SGLT2 inhibitors’ origin dates back to the beginning of the 19th century, when in 1835 Laurent-Guillaume de Koninck and Jean Servais Stats discovered phlorizin, a glycoside present in the roots, leaves, and fruits of the apple tree. However, it was not until 1886 that Freiherr Von Mering described its glucosuric and hypoglycaemic properties [2]. A century later, it was shown that the administration of subcutaneous phlorizin improved the glycaemic profile in pancreatectomized rats. However, this finding was unsuitable for clinical development due to phlorizin’s metabolic instability and nonselective SGLT inhibition [3, 4].

Further chemical research to pursue a selective SGLT2 inhibition led to the development of dapagliflozin in 2008. This agent had a longer half-life, high hydrolysis resistance, and a greater affinity for SGLT2 receptors [5]. Dapagliflozin was the first SGLT2 inhibitor approved in the European Union in 2012, and was followed by canagliflozin (2013), empagliflozin (2014), ertugliflozin (2017), and sotagliflozin (2018).

Under physiological circumstances, the vast majority of the filtered glucose in the glomerulus is reabsorbed by co-transporters SGLT 1 and 2, coupled with sodium. SGLT1 (low-capacity/high-affinity) is expressed in the intestine, heart, and kidney. The contribution of SGLT1 in glucose reabsorption is minimal compared with SGLT2 (low-affinity/high-capacity), expressed in the proximal tubule of the kidney and responsible for the reabsorption of 90% of the filtered glucose [6, 7]. Thus, SGLT2 inhibition leads to glycosuria and natriuresis, the magnitude of which depends on the circulating glucose concentration and kidney function, decreasing in patients without hyperglycaemia and an estimated glomerular filtration rate (eGFR) 45 mL/min/m${}^2$ [8].

The primary goal in acute heart failure (AHF) is water and sodium removal. Commonly, variable doses of intravenous loop diuretics are employed to achieve euvolemia. When used in combination with loop diuretics, SGLT2 inhibitors increase the amount of 24-hour urinary volume by approximately 500 mL. Although initial natriuresis is considered to play a role during the first days of treatment, it has not been confirmed in clinical studies. There is no long-term increase in urinary sodium excretion because of compensatory sodium reabsorption distal to the macula densa. Therefore, osmotic diuresis seems to be the main driver of increased urinary output. Moreover, some small studies suggest that SGLT2 inhibitors bear complementary diuretic properties over traditional loop diuretics, with a predominant tissue decongestion effect rather than an major repercussion on intravascular volume. Prevailing reduction of intersticial volume could lead to better tissue perfusion and renal hemodynamics [9, 10, 11].

In cases of persistent congestion, urine sodium excretion from loop diuretics can be improved by adding thiazide diuretics. However, sequential nephron blockade with loop and thiazide therapy has been associated with an increased risk of worsening kidney function, electrolyte abnormalities, and neurohormonal activation compared to loop diuretic monotherapy. SGLT2 inhibitors may counteract these adverse events through more electrolyte-free water clearance. The addition of SGLT2 inhibitors to intravenous loop diuretic therapy is expected to provide additional osmotic diuresis while minimizing ionic disorders and avoiding activation of the sympathetic nervous system or renin-angiotensin system [12, 13].

On the other hand, metabolic shift towards ketone body production and free fatty acids utilization may be of great importance during hospital admission. By shunting substantial amounts of carbohydrate into urine, glucose oxidation is progressively substituted by lipid oxidation to generate energy. Under conditions of mild hyperketonemia, $\beta$-hydroxybutyrate is freely consumed by the heart and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level [14]. Besides, preferential oxidation of ketone bodies may decrease the amount of toxic intracellular lipid metabolites, which could improve cardiac steatosis and left ventricular remodeling. Furthermore, treatment with SGLT2 inhibitors leads to an initial rise in haematocrit, explained by a reduction in plasma volume secondary to the induced osmotic diuresis, and an increase in erythropoietin production due to an enhancement in renal blood flow [15]. Hemoconcentration subsequently promotes oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift [16].

Some additional mechanisms of action may be of interest. SGLT2 inhibitors are associated with a mild acute decrease in eGFR secondary to glomerular afferent arteriolar vasoconstriction, which results in a reduction in albuminuria and a better preservation of the renal function over the long-term [17]. Through drug-related glycosuria, SGLT2 inhibitors improve glycaemic control and reduces body mass via calorific loss. A mild decrease in blood pressure and plasma uric acid levels are also observed [18]. Likewise, anti-inflammatory responses, reduction of reactive oxygen species, endothelial function improvement and neuromodulatory effects have been reported. However, their importance is yet to be determined [19, 20, 21, 22]. An overview of SGLT2 inhibitors’ mechanism of action is shown in Fig. 1.

