In-silico screening and identification of glycomimetic as potential human sodium-glucose co-transporter 2 inhibitor.

Sodium-glucose co-transporter 2 (SGLT2) is one of the important targets against type II diabetes mellitus. A typical SGLT2 inhibitor acts by inhibiting glucose reabsorption, thus lowering the blood glucose level. Unlike SGLT1, SGLT2 is responsible for almost 90% glucose reabsorption from glomerular filtrate. The current SGLT2 inhibitors include gliflozins, often prescribed as second or third-line agents in diabetes mellitus. The SGLT2 inhibitors also benefit patients with heart and kidney disease. Due to instability issues with the natural O-aryl glycoside analogues C-glycoside analogues were developed and showed improved stability. Despite enhanced bioavailability and selectivity of newer derivatives, some serious side effects are associated with gliflozin analogues. At the present study, we applied in-silico approaches to find new glycomimetic compounds as potent SGLT2 inhibitors that could show improvement in side effects associated with current analogues. This work applied both ligand-based and structure-based drug approaches to find potential compounds. We developed a 3D-QSAR method to screen potential inhibitors from a library of ten thousand compounds and performed docking studies. The compounds were ranked based on predicted pIC50 and docking score. An initial screening of five thousand compounds was conducted, and the subsequently selected top 12 compounds were based on binding free energy calculations. These selected compounds were subjected to molecular dynamics (MD) simulations. Remarkably, our simulations identified nine compounds that exhibited significant and sustained binding affinity compared to the co-crystallized Empagliflozin. Collectively, considering the anticipated pharmacokinetic profiles and toxicity assessments, several of these compounds emerged as promising candidates for further in-depth evaluation.

Performance of the ACMG-AMP criteria in a large familial renal glucosuria cohort with identified SLC5A2 sequence variants.

Familial Renal Glucosuria (FRG) is a co-dominantly inherited trait characterized by orthoglycaemic glucosuria. From 2003 to 2015 we have reported several cohorts validating SLC5A2 (16p11.2), encoding SGLT2 (Na+/glucose cotransporter family member 2), as the gene responsible for FRG. The aim of this work was to validate the variants identified in our extended FRG cohort of published, as well more recent unreported cases, according to the ACMG-AMP 2015 criteria. Forty-six variants were evaluated, including 16 novel alleles first described in this study. All are rare, ultra-rare or absent from population databases and most are missense changes. According to the ACMG-AMP standards, only 74% of the variants were classified as P/LP. The lack of descriptions of unrelated patients with similar variants or failing to test additional affected family members, averted a conclusion for pathogenicity in the alleles that scored VUS, highlighting the importance of both family testing and variant reporting. Finally, the cryo-EM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state improved the ACMG-AMP pathogenicity score by identifying critical/functional protein domains.

Molecular docking and dynamics simulation of Orthosiphon stamineus against SGLT1 and SGLT2.

Orthosiphon stamineus Benth a traditional medicine used in the treatment of diabetes and kidney diseases. Sodium-glucose co-transporter (SGLT1 and SGLT2) inhibitors are the novel group of drugs used to treat patients with type 2 diabetes mellitus. In this study 20 phytochemical compounds from Orthosiphon stamineus Benth were obtained from 3 databases viz Dr.Duke's phytochemical, Ethno botanical database and IMPPAT. They were subjected to physiochemical, drug likeliness, and ADMET and toxicity predictions. Homology modeling and molecular docking against SGLT1 and SGLT2 were performed and the stability of the selected drug molecule was validated by molecular dynamic (MD) simulation for 200 ns. Among the 20 compounds, 14-Dexo-14-O-acetylorthosiphol Y alone showed higher binding affinity with SGLT1 and SGLT2 protein with the binding energy of -9.6 and -11.4 Kcal/mol respectively and had highest affinity towards SGLT2 inhibitor. This compound also satisfied Lipinski rule of 5 and had a good ADMET profile. The compound is non-toxic to marine organisms and to normal cell lines and non-mutagenic. The RMSD value attained equilibrium at 150 ns with the stability around 4.8 Å and no significant deviation was reported from 160 to 200 ns for SGLT2. Our study suggests that 14-Dexo-14-O-acetylorthosiphol Y showed promising results against the SGLT2 and could be considered as a potent anti-diabetic drug.Communicated by Ramaswamy H. Sarma.

Clinical features of pediatric renal glucosuria cases due to SLC5A2 gene variants.

