Observations derived from good structured randomized controlled trials indicate that SGLT-2i inhibitors exhibit a mitigating effect on the progression of cardiovascular and kidney diseases, irrespective of the presence or absence of diabetes [58]. Furthermore, in individuals with CKD and notable albuminuria, the administration of the SGLT-2i dapagliflozin has demonstrated a reduction in the risk of precipitous declines in kidney function, characterized by a twofold increase in serum creatinine levels between two consecutive study visits with a median time-interval of 100 days [59]. However, typically, the control of elevated blood glucose levels in hospitalized patients relies on insulin therapy. The abstention from oral agents during hospitalization is grounded in their diminished hypoglycemic efficacy relative to insulin, potential interactions with concurrently prescribed medications, and various safety concerns associated with altered pharmacokinetics, particularly in instances of renal or hepatic dysfunction [60]. Issues of concern encompass identified correlations between SGLT-2i and an elevated risk of DKA, hypovolaemia [60], disruptions in electrolyte and acid–base balance [61], urinary tract infections [62], as well as an early decrease in glomerular filtration rate induced by tubuloglomerular activation and reduced intraglomerular pressure [63]. Indeed, observational data from real-world settings indicate that the occurrence of DKA continues to be a point of concern in the context of using SGLT-2i [64] especially if specific medical conditions as for example acute infectious illness, urgent surgical procedures, or extended periods of fasting, co-exist [3].

Cytokine storm observed in patients with SARS-CoV-2 denotes an aberrant hyperactivation of the immune system characterized by dysregulated proinflammatory cytokine production. This dysregulation precipitates an excessive infiltration of immune cells into pulmonary tissues, inducing consequential tissue damage. Furthermore, this immune cell infiltration may extend to diverse tissues and organs, thereby engendering dysfunction across multiple organ systems. Key cytokines implicated in disease severity encompass tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), IL-6, IL-1β, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor indicating that the judicious management of the hyperinflammation assumes paramount importance in the therapeutic intervention for COVID-19 disease [65]. Demonstrating efficacy in patients with severe COVID-19, corticosteroids, IL-6 inhibitors, and Janus kinase inhibitors [66] have been established as agents capable of reducing mortality [57] underscoring the modifiable nature of inflammation and the potential for improvement in clinical outcomes through anti-inflammatory therapeutic interventions.

In addition to their glucose-lowering properties, SGLT-2i have been observed to contribute to the establishment of an anti-inflammatory environment through various physiological mechanisms as for example the attenuation of the activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome leading to elimination of the production and expression of proinflammatory cytokines, including IL-1β [38], IL-1, IL-6, and TNF-α [67]. Additionally, they hinder glycolysis, a pathway utilized by respiratory pathogens, and promote lipolysis, diminish oxidative stress, alongside enhancing endothelial function and oxygen-carrying capacity and tissue hypoxia through elevation of the erythropoietin concentrations [3]. The beneficial effects of SGLT-2i on inflammatory cascades may be of significant importance in patients underwent MV, which is also associated with the development of severe inflammatory reactions [68,69,70]. Furthermore, SGLT2i appears to enhance the expression of ACE2 receptors, consequently elevating Angiotensin 1–7 levels, known for their protective effects against COVID-19-related ARDS. Moreover, these inhibitors may potentially mitigate myocarditis, reduce the risk of arrhythmias, impede heart failure progression, and attenuate kidney injury in affected individuals [71]. Nevertheless, considering the potential adverse events such as DKA, hypotension and hypovolaemia, along with genital mycotic infections that may be exacerbate during acute illness [72], and given the wealth of pertinent recently published studies and the prevailing uncertainties regarding the use of SGLT-2i during acute illness, this systematic review aims to provide evidence regarding the application of SGLT-2i in patients undergoing acute illness, using as model patients with SARS-CoV-2 infection.

COVID-19-induced cytokine storm and SGLT-2 Inhibitors

Especially patients with DM-2, but also those with CKD as well as cardiovascular disease, experience an increase in IL-6 levels due to low-grade inflammation [73]. Low-grade systemic inflammation is associated with elevated uric acid and therefore linked with elevation of IL-6, C-reactive protein and TNF-α in the bloodstream [74]. All three underlying diseases are associated with an increased risk of severe COVID-19 progression [75]. Indeed, Chia et al [76] demonstrated that individuals from the general population with elevated IL-6 levels were significantly more likely to develop HFpEF than those with normal levels [76]. However, as is well known, all are also indications for SGLT-2i use. SGLT-2i are thought to decrease lactate accumulation by reversing the acid-base cytokine balance and preventing decrease of cytosolic pH. This results in inhibition of inflammatory pathways and subsequent cytokine storm, which in turn could damage the cells [77].

