Proximal versus distal diuretics in congestive heart failure

ABSTRACT Volume overload represents a hallmark clinical feature linked to the development and progression of heart failure (HF). Alleviating signs and symptoms of volume overload represents a foundational HF treatment target that is achieved using loop diuretics in the acute and chronic setting. Recent work has provided evidence to support guideline-directed medical therapies, such as sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor (MR) antagonists, as important adjunct diuretics that may act synergistically when used with background loop diuretics in people with chronic HF. Furthermore, there is growing interest in understanding the role of SGLT2 inhibitors, carbonic anhydrase inhibitors, thiazide diuretics, and MR antagonists in treating volume overload in patients hospitalized for acute HF, particularly in the setting of loop diuretic resistance. Thus, the current review demonstrates that: (i) SGLT2 inhibitors and MR antagonists confer long-term cardioprotection in chronic HF patients but it is unclear whether natriuresis or diuresis represents the primary mechanisms for this benefit, (ii) SGLT2 inhibitors, carbonic anhydrase inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, but implications on long-term outcomes remain unclear and warrants further investigation, and (iii) a multi-nephron segment approach, using agents that act on distinct segments of the nephron, potentiate diuresis to alleviate signs and symptoms of volume overload in acute HF.


INTRODUCTION
The retention of sodium and water and consequential fluid accumulation in the extracellular compartment is a cardinal feature of heart failure (HF), irrespective of the left ventricular ejection fraction [1 , 2 ].The expansion of the extracellular volume, manifesting as volume overload, represents a leading cause for HF hospitalization, with severity of volume overload associated with adverse HF outcomes [3 , 4 ].Alleviating volume expansion through the use of loop diuretics is a cornerstone of HF treatment [5 -7 ].However, achieving decongestion represents a longstanding challenge due to multiple physiological adaptations that favour the retention of sodium, with persistent fluid overload despite increasing diuretic dosing (i.e.diuretic resistance) representing a cardinal sign of worsening HF.Indeed, low urine output in response to loop diuretics or the need for repeated short-term intravenous administration of loop diuretics, are both associated with mortality in the acute HF setting [8 , 9 ].Furthermore, high diuretic dose requirements or dose escalation in the chronic HF setting are associated with hospitalization [10 -12 ].
Accordingly, there is growing interest in understanding the diuretic and natriuretic properties of contemporary medical therapies such as sodium glucose cotransporter 2 (SGLT2) inhibitors, carbonic anhydrase (CA) inhibitors, thiazide diuretics, and mineralocorticoid receptor (MR) antagonists, and their roles in managing volume overload in HF, especially as adjuncts to loop diuretic therapy.The current review aims to summarize existing physiological and clinical evidence on the use of SGLT2 inhibitors, CA inhibitors, thiazide diuretics, and MR antagonists in managing HF and their role as adjunctive diuretic agents in the acute and chronic setting.

Proximal tubular diuretics
Under normal physiological conditions, the proximal tubule is responsible for two-thirds of sodium reabsorption, principally mediated through the sodium-hydrogen exchanger isoform-3 (NHE3) and the sodium glucose cotransporter-2 (SGLT2) (Fig. 1 ) [1 ].Neurohormonal activation, including increased plasma levels of norepinephrine, angiotensin II, and vasopressin, characterizes an early physiological manifestation contributing to sodium and bicarbonate (HCO 3 ) retention in HF by upregulating SGLT2, Na-HCO 3 , and NHE3 activity in the proximal tubule [13 ].Importantly, increased proximal tubular reabsorption leads to decreased downstream sodium delivery thereby influencing the effectiveness of loop diuretics.