Fig. 1.

Mechanisms of action of SGLT2 inhibitors. Use of SGLT2 inhibitors produces a reduction in glucose reabsorption in the proximal tubule of the kidney, which increases glycosuria and intensifies sodium excretion, promoting an increment in osmotic diuresis. This results in a better glycaemic control, weight loss and blood pressure lowering. On the other hand, shift to fatty substrate utilization improves myocardial energetics and calcium handling. Moreover, SGLT2 inhibitors reduce proteinuria and increase erythropoietin production, which induces a greater renal function preservation over the mid-long term. Abbreviations: EPO, erythropoietin; SGLT2, sodium-glucose co-transporter 2.

In the last decades, regulatory entities in Europe and United States of America mandated pharmaceutical companies to carry out cardiovascular outcome trials in order to rule out an increase in cardiovascular risk associated with the use of hypoglycaemic drugs. Quite unexpectedly, studies performed with SGLT2 inhibitors in this setting showed a relevant decrease in cardiovascular morbimortality.

This benefit was firstly noted in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPAREG-OUTCOME) trial, in which the use of empagliflozin in diabetic patients with established cardiovascular disease was associated with a significant 14% reduction in the combined endpoint of heart attack, stroke, and cardiovascular death, compared to placebo [23]. Along the same lines, the Canagliflozin Cardiovascular Assessment Study (CANVAS) program demonstrated a 14% reduction in major adverse cardiovascular events and a 33% reduction in hospitalization for HF in diabetic patients with high cardiovascular risk treated with canagliflozin. In addition, the composite outcome of sustained 40% reduction in eGFR, need for renal-replacement therapy, or death from renal causes occurred less frequently among participants in the canagliflozin group [24]. The cardiovascular and renal protection observed in EMPAREG-OUTCOME trial was independent of glycaemic control, suggesting a mechanism of benefit beyond blood glucose-lowering [25].

In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, dapagliflozin showed a 17% reduction in the composite endpoint of cardiovascular death and hospitalization for HF in a broad population of patients with type 2 diabetes [26]. On the other hand, ertugliflozin in the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes (VERTIS-CV) trial was shown to be non-inferior to placebo in diabetic patients with prior history of cardiovascular disease [27].

More recently, the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial enrolled patients with type 2 diabetes and chronic kidney disease. Sotagliflozin, a dual SGLT inhibitor, resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF, but was associated with an increase in adverse events such as diabetic ketoacidosis, genital mycotic infections, diarrhea and volume depletion [28].

A recent meta-analysis confirmed that SGLT2 inhibitors reduce cardiovascular outcomes in patients with type 2 diabetes mellitus. There was a significant heterogeneity on outcomes between specific agents but a consistent risk reduction in HF hospitalizations, regardless of prior history of atherosclerotic cardiovascular disease or baseline kidney function [29].

AHF is a complex pathophysiological clinical syndrome. The natural history of HF syndrome is progressive, with periods of relative stabilization interspersed with periods of decompensation. AHF refers to rapid or gradual onset of symptoms and/or signs of HF, severe enough for the patient to seek urgent medical attention. AHF is one of the most common causes for hospital admission, with patients hospitalized once a year on average after the initial diagnosis, and is associated with a high risk of mortality. Compared to CHF, there is less robust evidence to guide diagnosis, risk stratification, and management [46, 47, 48].

Heart failure treatment during hospital admission largely relies on clinical expertise and experience. For decades, every study attempting to introduce a new intervention in this field showed neutral or negative findings. Only a few recent studies have presented promising results, indicating that sacubitril-valsartan, omecamtiv mecarbil and ferric carboxymaltose may be appropriate in this challenging clinical setting [49, 50, 51, 52].

On the other hand, the hospitalization period offers clinicians the opportunity to initiate guideline-directed therapies that have been shown to improve long-term morbidity and mortality. It is well known that patients who are not started on neurohormonal medication during admission have less probability of being under treatment with life-saving drugs over the next months [53, 54].

SGLT2 inhibitors have specific properties which may be of great value for AHF syndromes. As previously mentioned, they have proven to reduce HF hospitalizations in stable CHF patients, both in HFrEF and HFpEF, in quick and sustained fashion [33, 34, 44]. At the same time, SGLT2 inhibitors could be of great help in achieving euvolemia during an AHF admission, due to their differential but complementary diuretic effects over traditional loop diuretics. Furthermore, mechanisms of action of these agents are diverse and additive to inhibition of neurohormonal pathways, and could boost in-hospital renin-angiotensin-aldosterone system inhibitors’ prescription and uptitration [8].

