuretics but without a reported benefit on symptoms.¹⁴⁰ Conventional diuretics may preferentially act to remove excess fluid from the interstitial space, with little change in total blood volume, cardiac filling pressures, or symptoms.⁸⁹

Effect of SGLT2 Inhibitors on Congestion in Acutely Decompensated Heart Failure

Three double-blind, placebo-controlled trials have evaluated the effects of SGLT2 inhibitors in patients with acutely decompensated heart failure, treated for ≤90 days: EMPAG-HF (Empagliflozin in Acute Decompensated Heart Failure),⁸⁰ EMPA-RESPONSE-AHF (Empagliflozin Response Acute Heart Failure),^12,77 and EMPULSE (Empagliflozin in Patients Hospitalized for Acute Heart Failure).^118,141 The largest trial (EMPULSE [Empagliflozin in Patients Hospitalized for Acute Heart Failure]) enrolled 530 patients (NT-proBNP ≈3200 pg/mL) who (after in-hospital stabilization) were randomized to placebo or empagliflozin (10 mg/d) for 3 months. Empagliflozin reduced a composite symptom score, with benefits seen as early as 15 days, but with modest changes in NT-proBNP. Although patients were required to have pulmonary congestion or peripheral edema at randomization, the effects of empagliflozin on signs of fluid retention were not reported. Treatment with empagliflozin did not spare the use of loop diuretics; the number of patients receiving furosemide (>40 mg/d) was numerically more frequent in the empagliflozin group. Changes in body weight and hematocrit could not be ascribed to a diuresis, because they can be influenced by the rapid effects of empagliflozin to induce urinary caloric loss and erythropoiesis.

How did SGLT2 inhibition improve symptoms in patients with acutely decompensated heart failure at 15 days? Although urinary volume and sodium excretion were not measured in the EMPULSE trial, 2 earlier trials performed these assessments in the same clinical setting. In the EMPAG-HF trial,⁸⁰ 60 patients were randomized within 12 hours of admission (NT-proBNP ≈4800 pg/mL) to placebo or empagliflozin for 5 days. In the EMPA-RESPONSE-AHF trial,^12,77 79 patients were randomized within 24 hours of admission (NT-proBNP ≈5200 pg/mL) to placebo or empagliflozin for 30 days. In both studies, SGLT2 inhibition increased urinary volume without an effect on fractional sodium excretion, total urinary sodium excretion, body weight, or NT-proBNP. Neither trial reported changes in edema or in signs of pulmonary congestion. These findings suggest that the water diuresis produced by SGLT2 inhibitors in patients with acutely decompensated heart failure is insufficiently durable to reduce body weight or NT-proBNP. Similarly, although urinary assessments were not performed, it seems unlikely that a water diuresis contributed to the findings in the EMPULSE trial, because empagliflozin reduced serum sodium concentration in that study, an effect that is inconsistent with an increase in free water clearance.¹⁴¹

Early Effects of SGLT2 Inhibitors in Chronic Heart Failure

Rather than reflecting a diuresis, the effect of SGLT2 inhibitors to improve symptoms at 15 days in the EMPULSE trial parallels a similar early reduction in symptoms and in the risk of hospitalization for heart failure in large-scale trials, which reaches nominal levels of statistical significance within 2 to 4 weeks.^142,143 Some investigators have proposed that this statistical event supports an action of SGLT2 inhibitors to promote a diuresis.¹⁴³ However, a similar early statistical event on heart failure hospitalizations is seen after the initiation of sacubitril/valsartan,¹⁴⁴ although the drug does not produce a natriuretic effect, even when combined with loop diuretics.^145,146 Early-onset statistical significance is also seen with β-blockers,¹⁴⁷ although these drugs typically promote early sodium retention. Because the benefits of SGLT2 inhibitors in heart failure are not time dependent,¹⁴⁸ the achievement of early statistical significance is merely a function of the duration of follow-up required to accrue a sufficient number of events rather than an indicator of a mechanism of action. It is therefore noteworthy that the effect of SGLT2 inhibitors to induce nutrient deprivation signaling and promote autophagy emerges rapidly^3,4 and are poised to make a meaningful difference in patients who are acutely ill or on the brink of decompensation at the time of randomization.