SGLT2 inhibitors
SGLT2 inhibitors are the most recent addition to guidelinedirected medical therapy in HF patients with either reduced (HFrEF) or preserved (HFpEF) ejection fraction [14 -19 ].These medications have natriuretic and diuretic effects, as evaluated in numerous mechanistic and clinical studies (Table 1 ).Whether and to what extent the diuretic effects of SGLT2 inhibition contribute to improvements in HF outcomes remains a point of active debate.
Figure 1: Schematic of the nephron with the site of action of adjunctive diuretic agents.SGLT2 inhibitors act on the SGLT2 and the NHE3 in the proximal tubule.CA inhibitors also act in the proximal convoluted tubule to prevent sodium and bicarbonate (HCO 3 ) reabsorption through the NHE3 and Na-HCO 3 cotransporters.Both SGLT2 inhibitors and CA inhibitors allows for increased distal delivery of sodium that may facilitate loop diuretic action.Loop diuretics act in the thick ascending limb by inhibiting the NKCC.Thiazide diuretics act on the distal convoluted tubule by inhibiting NCC and may be beneficial in the setting of distal tubular hypertrophy, a major mechanism of diuretic resistance.MR antagonists act in the late distal collecting tubule and collecting duct, by inhibiting the binding of aldosterone to the MR in the principal cells.This results in decreased sodium-potassium ATPase (NKA) and epithelial sodium channel activity at the basolateral and luminal membrane, respectively, resulting in increased natriuresis and potassium retention.Last, AVP can bind to the V 2 receptor in the collecting duct to initiate secondary signalling and increased aquaporin permeability, leading to increased free water reabsorption.
Within the proximal tubule, SGLT2 is normally responsible for ∼5% of total sodium reabsorption in the kidneys [20 ].SGLT2 inhibition reduces proximal tubular sodium and glucose reabsorption to promote natriuresis, glucosuria, and accompanying osmotic diuresis [21 ].These medications also induce concurrent NHE3 inhibition [22 ], which further drives proximal tubular natriuresis and increased sodium delivery to the downstream macula densa.This is hypothesized to restore tubuloglomerular feedback leading to reductions in intraglomerular pressure and glomerular filtration rate, clinically manifesting as an acute and reversible decline in eGFR [23 ].Inhibition of proximal tubular glucose and sodium reabsorption is also thought to have favourable effects on renal energetics, with subsequent effects on hypoxia, inflammation, and fibrosis [24 , 25 ].

Natriuresis and diuresis in chronic HF
Acute SGLT2 inhibition causes an initial increase in proximal tubular natriuresis and parallel increase in total natriuresis, measured using fractional sodium and lithium excretion [26 , 27 ].This acute natriuretic response is further accentuated during concurrent SGLT2 inhibitor and loop diuretic administration, suggesting a synergistic response probably driven by upstream SGLT2 inhibition causing greater sodium delivery to the downstream loop of Henle [26 ].While the SGLT2 inhibitor-mediated increase in total natriuresis was evident following 14 days of treatment [26 ], counterregulatory adaptations to tubular sodium handling can promote tachyphylaxis to total natriuresis [27 ].For instance, proteomic analyses have found that empagliflozin can increase circulating CA and uromodulin, which can cause counterregulatory increases sodium reabsorption in the proximal tubule and loop of Henle, respectively [28 ].SGLT2 inhibition can also activate aldosterone, due to intravascular volume contraction, further promoting sodium reabsorption in the distal tubule, while osmotic diuresis associated with SGLT2 inhibitor-mediated glucosuria can increase vasopressin to promote fluid retention [29 , 30 ].Perhaps as a result of these physiological changes, attenuated natriuresis was observed at 14 days compared to 1 day of SGLT2 inhibitor treatment, despite remaining elevated compared to placebo at 14 days [27 ].Furthermore, urinary sodium excretion or fractional excretion of sodium were not different following longerterm (4-6 weeks) treatment with SGLT2 inhibitors compared to placebo control [31 , 32 ].Collectively, these findings suggest that counterregulatory adaptations to tubular sodium handling may offset the diuretic effect of SGLT2 inhibition in chronic HF patients.
The effects of SGLT2 inhibition on reducing plasma volume [26 , 33 -35 ] and extracellular volume also appear modest [33 , 36 , 37 ].The EMPIRE-HF trial examined the change in extracellular volume using EDTA in HF patients randomized to empagliflozin versus placebo for 12 weeks [33 ].Empagliflozin reduced estimated extracellular volume compared with placebo by a modest 0.12 l.Other studies also examined changes in extracellular volume with SGLT2 inhibition, often using bioimpedance spectroscopy, and demonstrated reductions ranging from 0.5 to 1 l that tended to attenuate with time [36 ].These results are consistent with the tubular effects of SGLT2 inhibition discussed before.Furthermore, mechanistic studies have consistently demonstrated no effect of SGLT2 inhibition on N-terminal pro-B-type natriuretic peptide (NT-proBNP) following shorter-term (2-24 weeks) treatment [26 , 31 , 33 -35 , 38 ].This finding aligns with the inconsistent reductions in surrogates for cardiac filling pressures following 12 weeks of SGLT2 inhibitor treatment [38 , 39 ].
Across several dedicated HF outcome trials, SGLT2 inhibition consistently improved composite outcomes that included HF hospitalization.Mediation analyses have identified that haemoconcentration, reflected by a rise in haematocrit, represents an important contributor to improved HF outcomes [40 ].However, it is unclear whether haemoconcentration occurs secondary to plasma volume contraction or erythropoiesis [41 ].Furthermore, statistical significance in the composite HF outcomes was achieved by 4 weeks of therapy, in contrast to kidney outcome trials [42 , 43 ].This relatively rapid cardioprotective effect appears to coincide with the natriuresis and diuresis responses augmented early following treatment initiation, implying that acute diuresis may contribute to early cardioprotection.By contrast, other secondary analyses of HF outcome trials provide stronger evidence to support the notion that non-diuretic mechanisms largely contribute to the observed long-term cardioprotection.Secondary analysis of the EMPEROR-Reduced trial examined a sub-group of patients with volume overload in the 4 weeks before randomization [44 ].These participants were more likely to be on higher doses of loop diuretic and experience a HF event.However, there was no heterogeneity in the benefit of SGLT2 inhibition among participants with and without volume overload, arguing against natriuresis and diuresis being the primary mediators of the effects of empagliflozin.In addition, secondary analysis of DAPA-HF found that dapagliflozin did not alter furosemide dosing over the course of study [45 ], yet secondary analyses of DELIVER and EMPEROR-Preserved found that dapagliflozin and empagliflozin were associated with greater likelihood for loop diuretic de-escalation, and lower likelihood for loop diuretic intensification or initiation [11 , 12 ].Regardless, improved HF outcomes with SGLT2 inhibitors were consistently independent of background diuretic dose or severity of volume overload [11 , 12 , 45 ].Last, EMPEROR-Reduced found that empagliflozin improved HF outcomes irrespective of the baseline NT-proBNP [4 ].Taken together, these results do not appear to argue in favour of overwhelming diuretic effects with SGLT2 inhibition as the primary mechanism responsible for improvements in HF outcomes, but rather potential improvements in cardiac function and maintenance of kidney function that ultimately improve sodium balance and volume status.