Last but not least, administration of SGLT2 inhibitors is simple and does not require special monitoring. It is prescribed as a once-daily single-dose tablet, which does not need further titration. It is usually well tolerated, with a marginal effect on blood pressure and no effect on heart rate, and generally preserves rather than worsens renal function [40, 41, 55, 56].

Sotagliflozin was the first SGLT2 inhibitor to be tested in AHF [57]. The Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial included patients with type 2 diabetes hospitalized with worsening HF, both with HFrEF and HFpEF (ejection fraction 50% in 79% of the patients, respectively). The first dose of sotagliflozin or placebo was administered during the first days after an episode of AHF decompensation. Patients were clinically and hemodynamically stable. Inclusion criteria comprised transition from intravenous to oral diuretic therapy, no need for vasodilator, inotropic nor oxygen therapy, and systolic blood pressure of at least 100 mmHg. Patients had a median age of 70 years, a glycated hemoglobin level of 7.1%, an estimated eGFR of 49.7 mL/min/m${}^2$, and a median NT-proBNP level of 1800 pg/mL, and could start the study medication during admission (596 patients, 48.8%) or within three days after hospital discharge (626 patients, median two days). Despite early termination because of loss of funding from the sponsor, sotagliflozin reached the primary endpoint of reducing the total number of deaths from cardiovascular causes and hospitalizations and urgent visits from HF at a median follow-up of 9 months (245 vs. 355 events, HR 0.67, 95% CI 0.52–0.85). The benefit was driven by a reduction in HF hospitalizations and urgent visits (40.4% vs. 63.9%, HR 0.64, 95% CI 0.49–0.83), and was consistent among prespecified subgroups stratified according to geographic region, LVEF, timing of the first dose of the medication, sex, age and renal function. As sotagliflozin inhibits both SGLT2 and SGLT1 receptors, diarrhea (6.1% vs. 3.4%) and hypoglycemia (1.5% vs. 0.3%) were more common with sotagliflozin than with placebo.

Some trials regarding SGLT2 inhibition in AHF hospitalized patients have recently been concluded. The Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (EMPA-RESPONSE-AHF) pilot study was a randomized, double-blind, placebo-controlled, multicentre trial that enrolled 80 AHF patients with or without diabetes [58]. Patients need to have signs and symptoms of fluid overload, high natriuretic peptides (NT-proBNP $\ge$1400 pg/mL), and requirements of intravenous loop diuretics. Randomization was performed in the first 24 hours after admission, and treatment was continued through day 30. No difference was observed in any of the primary endpoints, which comprised change in visual analogue scale dyspnea score, diuretic response, change in NT-proBNP, and length of stay. However, empagliflozin was safe, well-tolerated, increased urinary output, and reduced a combined endpoint of worsening HF, rehospitalization for HF, or death at 60 days.

Few small real-life observational studies have confirmed SGLT2 inhibitors’ safety during an AHF admission and emphasize the importance of continuing this antidiabetic drug class at discharge [59, 60]. Two limited sample size randomized trials and three observational studies have suggested an increase in urinary output, total fluid loss, and hemoconcentration with the use of SGLT2 inhibitors during the hospitalization, and a subsequent decrease in congestion and need for loop diuretics at discharge [61, 62, 63, 64, 65].

The biggest evidence supporting the utilization of SGLT2 inhibitors during AHF admission comes from the Empagliflozin in Patients Hospitalized for Acute Heart Failure (EMPULSE) trial, whose results have been recently communicated during the American Heart Association 2021 congress [66]. In this trial, 530 AHF stabilized patients with elevated NT-proBNP ($\ge$1600 pg/mL) requiring at least 40 mg of iv furosemide per day, and eGFR $\ge$20 mL/min/m${}^2$ were included. Patients were randomized from day 1 to day 5 after admission, and while still being in the hospital, to empagliflozin 10 mg or placebo. Using a win-ratio approach, empagliflozin significantly reduced the combined primary endpoint of death, the number of HF events, time to first HF event, and change from baseline in KCCQ total symptom score at 90 days (clinical benefit of 53.9% vs. 39.7%, win ratio 1.36, 95% CI 1.09–1.68). Less than half of the patients were diabetic, and two-thirds had a LVEF below 40%. The benefit was consistent across different subgroups and numerically favored empagliflozin for each of the individual components of the primary outcome (death 4.2% vs. 8.3%, HF event 10.6% vs. 14.7%). Body weight was early and steadily reduced with empagliflozin (weight loss of 1.5 kg, present at day 15 after randomization). Serious adverse events were more frequent in the placebo group. Table 1 (Ref. [57, 58, 66]) shows a comparison of SOLOIST-WHF, EMPA-RESPONSE-AHF, and EMPULSE studies.

