Sodium-glucose Cotransporter-2 Inhibitors and Loop Diuretics for Heart Failure: Priming the Kidney’s Natriuretic and Metabolic Reserve

Data from large clinical trials testing the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus have shown their uniform benefit towards reducing the risk of heart failure hospitalizations. This benefit motivated study of these agents in patients with existing heart failure with or without diabetes, as it was thought the effect was mediated by factors beyond glycemic control. Dovetailing with these prior studies, observations from the pivotal Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed the beneficial impact of dapagliflozin in patients with heart failure with reduced ejection fraction with or without diabetes on the risk of worsening heart failure or death from cardiovascular causes in comparison with placebo.¹

The diuretic effects and the favorable impact of SGLT2 inhibition on renal physiology are attractive candidate mechanisms for their beneficial effects in heart failure.² SGLT2 is located in the S1 segment of the proximal convoluted tubule (PCT) of the nephron and reabsorbs 90% of the glucose in the glomerular filtrate back into circulation. Glucose reabsorption is coupled with sodium reabsorption and is energetically driven by the electrochemical sodium potential generated by the basolateral Na/K-ATPase. Because the PCT reabsorbs up to 2/3 of the filtered sodium, pharmacologic inhibition of SGLT2 may have a substantial impact on renal sodium and water homeostasis when coupled with loop diuretics. Therefore, ramifications of combined loop diuretic use and SGLT2 inhibition need further clarification.

In this issue of Circulation, two separate studies provide several notable observations that inform the cardiorenal implications of concomitant SGLT2 inhibitor and loop diuretic therapy for patients with heart failure.^3,4 In a placebo controlled study involving 20 participants with diabetes and chronic, stable heart failure, Griffin, et al. observed that empagliflozin had an additive natriuretic effect when given three hours prior to intravenous bumetanide as measured by a serial increase in fractional excretion of sodium (FENa). In parallel, empagliflozin was associated with reductions in blood volume, plasma volume, total body water, and weight over time. Interestingly, empagliflozin-potentiated FENa appeared to be independent of glycosuria suggesting that enhanced natriuresis may be mediated by factors beyond segmental nephron blockade of sodium reabsorption with SGLT2 inhibition. In exploratory subanalyses, compared wtih placebo, empagliflozin increased erhythropoetin at 14 days and attenuated increases in urinary kidney injury molecule-1, with no important differences in norepinehpherine. Furthermore, empagliflozin was associated with increased uricosuria, a well-described effect of SGLT2 inhibition attributed to increased concentration of luminal glucose in the PCT that competes with urate for GLUT9b.⁵

In the second study involving a post hoc analysis of 4,616 participants with chronic heart failure with reduced ejection fraction with or without diabetes who were randomly assigned to dapagliflozin or placebo in the DAPA-HF trial, Jackson and colleagues report that the long-term benefit of dapagliflozin was consistent across administered doses of loop diuretics. Dapagliflozin reduced fatal and non-fatal heart failure events and improved quality of life by the Kansas City Cardiomyopathy Questionnaire across a wide range of diuretic dosages. There appeared to be a higher incidence of reportedvolume depletion in participants randomly assigned dapagliflozin who received higher loop diuretic doses, although absolute rates were low. This was counterbalanced by an inconsistent signal of higher renal adverse events in the placebo arm. In addition, participants that received dapagliflozin were more likely to decrease and less likely to increase their loop diuretic doses over time in comparison with placebo. Despite these observations, the frequency of study drug discontinuation was relatively low (3-5%) and did not differ between dapagliflozin and placebo across increasing loop diuretic doses suggesting that the combined use of SGLT2 inhibitors and loop diuretics is well-tolerated – a reassuring observation that allays concerns about this combination. In addition, serial measures of weight, creatinine, and NT-proBNP between dapagliflozin and placebo were comparable across strata of baseline loop diuretic dose. These findings would seem to argue against a synergistic diuretic effect.

So how can we reconcile these observations from these two studies? On one hand, we have a small but carefully conducted mechanistic clinical trial that observed a synergistic natriuretic effect of SGLT2 inhibition when combined with a loop diuretic that remained directionally consistent with other markers of decongestion. On the other hand, we have post-hoc data from a large clinical trial suggesting a persistent long-term benefit of SGLT2 inhibition that appears to have little to no relationship according to loop diuretic use or dosage with regards to safety or some markers of long-term decongestion. However, one may have to concede that the hypothesis that therapies which increase short-term natriuresis translate to long-term decongestion is primarily based on the longstanding assumption that maintenance of euvolemia in patients with heart failure is driven solely by blockade of renal sodium channels. After all, it has been demonstrated that in healthy subjects the first-dose effect on sodium excretion with loop diuretic and SGLT2 inhibitor is not additive and synergism develops only after a week in healthy subjects.⁶ Instead, such findings may highlight the diverse set of intricate metabolic pathways at the PCT that may be critical for neurohormonal balance in heart failure and a favorable reset of renal homeostasis.⁷