Natriuresis and diuresis in acute HF
The efficacy of SGLT2 inhibitors on alleviating volume overload in the setting of acute HF have been investigated in several randomized control trials [46 -50 ].In the EMPA-RESPONSE-AHF trial, treatment with empagliflozin did not alter diuretic efficiency, defined as the change in body weight relative to loop diuretic dose, or NT-proBNP compared to placebo [46 ].Furthermore, the increased urine output during treatment was mediated by glucosuria rather than natriuresis [47 ].In the EMPAG-HF trial, higher empagliflozin dosage and earlier initiation following hospitalization resulted in increased urine output and loop diuretic efficiency, while decreasing NT-proBNP [48 ].In addition, in patients with evidence of diuretic resistance, dapagliflozin demonstrated similar decongestive responsiveness compared to metolazone at 96 hours following treatment [49 ].Finally, the EMPULSE trial demonstrated that early inpatient initiation of empagliflozin reduced the hierarchical composite outcome of all-cause mortality, HF events, or symptoms at 90 days versus placebo [50 ], while also improving diuretic efficiency and causing larger reductions in NT-proBNP within 30 days.These data collectively support an acute diuretic effect with SGLT2 inhibition contributing to clinical benefit.

Summary
There is clear consensus that SGLT2 inhibition offers clinically meaningful benefits in the setting of HF.However, it is unclear to what extent, if any, these benefits are mediated by the diuretic effects of SGLT2 inhibitors.Natriuresis and diuresis appear to characterize early effects of SGLT2 inhibition that subsequently attenuates with time, suggesting activation of alternate pathways that confer clinical benefit (Fig. 2 ).It has also been proposed that a persistent effect of SGLT2 inhibition on proximal tubular natriuresis resets volume homeostasis which may allow individuals to better manage episodes of volume expansion, preventing exacerbations of HF.

Carbonic anhydrase inhibitors
CA is a membrane-bound and luminal enzyme located in the proximal convoluted tubule, responsible for sodium and HCO 3 reabsorption.Under normal physiological conditions, the breakdown and subsequent reabsorption of HCO 3 into proximal tubule facilitates sodium reabsorption through the NHE3 and Na-HCO 3 cotransporters, located on the apical and basolateral membrane, respectively (Fig. 1 ).Thus, acetazolamide, a CA inhibitor, prevents proximal tubular HCO 3 reabsorption, subsequently limiting sodium reabsorption and resulting in natriuresis.