BACKGROUND: Familial renal glycosuria (FRG) is a rare renal tubular disorder characterized by a variable loss of glucose in the urine despite normal blood glucose levels, which is seen in a condition in which other tubular functions are preserved. In this study, the molecular and clinical characteristics of pediatric FRG cases due to SLC5A2 gene variants were defined. METHODS: Demographic features, diagnostic tests, and molecular analyses of patients with a diagnosis of FRG cases due to SLC5A2 gene variants were retrospectively analyzed between 2016 and 2019. RESULTS: The data of 16 patients who were clinically and genetically diagnosed with FRG in a 4-year period were analyzed. Seven (44%) of the cases were female and 9 (56%) were male. The median age at diagnosis was 6 years old (2 months old to 17 years old). Neuromotor development was found to be appropriate for the age in each case. Systemic blood pressure was evaluated as normal. A homozygous pathogenic variant in the SLC5A2 gene was detected in 14 patients in the genetic examination. A heterozygous variant was detected in one patient. In the other patient, two different heterozygous pathological variants were found in the SLC5A2 gene. CONCLUSIONS: It was revealed that growth and development were normal in children with glucosuria due to variations in the SCL5A2 gene. Renal function tests and urinary amino acid excretion were also within normal values. In our case series, the most common genetic variation in the SCL5A2 gene was the A219T (c.655G>A) variant.

Structural basis of inhibition of the human SGLT2-MAP17 glucose transporter.

Human sodium-glucose cotransporter 2 (hSGLT2) mediates the reabsorption of the majority of filtrated glucose in the kidney1. Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes1. Here we determined the cryogenic electron microscopy structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to an overall resolution of 2.95 Å. Our structure shows eukaryotic SGLT-specific structural features. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle. Our work provides a framework for understanding the mechanism of SLC5A family glucose transporters and also develops a foundation for the future rational design and optimization of new inhibitors targeting these transporters.

Swertisin, a novel SGLT2 inhibitor, with improved glucose homeostasis for effective diabetes therapy.

Failing pancreas and subsequent loss of pancreatic ß cells worsen diabetic conditions which are further alleviated by the mounting up of glucose levels. Inhibition of sodium glucose cotransporter 2 (SGLT2) in the kidney responsible for glucose reabsorption strikingly reduces blood glucose levels. Bioactive swertisin showed a promising glucose-lowering effect. Hence, we aimed to mechanistically dissect the glucose lowering property of swertisin. A systematic in silico, in vitro, and in vivo approach was directed for target analysis of swertisin. Molecular docking was performed with Swertisn-hSGLT2 complex. Glucose uptake assay and protein expression for SGLT2 and regulatory proteins were performed under swertisin effect. Various physiological and metabolic parameters were evaluated in STZ induced BALB/c mice using swertisin treatment. SGLT2 expression was evaluated in the kidney tissue of mice. Swertisn-hSGLT2 molecularly docked complex showed similar binding energy compared to the Canagliflozin-hSGLT2 complex. Swertisin inhibited glucose uptake and decreased expression of SGLT2 in HEK293 cells. Swertisin does not affect GLUT mediated glucose transport. Swertisin treated diabetic mice demonstrated remarkable improvement in overall glucose homeostasis. Reduced expression of SGLT2 was found in kidney tissue along with reduced PKC expression which is one of the key regulators of SGLT2. Our study explored SGLT2 as a selective target of swertisin for its swift glucose-lowering action which not only inhibits SGLT2 but also reduces its expression in diabetic condition. Thus, the potential property of swertisin as a glucose-lowering agent is remarkable which points towards the likelihood of a wider avenue of diabetes therapy.

Canagliflozin ameliorates hepatic fat deposition in obese diabetic mice: Role of prostaglandin E2.

Clinical and animal studies have suggested a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH). Although SGLT2 inhibitors have been shown to reduce hepatic fat deposition in association with loss of body weight, the mechanism of this action has remained unknown. We here show that the SGLT2 inhibitor canagliflozin ameliorated fatty liver and hyperglycemia without affecting body weight or epididymal fat weight in obese diabetic KKAy mice. Lipidomics analysis based on liquid chromatography and tandem mass spectrometry revealed that canagliflozin treatment increased the amounts of prostaglandin E2 (PGE2) and resolvin E3 in the liver of these mice. We also found that PGE2 attenuated fat deposition in mouse primary hepatocytes exposed to palmitic acid. Our results thus suggest that PGE2 may play an important role in the amelioration of hepatic fat deposition by canagliflozin, with elucidation of its mechanism of action potentially providing a basis for the development of new therapeutics for NAFLD-NASH.

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs.

The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium-glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (-)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH's adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of -5.65 kcal/mol and 71.95 µM, -5.50 kcal/mol and 92.97 µM, and -5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.

Marein ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway in db/db mice and high glucose-treated HK-2 cells.