Some trials regarding the effect of SGLT2 inhibitors during the acute setting are ongoing. The Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68) trial will evaluate the effect of in-hospital initiation of dapagliflozin on the clinical outcome of cardiovascular death or worsening HF in a randomized, double-blind, placebo-controlled design. For this purpose, 2400 patients with HFrEF will be enrolled. Study completion is expected for 2023 (ClinicalTrials.gov number, NCT04363697). The effects of early administration of dapagliflozin shortly after discharge will also be evaluated in HFrEF patients with the aim of preventing readmissions and urgent clinic visits of HF (ClinicalTrials.gov number, NCT04249778). In addition, the decongestive effect of dapagliflozin will be tested in a sample of 240 type 2 diabetic patients hospitalized with AHF and presence of congestion. Randomization against placebo on top of a protocolized diuretic therapy will be done within the first 24 hours of presentation to the emergency department (Efficacy and Safety of Dapagliflozin in Acute Heart Failure, DICTATE-AHF trial, ClinicalTrials.gov number, NCT04298229) [67]. Interestingly, A Study to Test Whether Empagliflozin Can Lower the Risk of Heart Failure and Death in People Who Had a Heart Attack (Myocardial Infarction) (EMPACT-MI) trial will evaluate the effect of empagliflozin in an estimated sample size of 5000 patients hospitalized with acute myocardial infarction at high risk of HF. It is a randomized, double-blind, and placebo-controlled study. The treatment will be started during the first 14 days after hospital admission, and the primary outcome is a composite of time to first heart failure hospitalization or all-cause mortality with an expected follow-up of 24 months (ClinicalTrials.gov number, NCT04509674).

As formerly indicated, SGLT2 inhibitors do not induce clinically important modifications in blood pressure, renal function, or potassium levels. During hospital admission, fluid balance and adjustment of diuretic dose can be challenging. However, there was no signal of hypotension or worsening renal failure among empagliflozin groups in EMPA-RESPONSE-AHF or EMPULSE trials [58, 66].

In line with observed in CHF trials, SGLT2 inhibitors were associated with an increase in genital infections within the AHF hospitalization. However, the absolute number of these complications was low, around 1% of treated patients. Nevertheless, women, especially the diabetic and obese, and those with prior history of genital infection are at the highest risk, so counselling and education about personal hygiene and close monitoring and follow-up could be useful in these subgroups [68, 69].

Nonetheless, the most dreadful secondary effect regarding using SGLT2 inhibitors during an AHF admission is the development of euglycaemic ketoacidosis. Shift to fatty substrate utilization in response to SGLT2 inhibition produces ketones. Rise in ketone levels is usually well-tolerated, but in certain circumstances, like fasting, surgery, infections, or preshock, there may be a meaningful degree of partial insulin deficiency, which enhances the risk of developing ketoacidosis. This increased risk is almost exclusively limited to diabetic patients, especially those treated with insulin or with a low body mass index [70, 71]. Notwithstanding, published data are very reassuring. Among more than 900 patients receiving SGLT2 inhibitors in SOLOIST-WHF, EMPA-RESPONSE-AHF, and EMPULSE trials, only 2 cases of euglycaemic ketoacidosis were described. Moreover, the use of dapagliflozin in non-critically ill COVID-19 hospitalized patients with at least one cardiometabolic risk factor showed only 2 cases of diabetic ketoacidosis (0.3% of the dapagliflozin treated patients). It seems that once critically ill and fasting patients are excluded, prescribing SGLT2 inhibitors in the acute setting is safe and well-tolerated [57, 58, 66, 72]. Fig. 2 summarizes the benefits and risks associated with in-hospital administration of SGLT2 inhibitors.

Fig. 2.

Benefits and risks associated with in-hospital administration of SGLT2 inhibitors. Early prescription of SGLT2 inhibitors during an acute heart failure admission is favoured due to its beneficial cardiac and renal properties, easy use and absence of relevant blood pressure or electrolyte changes. However, it may be associated with a small but increased risk of genital infection or euglycaemic ketoacidosis, particularly in certain predisposed patients. Abbreviations: BP, blood pressure.