Natriuresis and diuresis in chronic HF
The natriuretic properties of acetazolamide were initially investigated for chronic HF treatment in the mid-1950s [51 , 52 ].However, the rapid diuretic resistance resulting from chronic treatment and the simultaneous emergence of loop diuretics precluded future use.As a result, CA inhibitors are not recommended for the treatment of chronic HF [5 , 7 ].

Natriuresis and diuresis in acute HF
Acetazolamide has been investigated as an adjunct to loop diuretics in the setting of acute HF (Table 1 ).Acetazolamide was first explored in the DIURESIS-CHF trial, which enrolled acute HF patients presenting with evidence of volume overload and clinical suspicion for loop diuretic resistance [53 ].Treatment with the combination of acetazolamide and loop diuretics versus highdose loop diuretic monotherapy had no effect on the primary endpoint of 24-hour urinary sodium excretion, or the secondary outcomes of NT-proBNP [53 ].However, combination therapy was associated with improvements in loop diuretic efficiency, defined in this study as natriuresis relative to loop diuretic dose, and a nominal improvement in time to hospital readmission.
The ADVOR trial was a multicentre randomized control trial of acute HF patients treated with intravenous acetazolamide or placebo in addition to standardized intravenous diuretic therapy [54 ].The primary outcome of 'successful decongestion' was defined as the absence of residual congestion after 72 hours of treatment, with congestion graded on the basis of peripheral oedema, pleural effusion, or ascites.Successful decongestion occurred in 42% and 31% receiving acetazolamide and placebo, respectively, despite only a modest increase in diuresis based on urine output at 48 hours.Acetazolamide also increased total natriuresis, based on urinary sodium excretion [55 ].While the ADVOR trial found that acetazolamide had no impact on the secondary outcome of death from any cause or HF rehospitalization at 3 months [54 ], greater natriuretic responsiveness was associated with favourable outcomes [55 ].
In secondary analyses of the ADVOR trial, patients with higher baseline serum HCO 3 had a more pronounced reduction in congestion [56 ].Higher serum HCO 3 may reflect upregulation of HCO 3 reabsorption in the proximal tubule secondary to sympathetic and neurohormonal overactivation [13 ].Loop diuretic use is also associated with a higher incidence of metabolic alkalosis, which can further drive neurohormonal overactivation and attenuate diuretic effectiveness [57 ].Patients undergoing diuresis with loop diuretics frequently develop elevated HCO 3 related to chloride depletion, which thereby impairs HCO 3 elimination through Pendrin, a chloride-HCO 3 exchanger found in type-B intercalated cells.In the ADVOR trial, elevated baseline HCO 3 levels were associated with higher doses of loop diuretics, higher serum sodium levels, and more pronounced peripheral oedema.These findings provide evidence to support the notion that acetazolamide may exert benefit by targeting excessive neurohormonal activation, to mitigate development of metabolic alkalosis and subsequent diuretic resistance.Interestingly, the decongestive effects of acetazolamide were consistent across the spectrum of left ventricular ejection fraction, despite established therapies targeting neurohormonal overactivation having proven benefit only in HFrEF [58 ].
It is important to consider that the ADVOR trial was conducted prior to the routine use of SGLT2 inhibitors for chronic HF, with prior treatment with an SGLT2 inhibitor representing an exclusion criterion.Thus, extrapolation to the current era in which SGLT2 inhibitors are indicated for HFrEF and HFpEF patients is uncertain given that both achieve diuresis and natriuresis via proximal tubular natriuresis including NHE3 inhibition effects.Further, those with advanced chronic kidney disease (eGFR < 20 mL/min/1.73m 2 ) were excluded from ADVOR, while individuals treated with an intravenous loop diuretic dose of > 80 mg furosemide equivalent during the index hospitalization did not proceed to randomization, suggesting those with severe diuretic resistance may have been excluded.Thus, future trials will be required to conclusively determine treatment efficacy in these highrisk patient cohorts.

Summary
Acetazolamide can be considered as an adjunctive treatment to loop diuretics in admitted patients with acute HF.Use of acetazolamide in HF patients in the chronic setting, or acute setting in high-risk patients, such as those with advanced chronic kidney disease or severe diuretic resistance, require further prospective work.