Marein, an active component of the Coreopsis tinctoria Nutt. plant, is known to improve diabetic nephropathy (DN). However, its anti-diabetic functions in DN and potential mechanisms remain unclear. The aim of this study was to elucidate the effects and mechanisms of Marein in diabetic db/db mice with DN, and in high glucose-treated HK-2 cells. In vivo, treating diabetic db/db mice with Marein for 12 consecutive weeks restored diabetes-induced hyperglycemia and dyslipidemia, and ameliorated renal function deterioration, glomerulosclerosis, and renal ectopic lipid deposition. Marein exerted renoprotective effects by directly inhibiting renal tubule sodium glucose transporter 2 (SGLT2) expression, and then activating the AMP-activated protein kinase (AMPK)/acetyl CoA carboxylase (ACC)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) pathway in db/db mice. Meanwhile, Marein ameliorated fibrosis and inflammation by suppressing the pro-inflammatory factors interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), and expression of the extracellular matrix proteins, fibronectin (FN) and collagen 1 (COL1) in diabetic mice. In vitro, MDCK monolayer cells were established to explore the characteristics of Marein transmembrane transport. Marein was found to be absorbed across the membrane at a medium level that involved active transport and this was mediated by SGLTs. In HK-2 cells, Marein decreased uptake of the fluorescent glucose analog, 2-NBDG, by 22 % by inhibiting SGLT2 expression. In high glucose-treated HK-2 cells, Marein decreased SGLT2 expression and increased phosphorylated (p)-AMPK/p-ACC to improve high glucose-induced cellular dysfunction. Furthermore, Marein treatment decreased SGLT2 expression in SGLT2-overexpressing HK-2 cells. In addition, molecular docking and dynamics analysis revealed that SGLT2 was a direct target of Marein. Collectively, our results demonstrated that Marein ameliorates DN by inhibiting renal SGLT2 and activating p-AMPK, suggesting Marein can potentially prevent DN by suppressing renal SGLT2 expression directly.

5,5-Difluoro- and 5-Fluoro-5-methyl-hexose-based C-Glucosides as potent and orally bioavailable SGLT1 and SGLT2 dual inhibitors.

(2S,3R,4R,5S,6R)-2-Aryl-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols and (2S,3R,4R,5S,6R)-2-aryl-5-fluoro-5-methyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols were discovered as dual inhibitors of sodium glucose co-transporter proteins (e.g. SGLT1 and SGLT2) through rational drug design, efficient synthesis, and in vitro and in vivo evaluation. Compound 6g demonstrated potent dual inhibitory activities (IC50 = 96 nM for SGLT1 and IC50 = 1.3 nM for SGLT2). It showed robust inhibition of blood glucose excursion in an oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats when dosed at both 1 mg/kg and 10 mg/kg orally. It also demonstrated postprandial glucose control in db/db mice when dosed orally at 10 mg/kg.

A Paradigm Shift in the Treatment of Type 2 Diabetes and Heart Failure.

Despite good control of all risk factors for myocardial infarction, including blood glucose, blood pressure, lipids, and smoking, the probability of heart failure is significantly higher in diabetic patients than in healthy individuals. This observational study shows that the current treatment guidelines, which focus on the prevention of myocardial infarction, are insufficient in preventing heart failure development. Now, understanding the mechanisms of heart failure in diabetic patients and developing treatment guidelines based on these mechanisms are urgently needed. Instead of narrowly viewing that heart failure is caused by poor cardiac function, we need to take a bird's-eye view that heart failure is caused by a shift in the hemodynamic set point (blood pressure, heart rate, circulating blood volume, and autonomic balance) toward overloading the heart due to the persistent drive of the pathological kidney-brain-heart coupling. Clinical evidence, which shows that sodium-glucose-coupled transporter [Na＋/glucose co-transporter (SGLT)-2] inhibitors slowed the progression of chronic kidney disease (CKD) and reduced heart failure hospitalizations and deaths, underscores the importance of the renocardiac syndrome in heart failure development in diabetic patients.

SGLT2 inhibitors for genetic and acquired insulin resistance: Considerations for clinical use.

Administration of an sodium-glucose cotransporter 2 inhibitor to individuals with insulin resistance reduces the level of glucose disposal necessary to maintain glycemia as a result of the induced increase in urinary glucose excretion. The amount of insulin required for a certain level of glucose disposal, on which the evaluation of insulin resistance is usually based, might thus decrease even without amelioration of insulin resistance.

Sodium-glucose cotransporter 2 inhibitors improved time-in-range without increasing hypoglycemia in Japanese patients with type 1 diabetes: A retrospective, single-center, pilot study.