It has already been scientifically shown that SGLT-2i-induced lowering of the low-grade inflammation leads to a subsequent lowering of IL-6 and TNF-α levels in the blood [78,79,80,81]. Thus, the guideline-appropriate use of SGLT-2i in patients also appears reasonable in the acute phase of Sars-Cov-2 infection in the synopsis of the available studies. After searching large databases, no studies could be found that examined cytokine-levels when SGLT-2i were taken in critically ill patients. Given the available data, lower levels and thus a lowered inflammatory response would be conceivable. However, this effect has not been clinically demonstrated at this time.

A single prospective in vitro study was identified, focusing on the potential anti-inflammatory and protective properties of empagliflozin in the context of patients suffering from COVID-19. The central hypothesis of this study postulated that the inflammatory response observed in COVID-19 patients may contribute to endothelial dysfunction by means of upregulated, redox-sensitive SGLT-2 expression. Consequently, the investigation aimed to scrutinize the protective effects of inhibiting SGLT-2 with empagliflozin. This research entailed the collection of human plasma samples from three distinct cohorts, namely, patients with acute, subacute, and chronic COVID-19 conditions (n = 100), individuals without COVID-19 but exhibiting cardiovascular risk factors (n = 50), and a control group comprising healthy volunteers (n = 25). Porcine coronary artery endothelial cells were subjected to plasma exposure at a concentration of 10%. To evaluate the study’s outcomes, a suite of analyses was conducted, including Western blot assessments and immunofluorescence staining to gauge protein expression levels, quantitative reverse transcription-polymerase chain reaction to measure mRNA expression, and dihydroethidium staining to quantify oxidative stress. The research also encompassed the assessment of platelet adhesion, aggregation, and thrombin generation. The findings from this investigation unveiled heightened plasma levels of key proinflammatory cytokines, including interleukin IL-1β, IL-6, TNF-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 in COVID-19 patients. Notably, exposure of ECs to COVID-19 plasma characterized by elevated proinflammatory cytokine levels (specifically, IL-1β, IL-6, and TNF-α) precipitated a redox-sensitive upregulation of SGLT-2 expression. This molecular response, in turn, fostered endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. Crucially, the study demonstrated that the stimulatory effect of COVID-19 plasma could be attenuated through the use of neutralizing antibodies against proinflammatory cytokines and empagliflozin. In conclusion, the authors deduced that, in patients afflicted with COVID-19, proinflammatory cytokines induced the redox-sensitive upregulation of SGLT-2 expression in endothelial cells [82], which subsequently led to endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. Consequently, the inhibition of SGLT-2 via empagliflozin presents itself as a promising strategy for restoring vascular homeostasis in the context of COVID-19 [83].

SGLT-2 inhibitor in patients with diabetes mellitus and COVID-19

Individuals with DM-2 exhibit an elevated likelihood of hospitalization and face an augmented risk of severe outcomes and mortality [82] associated with COVID-19, as outlined by Zhang and co-workers [84]. Specifically, the risk for severe pneumonia is amplified by 2.3-fold, with a corresponding 2.5-fold increase in mortality [85]. This heightened susceptibility can be primarily attributed to two interconnected mechanisms: Firstly, a substantial proportion of patients with DM-2 are characterized by overweight. This adiposity contributes to an increased prevalence of cytokines, released by resident macrophages, adipocytes, and endothelial cells [86]. Consequently, the preexisting state of chronic inflammation is exacerbated during SARS-CoV-2 infection, culminating in a cytokine storm [87]. Importantly, the administration of SGLT-2i has been associated with a reduction in body weight [88], which, in turn, contributes to the amelioration of chronic inflammation in obese patients [89]. Conversely, heightened blood glucose concentrations prompt heightened expression of ACE2 in the pulmonary system [87] facilitating the internalization of the virus into the body [90]. To mitigate the potential severity of a COVID-19 infection, precise control of blood glucose levels is strongly recommended. On the other hand, elevated blood glucose levels stimulate increased expression of ACE-2 in the lung [87], which mediates the internalization of the virus to the body [90]. To avoid severe COVID-19 courses as far as possible, a tight adjustment of blood glucose levels is strongly recommended. Notably, the association between elevated HbA1c levels and increased mortality during COVID-19 has been established [91]. The higher the HbA1c-levels, the higher the mortality during COVID-19 with the levels of HbA1c presenting a linear correlation with mortality [91].

Existing evidence indicates that individuals with DM-2 undergoing treatment with SGLT-2i while suffering from COVID-19 manifest reduced mortality rates [28, 34, 41, 42]. According to Shestakova’s et al. [42], the favorable impact of SGLT-2i on the course of COVID-19 is ascribed to their capacity for diminishing oxidative stress, imparting an antioxidant effect, and modulating endothelial function [42]. Khunti et al. [34] observe a more pronounced beneficial effect in patients with diabetes mellitus and elevated body mass index or a history of cardiovascular disease during COVID-19, attributing this effect to the heightened cardio- and renoprotective properties intrinsic to this drug class [34].