Distal tubular diuretics
The distal convoluted tubule accounts for < 10% of sodium reabsorption through the sodium-chloride cotransporter (NCC) (Fig. 1 ) [ 1 ,2 ].However, distal sodium reabsorption can be altered by a variety of factors such as neurohormonal activation, tubular flow rate, aldosterone, and vasopressin, each of which can impact either the pathological development or therapeutic treatment of HF.Importantly, in the setting of chronic diuretic use or chronic HF, hypertrophy of the distal tubule increases distal tubular sodium reabsorption, contributing to sodium retention and is a major mechanism of diuretic resistance [59 ].

Thiazide diuretics
Thiazide diuretics have conventionally been considered a first line adjunct to augment diuresis, targeting the maladaptive distal tubular hypertrophy, by decreasing sodium reabsorption in the distal convoluted tubule through inhibition of the Na-Cl cotransporter (Fig. 1 ).Thiazide diuretics include metolazone, which has a long duration of action and is effective in those with advanced chronic kidney disease, hydrochlorothiazide, chlorothiazide, and chlorthalidone.Both metolazone and hydrochlorothiazide cause similar acute changes in body weight, urine output, diuretic efficiency, and patient congestion scores, suggesting that neither have established superiority [60 ].However, in the acute HF setting, metolazone treatment was associated with increased mortality compared to high-dose loop diuretic treatment in propensity analyses, although this may be attributed to confounding by indication [61 ].Other thiazide diuretics, such as intravenous chlorothiazide and oral chlorthalidone, have also been used to promote diuresis to mitigate volume overload in acute HF; although the only available evidence supporting this practice is observational in nature [62 , 63 ], and randomized controlled trial data is lacking.

Natriuresis and diuresis in chronic HF
Thiazide diuretics are most frequently utilized concurrently to loop diuretics for treating chronic HF patients in clinical practice, particularly in the setting of loop diuretic resistance.Indeed, loop diuretics and thiazide diuretics can act synergistically to help achieve adequate diuresis [64 ].This synergistic response, mediated by distinct tubular mechanisms of action for sequential nephron blockade, forms the physiological rationale for combined loop and thiazide diuretics in consensus statements [5 ].While observational studies support the addition of thiazide diuretics, such as metolazone, to improve weight loss and decongestion in patients with chronic HF [65 ], there is a lack of randomized controlled trial evidence in this setting.

Natriuresis and diuresis in acute HF
Several earlier trials have shown that the addition of a thiazide diuretic can increase diuresis and natriuresis in acute HF patients with profound loop diuretic resistance [66 -68 ].For instance, the 3T trial that randomized 60 patients with acute HF to metolazone, intravenous chlorothiazide, or tolvaptan, found that all strategies augmented urine output and weight loss [60 ].The CLOROTIC trial provides new evidence for targeting the distal tubule with thiazide diuretics [69 ].Patients with acute HF treated with background intravenous loop diuretics were assigned to either oral hydrochlorothiazide or placebo for 72 hours.Patients treated with hydrochlorothiazide observed larger reductions in body weight, although no difference in the co-primary endpoint of dyspnoea was observed.Further, the reductions in body weight did not persist at discharge.Hydrochlorothiazide also augmented urine output and increased natriuresis at 96 hours.No difference in serious adverse event risk was noted, although hypokalaemia occurred in 41% and 16% of patients prescribed hydrochlorothiazide and placebo, respectively.In addition, increases in serum creatinine were more common with hydrochlorothiazide, although this may be reflective of achievement of diuretic effect.In summary, the CLOROTIC study provides evidence that thiazide may provide a modest beneficial effect on natriuresis and diuresis in acute HF.

Summary
While thiazide diuretics are routinely used as adjunctive diuretics in chronic HF and recommended in clinical guidelines, there is a lack of randomized controlled data supporting beneficial impact on long-term outcomes.In addition, the CLOROTIC trial provides new evidence that hydrochlorothiazide may be used in the setting of acute HF to achieve decongestion.

