SGLT2i represents a novel class of drugs originally approved as antidiabetic agents but, after landmark trials, approved as HFrEF therapy [1]. The glucose co-transport protein is located in the renal proximal tubules, and SGLT2i promotes urinary glucose excretion by inhibiting glucose and Na⁺ reabsorption from there. However, the exact mechanisms of SGLT2i action in HFrEF remain a mystery, with several questions to be answered [29,30]. So far, a number of mechanisms have been suggested, including anti-inflammatory, antifibrotic, antioxidative, and antiapoptotic properties, with improved hemodynamics and ventricular unloading due to a reduction in blood pressure, weight loss, and arterial stiffness. SGLT2i has also demonstrated a reduction in uric acid levels and in epicardial adipose tissue with improved paracrine regulation of adipokines and decreased serum leptin levels [31]. They also improve cardiac energy as they boost glucagon utilization and shift metabolism from fatty-acid oxidation to glucose. Finally, the inhibition of sodium–hydrogen exchange via a direct cardiac effect can lead to a reduction in cardiac remodeling [29,32]. Regarding plasma Na⁺ and K⁺ levels, recent evidence suggests that treatment with SGLT2i does not prevent hyponatremia [33], whereas it reduces the risk of hyperkalemia but has a minimal effect on decreasing serum K⁺ [34].

SGLT2i are called “smart diuretics” as they lead to a sort of “pharmacological ultrafiltration” with a significant decrease in volume overload and enhancement of ventricular function, breaking the heart and kidney vicious circle. The effects of empagliflozin on clinical outcomes in patients with acute decompensated HF (EMPA-RESPONSE-AHF) trial was a randomized controlled trial that demonstrated that the use of SGLT2i empagliflozin (vs. placebo) increased urinary output until day 4 of hospitalization and reduced the combined endpoint of worsening HF, rehospitalization for HF, or death at 60 days [35]. Furthermore, the use of empagliflozin in the randomized EMPULSE (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure) trial was associated with clinical benefit, defined as death from any cause, number of heart failure events, and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio, compared to placebo [36]. Therefore, similar to ARNI, there is enough documentation for an early initiation of SGLT2i in HFrEF patients and it should be used in combination with RAAS and β blockade.

Beta-blockers are an established HFrEF therapy associated with improvement in symptoms, hospitalizations for HF, and morbidity [37]. Beta blockers and ACEIs can be administered simultaneously by the time the diagnosis of symptomatic HFrEF is confirmed, and no data supports commencing a beta-blocker prior to an ACEI and vice versa [1]. Beta-blockade should be started in clinically stable, euvolemic HFrEF patients at a low dose and steadily uptitrated to the maximum tolerated dose. In acutely decompensated HF patients, beta blockers should be initiated in the hospital with caution when the patient reaches hemodynamic stability. In patients suffering from atrial fibrillation (AF) and HFrEF, no benefit in outcomes has been demonstrated, but since these results originate from retrospective subgroup analysis and beta-blockers did not heighten any risk, administration applies to the AF patients also [1]. Beta-blockers prevent Na⁺ retention due to a blunting of the neurohormonal response [38]. In particular, a potential inhibition of renin secretion, which is in part beta-1 receptor-mediated, may affect the proximal reabsorption of Na⁺ via a decrease in angiotensin II production and/or an attenuation of the activity of the intra-renal sympathetic nervous system. An effect of beta-blockers on renin secretion may also modulate distal sodium reabsorption via aldosterone [38]. Hyperkalemia is an infrequent side effect of beta-blockers [39]. This might result from the inhibition of the sympathetic nervous system since β2 adrenergic agonists drive potassium into the cells by augmenting the activity of the Na⁺-K⁺ pump, and they also activate the inwardly directed Na⁺-K⁺-Cl⁻ cotransporter, a protein that enhances the active transport of Na⁺, K⁺, and chloride into cells [39].

The use of angiotensin-converting enzyme inhibitors (ACEIs) in HF has been well established and is related to symptom improvement, prolonged survival, and reduced HF hospitalizations. ACEIs are recommended in all HF patients unless contraindicated or not tolerated [40,41].