Observations from Griffin, et al. elegantly capture the potential for proximal nephron blockade of sodium reabsorption to rapidly synergize with blocking the sodium-chloride-potassium symporter in the thick ascending limb to increase natriuresis. This observation is likely more reflective of a widespread effect of SGLT2 inhibition on the PCT microenvironment and downstream tubular and glomerular homeostasis. For example, most of the filtered sodium is reabsorbed in the PCT by the sodium/hydrogen exchanger 3 (NHE3), which is blocked by an off-target effect of SGLT2 inhibitors.⁸ In tandem, inhibition of SGLT2 and NHE3 is additive to increased filtrate osmolality from glycosuria, since glycosuria additionally drives paracellular secretion of sodium that can lead to increased distal nephron sodium delivery. Increased sodium and chloride delivery to the macula densa can lower renin secretion, possibly decrease sympathetic nervous system activation, and affect tubuloglomerular feedback to regulate glomerular filtration.² Furthermore, maintaining chloride homeostasis may also have its own prognostic benefits given its broad role in maintaining electroneutrality, free water homeostasis, acid-base regulation, and loop diuretic resistance.⁹ In addition, the observed reduction in plasma volume is consistent with prior studies of SGLT2 inhibitors showing initial weight loss in patients with diabetes and may be mechanistically linked to SGLT2 inhibitor-mediated tissue sodium content.¹⁰ It is therefore likely that the decongestive properties of SGLT2 inhibitors are the summation of the complex interactions between sodium reabsorption in the PCT, the effects of glycosuria, and extrarenal sodium homeostasis between the peripheral tissues and intrerstitium.¹¹

Overall, these two important studies highlight that SGLT2 inhibitors may potentiate the short-term effects of loop diuretics in patients with chronic stable heart failure, but that somehow, these effects may not have a marked influence either the safety or efficacy of SGLT2 inhibitors long term. Whether different inclusion and exclusion criteria between the present report by Griffin et al compared with DAPA-HF influenced these observations is uncertain. For instance, the median NT-proBNP in the former study was 399 pg/mL and was lower than that required to gain entry into DAPA-HF¹ The DAPA-HF population might paradoxically gain more benefit from synergistic natriuresis with loop diuretics yet also be at heightened risk for adverse events such as hypotension and volume depletion. Outside of these observations, numerous questions remain. These include understanding whether the synergistic natriuretic effect of SGLT2 inhibitors with loop diuretics carries over to patients with decompensated heart failure or those with more substantial loop diuretic resistance. Whether or not short-term reduction in plasma volume by SGLT2 inhibition in patients with heart failure is sustainable is largely unknown.

This complex physiologic interplay between the favorable renal effects of SGLT2 inhibition and loop diuretic usage likely has different implications in the immediate and long-term settings that may explain the observations fromthese two studies. On one hand, it is quite possible, that the synergistic natriuretic effect between SGLT2 inhibition and loop diuretic use are short-lived, allowing for the kidney to recoup post-loop diuretic sodium losses leaving a more “homeostatically negative” sodium balance reflective of SGLT2 inhibition. This physiology may be plausible via the ability of loop diuretics to directly stimulate renin release in the afferent arteriole triggered by inhibited chloride transport via NKCC2 in the macula densa, thus heightening renal sodium avidity. In this case, if sodium intake remains high, sodium reabsorption could potentially match losses from the loop diuretic.¹² On the other hand, these observations may highlight the ability of SGLT2 inhibitors to prime the PCT and accentuate the natriuretic effects of intravenous loop diuretics. This phenomenon may be somewhat negligible in an otherwise stable heart failure population on chronic oral loop diuretics such as DAPA-HF. Yet, it is conceivable that this may facilitate better natriuretic “reserve” to maintain sodium and volume homeostasis.

Consistent across both studies and with prior observations was the impact of SGLT2 inhibition on red blood cell homeostasis.¹³ Within 2 weeks, empagliflozin increased erythropoietin levels in comparison with placebo and, in DAPA-HF, dapagliflozin use resulted in an analogous serial long-term increase in hematocrit in comparison with placebo. Importantly, the observations from Jackson, et al. highlight the independence of this observation from baseline loop diuretic use or dose – therapies that may influence plasma volume and may lead to hemoconcentration. Indeed, SGLT2 inhibition has the capacity to influence erythropoiesis and hematocrit that may result from hepcidin suppression and modulating iron homeostasis and may reduce renal cortical tubulointerstitial hypoxia and oxidative stress.^{14, 15} This may also work in concert with SGLT2 inhibitor-mediated uricosuria that may also reduce oxidative stress and inflammation leading to improved renal health.

In summary, these two important reports highlight the emerging relevance of PCT physiology to heart failure treatment and prognosis that has been largely overlooked. These findings provide key insights into the effects of SGLT2 inhibition in potentially priming the kidney’s natriuretic and metabolic reserves in patients with heart failure, reviving the primacy of the kidney’s influence on heart failure progression.