Mineralocorticoid receptor antagonists
There is longstanding evidence that aldosterone contributes to the development of volume overload [70 ].MR antagonists inhibit binding of aldosterone to the MR in the principal cells of the distal nephron [71 ].This causes downstream suppression of genes encoding for the Na-K ATPase at the basolateral membrane and the epithelial sodium channel at the luminal membrane, resulting in increased natriuresis and potassium retention (Fig. 1 ).First generation MR antagonists, such as spironolactone and eplerenone, were initially developed as steroidal hormones to directly mimic aldosterone binding, with consequential secondary off-target sex steroid-related side effects.Nonsteroidal MR antagonists, such as finerenone, were subsequently developed as highly selective and potent alternatives that similarly inhibit aldosterone binding in the principal cell, without sex steroid-related side effects [72 ].The incidence of hyperkalaemia associated with finerenone was also lower than that of steroidal MR antagonists [73 ].Further, finerenone also causes an initial eGFR dip [74 ] analogous to SGLT2 inhibitor treatment described above [23 ].However, the mechanisms responsible for the eGFR dip are probably not a reflection of natriuresis, as observed with SGLT2 inhibition, but rather on the basis of vascular effects.Further detail on the physiological differences between spironolactone, eplerenone, and finerenone in the setting of cardiorenal disease can be found elsewhere [75 ].
In the pivotal RALES and EMPHASIS-HF trials, spironolactone and eplerenone reduced the incidence of all-cause mortality and hospitalization in HFrEF patients [76 , 77 ], providing unequivocal evidence to support the inclusion of steroidal MR antagonists in guideline-directed medical therapy [5 ].By contrast, in the TOP-CAT trial, spironolactone did not reduce the incidence of all-cause death, cardiac arrest, or HF hospitalization in HFpEF patients [78 ], although the absence of a statistically significant effect on the primary outcome has been attributed to heterogeneity by region of enrolment [79 ].Last, finerenone demonstrated non-inferiority in exploratory outcome analyses compared to eplerenone in HFrEF patients [80 ].Forthcoming randomized clinical trials will further investigate finerenone in HFrEF and HFpEF (FINEARTS-HF: NCT04435626, CONFIRMATION-HF: NCT06024746, REDEFINE-HF: NCT06008197, FINALITY-HF: NCT06033950).

Natriuresis and diuresis in chronic HF
The use of spironolactone to elicit increases in natriuresis have been well-described [81 ].Short-term spironolactone treatment increased urinary sodium excretion, resulting in decreases in net sodium balance, body weight, and neurohormonal activation in HF patients abstaining from diuretic use [82 ].Furthermore, in severe HF patients with diuretic resistance, evident from persistent congestion despite maximal tolerable doses of loop diuretics and ACE inhibition, the addition of spironolactone further increased sodium excretion and decreased body weight [83 ], collectively supporting diuretic and natriuretic properties of spironolactone.MR antagonists also cause reductions in natriuretic hormones (Table 1 ).A secondary analysis of the RALES trial demonstrated that spironolactone decreased BNP following 3 months of treatment [84 ].Further, both eplerenone and finerenone elicited comparable reductions in NT-proBNP following 3 months in HFrEF patients [80 ], while spironolactone decreased NT-proBNP following 9 months in HFpEF patients [85 ].
Synonymous to SGLT2 inhibitors, the rapid time to statistical benefit (20 days) in the composite endpoints in HFrEF patients prescribed MR antagonists [86 ] suggests that the mechanisms responsible for cardioprotection are promptly activated following treatment initiation.While the fast-acting diuretic effects may intuitively represent an important mediator, it is important to recognize that MR antagonists also possess anti-hypertrophic, anti-inflammatory, and anti-fibrotic effects that largely mediate the cardiovascular benefits noted in clinical trials.Importantly, there is evidence to support that these mechanisms represent the primary actions responsible for long-term cardiovascular benefit of MR antagonists, as opposed to the natriuretic and diuretic properties.For example, in a secondary analysis of the TOPCAT trial, patients treated with spironolactone required lower doses of furosemide and thiazide diuretics compared to placebo [87 ].However, reductions in HF hospitalization were not solely explained by indices of diuresis, suggesting that non-diuretic mechanisms were responsible for mediating the observed clinical benefit [87 ].Furthermore, spironolactone elicited improvements in mortality most clearly observed in patients with the lowest NT-proBNP [88 ].Therefore, steroidal MR antagonists may have natriuretic and diuretic effects but the contribution of these changes to the overall cardiovascular benefit noted in dedicated clinical trials is unclear.