Additional analyses of the large-scale trials of SGLT2 inhibitors provide further evidence against a significant early diuretic effect of these drugs. In the EMPEROR-Reduced trial, 40% of the patients had recent volume overload before study enrollment and received larger doses of loop diuretics at baseline.¹¹⁷ However, those with recent volume overload were not more likely to show a reduction in cardiovascular death or hospitalization for heart failure with empagliflozin. The incidence plots separated immediately in patients without recent volume overload, but this separation occurred after 30 to 45 days in those with recent volume overload. Patients with recent volume overload were not more likely to show an improvement in functional class, decreases in body weight or natriuretic peptides, or increases in hematocrit during the first 4 weeks of treatment.

Some might ascribe a diuretic effect to SGLT2 inhibitors if these drugs were to influence the dose requirements of concurrently administered loop diuretics. In a 3-day randomized controlled trial of diuretic-resistant individuals, patients receiving dapagliflozin required more furosemide to achieve a smaller diuresis than those receiving metolazone.⁸¹ In the large-scale landmark trials with dapagliflozin and empagliflozin in patients with chronic heart failure, the dose of prescribed diuretics did not change in most patients.^117,149 Although SGLT2 inhibition reduced the need for diuretic intensification and increased the likelihood of diuretic dose reduction during long-term therapy,^117,149 only ≈5% of randomized patients experienced a change in diuretic dose that was attributable to SGLT2 inhibition, and drug-induced changes in diuretic dosing were not seen during the first 90 days.¹⁵⁰ Long-term changes in the doses of prescribed diuretics do not imply a diuretic action, because the use of diuretics (and the prevention of new-onset edema¹⁵⁰) is influenced by an effect of SGLT2 inhibitors to slow the progression of heart failure. A similar pattern of reduced intensification and greater dose reduction has been observed in large-scale trials with angiotensin receptor blockers and sacubitril/valsartan, which do not exert a diuretic effect in chronic heart failure.^151,152

It is noteworthy that treatments that produce short-term increases in sodium or water excretion do not generally reduce the subsequent risk of cardiovascular death or heart failure hospitalization. Although intensive short-term diuresis to achieve hemoconcentration in hospitalized patients is associated with lower cardiac filling pressures,¹⁵³ early decongestion has not been associated with improved outcomes in observational studies or clinical trials.^{138–141,154,155} More intensive treatment with intravenous loop diuretics yields a greater short-term diuresis, but does not reduce heart failure events at 60 days.¹³⁸ The addition of hydrochlorothiazide to a loop diuretic yields a modest diuretic effect, but no effect on death or rehospitalization at 90 days.¹³⁹ Acetazolamide potentiates the natriuretic response to loop diuretics, but has no effect on morbidity and mortality at 3 months.¹⁴¹ In a trial comparing short-term therapy with low or high doses of spironolactone, there was no between-group difference in major heart failure events after 30 to 60 days.¹⁵⁶ Last, in a large-scale trial in patients hospitalized for heart failure, vasopressin antagonism induced a short-term diuretic effect, but continued treatment for a median of 10 months did not reduce the risk of cardiovascular death or hospitalization for heart failure.^136,157

These observations, taken collectively, suggest that a short-term diuretic effect of SGLT2 inhibitors does not contribute meaningfully to the early or long-term ability of these drugs to reduce the risk of major heart failure events.

Effect of SGLT2 Inhibitors on the Risk of Volume Depletion

As a result of their potent natriuretic effects, loop diuretics can produce volume depletion (hypotension and worsening renal function), especially in patients receiving inhibitors of the renin-angiotensin system.¹⁵⁸ Because SGLT2 inhibitors are frequently coadministered with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, the risk of volume depletion has been prospectively evaluated in large-scale trials.

In a meta-analysis¹⁵⁹ of 8 major cardiovascular outcomes trials, volume depletion was reported in 4.4% of the placebo group and in 4.5% of the SGLT2 inhibitor group. The DAPA-HF trial noted an excess of volume depletion, but only in patients taking furosemide-equivalent doses ≥40 mg daily.¹⁴⁹ In patients not taking a loop diuretic, volume depletion was seen in 8.5% in the placebo group and 4.3% in the dapagliflozin group, whereas in patients receiving a furosemide-equivalent dose ≥40 mg daily, volume depletion was seen in 6.8% of placebo-treated patients and 9.0% of dapagliflozin-treated patients (treatment-by-furosemide dose interaction, P=0.012). A similar pattern of diuretic potentiation was seen in a pooled analysis of double-blind trials in type 2 diabetes.¹⁶⁰