ACEIs reduce the production of angiotensin II and degrade bradykinin. They are both mediators affecting the SNS, the vascular tone, the endothelium, and the myocardial performance. The hemodynamic effects of ACEI action include arterial and venous vasodilation, decreased systemic vascular resistance, a decrease in left ventricular filling pressure, and favorable ventricular remodeling [20,41].

Moreover, ACEIs have a selective efferent arteriolar vasodilatory effect, causing a mild to moderate reversible decline in renal function. They promote salt excretion and K⁺ retention by augmenting renal blood flow and reducing the production of aldosterone and antidiuretic hormone [20,41].

Angiotensin-receptor blockers (ARBs) are recommended for patients who cannot tolerate ACEI because of serious side effects [1]. Their effect on HFrEF has been variable, but unlike ACEIs, they have not demonstrated a reduction in mortality [42,43]. Serum electrolytes and renal function should be monitored during ACEI therapy, starting prior to therapy initiation, at 4 weeks, and after each significant increase in dose or clinical condition change [1]. ACEIs and ARBs increase the hazard of hyponatremia [44] and hyperkalemia (serum K⁺ > 5.5 mmol/L) [45].

ARNIs are a novel class of drugs that altered the scene in HF treatment. They combine RAAS inhibition through angiotensin II receptor blockage by valsartan with neprilysin inhibition by sacubitril. Their action has proven to outperform enalapril in reducing mortality risk and hospitalizations in HF patients [46].

Neprilysin is a neutral endopeptidase involved in the degradation of endogenous vasoactive peptides such as natriuretic peptides, bradykinin, and adrenomedullin. Neprilysin inhibition gives rise to these peptides and reduces the neurohormonal overactivation that results in Na⁺ retention, vasoconstriction, and reverse cardiac remodeling [46].

To date, numerous clinical studies have demonstrated the safety and efficacy of sacubitril/valsartan, both in the context of chronic as well as acute HF. The PARADIGM-HF trial showed that sacubitril/valsartan was superior to enalapril in reducing hospital admissions for worsening HF, cardiovascular mortality, and all-cause mortality in patients with HFrEF with EF ≤ 40%. Additional benefits included an improvement in symptoms and QOL, a reduced incidence of diabetes requiring insulin treatment, reduced eGFR decline, and a lower rate of hyperkalemia [46]. Two studies, the PIONEER-HF and the TRANSITION trial, established the safety and efficacy profile of sacubitril/valsartan in decompensated hospitalized patients with reduced ejection fraction. Of note, some of these patients had not previously received ACEi or ARBs. Therefore, according to the 2021 ESC Heart Failure Guidelines, sacubitril/valsartan may be considered (class of recommendation IIb) in ACEi naive patients with HFrEF [1,47,48].

Early sacubitril/valsartan initiation in stable HFrEF patients, independently of ACEi/ARBs therapy, seems beneficial [49,50]. An adequate blood pressure (BP) and an eGFR ≥ 30 mL/min/1.73 m² should be present in patients who are considered for sacubitril/valsartan initiation, and a washout period of at least 36 h in patients receiving ACEI treatment is mandatory to minimize the risk of angioedema [46]. ARNI may cause hyponatremia. Hyperkalemia is less common in patients treated with ARNI than those treated with ACEI/ARB, and ARNIs may attenuate the risk of hyperkalemia resulting from the intake of MRAs [51].

Mineralocorticoid receptor antagonists (MRAs) are well established in the treatment algorithm for HFrEF patients. Their benefits in this group of patients were proven years ago in landmark studies for spironolactone and eplerenone, respectively, demonstrating a risk reduction in death and hospitalization [52,53].

These agents are administered to HFrEF patients regardless of their blood pressure, as their impact on blood pressure is minor. Furthermore, there are no limitations regarding the congestion status of the patients, and they can be introduced safely to the congestive patient before hospital discharge [4].

MRAs are also indicated in the subset of patients with increased arrhythmic burden, as they have been reported to decrease the risk of sudden cardiac death in RALES and EMPHASIS—although the reduction in EMPHASIS was not statistically significant [50,51]. Along with beta-blockers and ARNI, they compose a group of drugs with documented reductions in sudden death [54].