Natriuresis and diuresis in acute HF
Dedicated clinical trials have sought to define the role of MR antagonists in the management of acute HF (Table 1 ).The ATHENA-HF trial examined the efficacy of high-and low-dose spirono-lactone for 96 hours versus placebo on the primary outcome of change in NT-proBNP levels [89 ].Of note, high-dose spironolactone had no significant effect on NT-proBNP compared to placebo or low-dose spironolactone.It also had no effect on urine output, weight change, loop diuretic dose, or patient reported outcomes [89 ].The lack of benefit with short-term MR antagonism in acute HF may related to the prolonged onset of action of spironolactone.Therefore, any decongestive effects may not have been appreciated during the short follow-up of ATHENA-HF [90 ].

Summary
MR antagonists have natriuretic and diuretic properties, which may be potentiated when combined with proximal acting diuretics.The extent to which these natriuretic and diuretic properties underlie the long-term cardioprotective effects remains unclear.Nonetheless, given the clear net benefit of MR antagonists, their use is indicated in people with chronic HFrEF, and forthcoming studies of nonsteroidal MR antagonists will further inform their use in HFpEF.

Vasopressin inhibitors
Arginine vasopressin (AVP) plays an integral role in free water regulation at the level of the distal tubule and collecting duct.AVP stimulates V 2 receptors, initiating secondary signalling to increase aquaporin channel permeability, facilitating the reabsorption of free water to ultimately cause fluid retention and hyponatraemia (Fig. 1 ).From a physiological standpoint, AVP, or surrogate markers such as copeptin, are elevated in HF patients [91 ], and elevated copeptin is associated with mortality in acute HF patients [92 ].

Natriuresis and diuresis in chronic HF
In chronic HF patients on stable loop diuretic treatment without evidence for volume overload, tolvaptan initiation resulted in a prompt increase in weight loss and reduction in oedema [93 ].However, there is no data to support the use of these agents in the setting of chronic HF [5 , 7 ].

Natriuresis and diuresis in acute HF
There is consistent evidence across multiple randomized controlled trials that the vasopressin receptor antagonist, tolvaptan, has no effect on symptoms of congestion or hard clinical outcomes in acute HF patients.The ACTIV trial demonstrated that tolvaptan acutely increased weight loss and urine volume compared to placebo, but had no impact on signs or symptoms of volume overload at hospital discharge or worsening HF at 60 days post-discharge [94 ].Importantly, the EVEREST trial subsequently demonstrated that all-cause mortality or cardiovascular death was similar in acute HF patients prescribed tolvaptan and placebo [95 ].Last, the TACTICS-HF and SECRET trials found no difference in the proportion of patients who showed clinical improvement in volume overload following initiation of tolvaptan [96 , 97 ].This may reflect that tolvaptan results in aquaresis (free water excretion) but does not result in natriuresis and therefore may not address sodium retention as the underlying pathophysiologic process driving HF.Nonetheless, tolvaptan is efficacious for treating hyponatraemia [98 ], which may be considered for severe hyponatraemia in the setting of acute HF.

Summary
These data provide convincing evidence that tolvaptan can lead to greater reductions in body weight and increase in urine volume during short-term usage.However, these changes do not translate into improvements in signs and symptoms of volume overload, and longer-term outcomes of mortality or cardiovascular death in acute HF patients.

Chronic HF
Current ESC guidelines recommend four classes of medications (beta blockers, RAAS blockade, MR antagonists, and SGLT2 inhibitors) for HFrEF that, when used simultaneously, result in the greatest relative risk reduction in cardiovascular outcomes and hospitalization [99 , 100 ].Conventional treatment strategies involve initiating treatment sequentially at low dosages, with careful monitoring prior to either up-titration or implementation of additional therapies.However, recent emergence of simultaneous initiation and rapid up-titration of multiple HF therapies is gaining attraction as a superior approach towards improving HF outcomes [101 , 102 ].The STRONG-HF trial demonstrated that, compared to usual care, high-intensity treatment strategies employing rapid implementation and up-titration of guideline-directed therapies, resulted in greater reductions in congestion and incidence of hospital readmission following discharge [103 ].However, reluctance towards adopting this approach arises from clinician concern of the potential risk of adverse effects including hyperkalaemia or medication intolerance, which require close patient monitoring.While loop diuretics, thiazide diuretics, and potassium binders may reduce hyperkalaemia, the kaliuretic effects of SGLT2 inhibitors have been recently shown reduce the incidence of hyperkalaemia associated with RAAS blockade or MR antagonists usage, and thus may also help to facilitate prescription of goal directed medical therapy [104 -106 ].Given the potential for SGLT2 inhibitors to mitigate the side effect of other medication classes, combination treatment with available guideline recommended treatments should be more achievable.