Summary and Conclusions

SGLT2 inhibitors block proximal tubular sodium and glucose reabsorption, but the nature and duration of any natriuretic or osmotic diuretic effect are the result of an interplay of the degree of SGLT2 and NHE3 upregulation, the extent to which downstream nephron mechanisms are activated in a compensatory manner, and the volume status and set point in individual patients. In euvolemic patients, counterregulatory sodium- and water-retaining downstream mechanisms are activated rapidly, thus truncating the duration of any observable diuresis. In fluid overloaded patients with acutely decompensated heart failure, the net early effect of SGLT2 inhibition is a water diuresis, but this aquaresis does not contribute to the early clinical improvement in these patients. The magnitude of any glycosuria-dependent effect is markedly attenuated in patients with a glomerular filtration rate <45 mL/min per 1.73 m²,¹⁵ and yet these patients still show a robust reduction in the risk of heart failure hospitalizations with SGLT2 inhibitors.^161,162 In patients with chronic heart failure, SGLT2 inhibitors may potentiate the natriuretic effect of loop diuretics, but in the short term, in patients with fluid retention, the effect of SGLT2 inhibitors to enhance the effect of loop diuretics appears to be smaller than with metolazone.⁸¹ There is little evidence that SGLT2 inhibitors alleviate edema or physical signs of congestion.

It should be noted that attenuation of the initial urinary response is an expected finding with any diuretic, because compensatory mechanisms must be activated to prevent volume depletion as patients approach euvolemia. Once volume overload is alleviated by loop diuretics, a new equilibrium is achieved, with sodium excretion matching intake. The goal of diuretic therapy is to change the internal set point, so that salt and water homeostasis is maintained at steady-state conditions characterized by diminished total body sodium and water stores.¹⁶³ The actions of SGLT2 inhibitors to increase fractional lithium excretion and promote glycosuria persist during long-term therapy, even when the volume status of patients is not changing, suggesting that SGLT2 inhibitors are poised to exert a durable effect to modulate the set point for volume homeostasis. If aberrations of sodium or water intake were to occur during long-term treatment, the activation of downstream counterregulatory mechanisms diminishes, and a net diuretic effect of the drugs would become clinically evident until the set point for volume homeostasis is reachieved.⁴² Studies evaluating the volume responses after salt loading or discontinuation of long-term therapy with SGLT2 inhibitors are needed to confirm this hypothesis. Yet, assuming that the effect of SGLT2 inhibitor on volume homeostasis occur and are durable, it is difficult to know if treatment-mediated changes in the volume set point (if any) contribute to the effect of these drugs to reduce the risk of major heart failure events. Short- or long-term use of many conventional natriuretic and aquaretic drugs has not reduced cardiovascular death or hospitalizations for heart failure,^{136,138–140,157} demonstrating that immediate changes in urinary sodium or water excretion do not yield long-term clinical benefits. It is possible that the effects of SGLT2 inhibitors on sodium avidity may differ from other agents, but the volume effect of these drugs is small. In contrast, the cardioprotective effects of SGLT2 inhibitors represent a direct beneficial effect to reduce cardiomyocyte stress and injury, which is independent of the binding to SGLT2 in the heart or the presence or actions of these drugs on SGLT2 in the proximal renal tubule.^3–5 Nevertheless, any durable changes in the volume set point produced by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular cardiac effects of these drugs to mediate their benefits on the clinical course of heart failure.

ARTICLE INFORMATION

Sources of Funding

None.

Disclosures

M.P. reports consulting fees from 89Bio, Abbvie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa, and Salamandra. J.M.T. reports grants or personal fees from 3iveLabs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Astra Zeneca, Novartis, Cardionomic, MagentaMed, Reprieve Inc, FIRE1, W.L. Gore, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon, Precardia, Relypsa, Regeneron, BD, Edwards Life Sciences, and Lilly. In addition, J.M.T. has a patent for treatment of diuretic resistance issued to Yale University and Corvidia Therapeutics Inc, a patent for methods for measuring renalase issued to Yale University, and a patent for treatment of diuretic resistance pending with Reprieve Inc. The other author reports no conflicts.