Caution is warranted when it comes to patients with HFrEF and hyperkalemia, as the use of MRAs can further increase serum K⁺ levels. Therefore, MRAs are administered carefully in patients with a serum K⁺ > 5.0 mmol/L. MRAs are currently contraindicated in patients with severe CKD (eGFR < 30 mL/min/1.73 m² or creatinine level >2.5 mg/dL) due to a lack of data, as this was the exclusion limit for RCTs like RALES and EMPHASIS [50,51,53]. However, patients with eGFR between 30 and 60 mL/min/1.73 m² are often not treated with MRAs, according to registries, due to fears of worsening renal function or hyperkalemia [55].

However, HF patients with mild to moderate CKD have been shown to benefit from MRAs. In fact, in a RALES sub-analysis that showed a 30% relative risk reduction for mortality, the patients who benefited the most were those with the lowest eGFR [52]. The EMPHASIS CKD-subgroup analysis also showed eplerenone to be “both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or worsening renal function” [55]. Based on this data, MRAs should be given to HF patients with non-severe CKD, provided that their renal function and K⁺ levels are closely monitored. Blood should be drawn at 1 and 4 weeks after initiating or increasing the MRA dose and on a frequent basis thereafter [4].

Neurohormonal inhibitors decrease adverse outcomes in patients with HFrEF but unfortunately increase the risk of hyperkalemia, especially for those with comorbidities such as CKD and/or DM [56,57]. Therefore, not surprisingly, physicians often prescribe suboptimal doses of the above-mentioned life-saving treatments to HFrEF patients due to the hazard of hyperkalemia. However, over the last few years, K⁺ binders have emerged as safe treatments for hyperkalemia in HF patients [58]. In particular, the administration of sodium zirconium cyclosilicate (ZS-9), a highly selective cation exchanger that entraps K⁺ in the intestinal tract in exchange for Na⁺ and hydrogen, as compared with placebo, led to a reduction in serum K⁺ levels in a cohort of ambulatory patients with baseline K⁺ levels of 5.0 to 6.5 mmol per liter [59]. The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE) was a phase 3, randomized, double-blind, placebo-controlled trial evaluating ZS-9 in outpatients with hyperkalemia (serum K⁺ ≥ 5.1 mEq/L) [60]. The study showed that ZS-9 lowered serum K⁺ to normal levels within 48 h compared with placebo, whereas all 3 doses of ZS-9 resulted in lower K⁺ levels and a higher percentage of patients with normal K⁺ levels for up to 28 days [60].

Patiromer, a non-absorbed, sodium-free K⁺ binding polymer that exchanges calcium for K⁺ in the gastrointestinal tract, led to a reduction in serum K⁺ levels, as compared with placebo, as well as a decrease in the recurrence of hyperkalemia in a cohort of patients with CKD who were receiving RAAS inhibitors and who had serum K⁺ levels of 5.1 to less than 6.5 mmol per liter [61]. More recently, the randomized DIAMOND (Patiromer for the Management of Hyperkalemia in Participants Receiving RAASi Medications for the Treatment of Heart Failure) trial demonstrated that patiromer use was safe in 1642 patients with HFrEF and RAASi-related hyperkalemia, and it was related to significantly lower hyperkalemia episodes, concurrent use of high doses of MRAs, and overall higher RAASi use [62,63].

In conclusion, the administration of K⁺ binders may not only lower the risk of hyperkalemia, but it also assists in the treatment of hyperkalemia in high-risk patients such as those with HF who receive RAAS inhibitors (especially MRAs).

Current guidelines recommend the use of intravenous loop diuretics to ameliorate symptoms of fluid overload in patients with acutely decompensated HF [1]. Loop diuretics act by competing with chloride to bind to the Na-K-2Cl (NKCC2) cotransporter at the apical membrane of the thick ascending limb of the loop of Henle and blocking the cotransporter, which inhibits the reabsorption of Na⁺ and chloride. Therefore, loop diuretics increase renal Na⁺ and water output and consequently alleviate the symptoms of congestion [64]. However, the use of loop diuretics is associated with electrolyte disturbances such as hyponatremia, hypokalemia, hypochloremia, and hypomagnesemia [65]. Torsemide has been reported to lead to fewer electrolyte disturbances compared to furosemide; however, the recent TRANSFORM-HF randomized clinical trial revealed no significant difference in all-cause mortality among patients discharged after hospitalization for HF (torsemide vs. furosemide) over 12 months [66].