We found that individuals with DM-2 taking SGLT-2i exhibit a lower risk of mortality, as reported by multiple studies [34, 41,42,43]. Foresta et al. (2023) suggests a trend towards reduced mortality and hospitalization for DM patients with COVID-19 under SGLT-2i, with significant in-hospital mortality reduction, particularly when combined with metformin [44]. Hospitalization risk reduction in DM-2 patients with COVID-19 under SGLT-2i was noted in studies by Wander et al. [43] and Foresta et al. [44] (not statistically significant) [43, 44]. However, three studies [51, 52] showed a neutral effect on hospitalization risk. The susceptibility to COVID-19 infection in DM-2 patients using SGLT-2i was not elevated [53]. Regarding ICU admission and MV, Yeh et al. [50] and Perez-Belmonte et al. [45] found no significant associations with prior use of SGLT-2i in DM-2 patients [45, 50]. Dalan et al. [54] suggested a marginally lower risk of MV in DM patients using SGLT-2i [54].

Nevertheless, counterarguments against the widespread utilization of SGLT-2i during the acute phase of infection include the following considerations: SGLT-2i may instigate volume depletion, arterial hypotension, and euglycaemic DKA. The emergence of the latter complication appears notably evident in patients with diminished carbohydrate intake due to acute illness and in those experiencing dehydration from fever, vomiting/diarrhea, and the osmotic/diuretic influences of COVID-19 [92]. Therefore, a judicious evaluation of the appropriateness of SGLT-2i usage is imperative, particularly in individuals with impaired glucose tolerance and subsequent insulin resistance, potentially leading to hyperinsulinism.

SGLT-2 inhibitors in patients with cardiometabolic risk factors and/or heart failure

SGLT-2i are recognized for their diverse applications, encompassing not only DM-2 but also heart failure, whether with preserved or reduced ejection fraction [4, 93]. Viral diseases, such as COVID-19, have been identified as potential triggers for heart failure [94]. Autopsy studies indicate that SARS-CoV-2 can directly invade cardiomyocytes, leading to direct cardiomyocyte damage [95]. Beyond the virus itself, the inflammatory response, characterized by elevated cytokine levels, contributes to myocardial damage [94].

Hospitalized COVID-19 patients often exhibit elevated levels of creatine kinase (CK) and lactate dehydrogenase (LDH) or increased troponin, indicative of myocardial damage [96,97,98]. Studies suggest that up to 62.3% of hospitalized COVID-19 patients experience myocardial damage, detectable through elevated high-sensitive cardiac troponin T (Weber). Patients with cardiac injury also demonstrate elevated IL-6 levels, with fulminant myocarditis attributed to a cytokine storm as a potential cause [10]. Preventing cytokine storm appears crucial, given its impact on cardiac function and, consequently, survival.

In addition, COVID-19 may contribute to cardiac remodeling, particularly with a right-dominant pattern. Left ventricular (LV) function is less frequently affected [99]. Viral infections, known to cause subacute myocarditis with limited ventricular function, underscore the importance of SGLT-2 inhibitors in guideline-based heart failure therapy, potentially preventing or reversing cardiac remodeling [75]. However, the impact of COVID-19-induced cardiac remodeling and the potential benefits of SGLT-2i in this context remain to a large extend unclear.

We found that dapagliflozin demonstrates a reduction in cardiovascular events in heart failure patients, and its use before contracting COVID-19 did not elevate severe outcomes. The combination of metformin and empagliflozin protected against COVID-19 hospitalization in those with cardiometabolic risk factors, but empagliflozin alone did not reduce the risk. Experimental evidence suggested dapagliflozin’s potential in mitigating SARS-CoV-2-mediated cardiorenal injury. However, the DARE-19 study found no significant benefits in patients with cardiometabolic risk factors, and a multicountry study reported no association between empagliflozin and COVID-19 outcomes in hospitalized adults [23, 24, 33, 52, 55, 57].

SGLT-2 inhibitors and acute kidney injury in patients with COVID-19

2021 McMurray and colleagues demonstrated the beneficial effects of SGLT-2i on chronic renal failure progression. In both patients with and without DM, the use of SGLT-2i reduced the risk of progression to chronic renal failure and significantly reduced mortality [4]. Causes of chronic renal failure are diverse. Among others, however, repeated AKI is a possible trigger. Patients with renal function impairment and COVID-19 have increased risk for adverse clinical outcomes, severe disease and higher in-hospital mortality compared to those with normal renal function [