Acute HF
The optimal treatment approach for alleviating signs and symptoms of volume overload in patients with acute HF, particularly in the setting of diuretic resistance, remains unestablished.Urgent requirements for rapid diuresis have led to the emergence of a targeted multi-nephron segment approach, using rapid or sequential initiation of combined CA inhibitors, loop diuretics, thiazide diuretics, and MR antagonists [107 , 108 ].In a retrospective study of acute HF patients with severe diuretic resistance, highintensity treatment using this multi-nephron segment approach resulted in greater diuresis and achievement of successful decongestion, compared to standard care [107 ].Analogous the AD-VOR trial, the use of background SGLT2 inhibitors was rare in the current study, and therefore the efficacy of dual proximal tubular natriuretic blockade with concurrent SGLT2 and CA inhibitors remains unknown.In addition, the order in which to introduce adjuncts to loop diuretics, and whether synergistic effects exist, remains largely unknown.However, it is notable that the diuretic response to CA inhibition in ADVOR was less than that observed with thiazide diuretics and SGLT2 inhibitors observed in the CLOROTIC and EMPAG-HF trials [48 , 69 ].Furthermore, it is also important to consider that the EMPULSE, ADVOR, and CLOROTIC trials have shown no effect of SGLT2 inhibition, CA inhibition, or thiazide diuretics on 30-day rehospitalization in patients with acute HF.Further prospective work is required to determine the efficacy of this intensive approach for achieving decongestion.

SUMMARY
Contemporary adjunct proximal and distal diuretics have been shown to elicit clear clinical benefit in the setting of acute and chronic HF.SGLT2 inhibitors and MR antagonists both cause short-term increases in natriuresis and diuresis; however, these mechanisms may not represent the primary actions responsible for long-term cardioprotection in chronic HF patients.Similarly, short-term treatment with SGLT2 inhibitors, CA inhibitors, and thiazide diuretics increase natriuresis in the acute HF setting, however, implications on long-term outcomes remain unclear and warrant further investigation to elucidate optimal treatment regimes.Last, a multi-nephron segment approach, using agents that act on distinct segments of the nephron, can further augment diuresis to alleviate signs and symptoms of volume overload in the acute setting.Future trials are required to determine efficacy of the multi-nephron segment approach whereby mechanisms of multiple therapies converge on similar nephron segments.received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, and Novo-Nordisk.

Table 1 :
Summary of RCTs of diuretic agents in patients with HF. fluid volume; PCWP: pulmonary capillary wedge pressure; PV: plasma volume.a Plasma volume estimated using the Strauss formula.b Plasma volume measured using indicator dilution with I-131 albumin.c Loop diuretic efficacy was defined as a change in body weight normalized to loop diuretic dose.d Successful decongestion was defined as the absence of signs of volume overload based on (i) no more than trace oedema, (ii) no residual pleural effusion, and (iii) no residual ascites.

Figure 2 :
Figure 2: Proposed conceptual model illustrating the proposed physiological time-course following initiation of SGLT2 inhibitor treatment.

FUNDING
M.N. is supported by a Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto.V.S.S., K.Y., and A.O. are supported by the University of Toronto Department of Medicine Eliot Phillipson Clinician Scientist Training Program.V.S.S. is also supported by the Banting and Best Diabetes Centre Postdoctoral fellowship at the University of Toronto, and the CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Research Award.K.Y. and A.O. are supported by Kidney Foundation of Canada Kidney Research Scientist Core Education and National Training (KRESCENT) Postdoctoral Fellowships.The KRESCENT program is co-sponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology, and CIHR.K.Y. is also supported by the Clarence Henry Trelford Clinician Scientist Award in Diabetes.A.O. is also supported by the Ted Rogers Centre for Heart Research, the University of Toronto Provost Post-Doctoral Fellowship Program, and the Canadian Institute for Health Research REDI Grant.D.Z.I.C. is supported by a Department of Medicine, the University of Toronto Merit Award, and receives support from the Canadian Institutes of Health Research, Diabetes Canada, and the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research.D.Z.I.C. is also the recipient of a five-year CIHR-Kidney Foundation of Canada Team Grant award.