AIMS/INTRODUCTION: Studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors increased time-in-range (TIR; percentage of time glucose level remains between 3.9 and 10.0 mmol/L [70-180 mg/dL]) and decreased glycemic variability in patients with type 1 diabetes. The aim of this study was to investigate the effects of SGLT2 inhibitors on TIR, glycemic variability and glucose control in Japanese patients with type 1 diabetes in a real clinical setting. MATERIALS AND METHODS: We designed a single-arm, retrospective cohort study to analyze data from patients starting to use ipragliflozin or dapagliflozin and who used a sensor-based flash glucose monitoring system between February 2019 and August 2019. We measured TIR, time above range >180 mg/dL (percentage of time with glucose level of >180 mg/dL or >10.0 mmol/L), time below range <70 mg/dL (percentage of time with glucose level of <70 mg/dL or <3.9 mmol/L), mean glucose and standard deviation, and coefficient of variation for glycemic variability, and then compared the data before and after SGLT2 inhibitors treatments. RESULTS: We enrolled 15 patients in the study. The total dosages of basal insulin decreased significantly, but the total doses of bolus insulin did not change significantly. TIR increased significantly by approximately 11.6%; the time below range <70 mg/dL remained unchanged; and the mean glucose and standard deviation decreased significantly, whereas the coefficients of variation did not. CONCLUSIONS: SGLT2 inhibitors improved TIR and the mean glucose level and standard deviation without increasing the time below range <70 mg/dL in patients with type 1 diabetes.

Sodium-glucose cotransporter 2 inhibitor effects on cardiovascular outcomes in chronic kidney disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events, specifically those related to heart failure in patients with type 2 diabetes. Reductions in major adverse cardiovascular event (MACE) outcomes are also observed, but confined largely to patients who have prior cardiovascular disease. Cardiovascular outcome benefits extend to patients with type 2 diabetes and reduced estimated glomerular filtration (eGFR) rate down to 30 mL/min/1.73 m2 and to patients with heart failure but without diabetes. Ongoing trials are exploring whether patients with chronic kidney disease (CKD) but without diabetes will gain similar benefits from this class of agents. Although some safety concerns have emerged, it seems likely that SGLT2 inhibitors will be used more widely in CKD patients to reduce their cardiovascular risk.

Role of sodium-glucose cotransporter 2 inhibition to mitigate diabetic kidney disease risk in type 1 diabetes.

Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D) and a major risk factor for premature death from cardiovascular disease (CVD). Current treatments, such as control of hyperglycaemia and hypertension, are beneficial, but only partially protect against DKD. Finding new, safe and effective therapies to halt nephropathy progression has proven to be challenging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated, in addition to glycaemic lowering, impressive protection against DKD and CVD progression in people with type 2 diabetes. Although these beneficial cardiorenal effects may also apply to people with T1D, supporting data are lacking. Furthermore, the increased rates of euglycaemic diabetic ketoacidosis may limit the use of this class in people with T1D. In this review we highlight the pathophysiology of DKD in T1D and the unmet need that exists. We further detail the beneficial and adverse effects of SGLT2 inhibitors based on their mechanism of action. Finally, we balance the effects in people with T1D and indicate future lines of research.

Sodium-glucose cotransporter 2 inhibition: which patient with chronic kidney disease should be treated in the future?

The advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors represents a major advance for people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). The results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial have clearly demonstrated that canagliflozin prevents kidney failure and cardiovascular events. The results from three other large-scale randomized trials, collectively enrolling >30 000 participants, have provided further evidence that the effects of SGLT2 inhibition on major kidney outcomes in people with T2DM may be present across the class, although this will only be known for certain when Dapagliflozin and Renal Outcomes and Cardiovascular Mortality in Patients with CKD (DAPA-CKD) (NCT03036150) and The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY) (NCT03594110) are reported over coming years. Importantly, the benefits of SGLT2 inhibition have been achieved in addition to the current standard of care. This review summarizes evidence for SGLT2 inhibition in people with T2DM and CKD, evaluates key patient characteristics and concomitant drug use that may influence the use of these drugs in people with CKD, discusses current guideline recommendations and explores how these drugs may be used in people with CKD in the future, including in combination with other treatments.

Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin-angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin-angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.

Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease?

This year the medical community was pleasantly surprised by the results of the first large outcome trial that primarily examined the renal effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) in subjects with diabetes and impaired kidney function. The Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial showed that CANA, relative to placebo, reduces the risk for end-stage renal disease, doubling of creatinine or renal death by 34% [hazard ratio 0.66 (95% confidence interval 0.53-0.81]. These effects were consistent across baseline estimated glomerular filtration rate (eGFR) and haemoglobin A1c subgroups. In this review we combine the results of the CREDENCE trial with those of several cardiovascular outcome trials with SGLT2 inhibitors and show that, unexpectedly, patients with lower eGFR levels may have greater benefit with respect to cardiovascular outcome than patients with normal kidney function. The cardio- and renoprotective effects of SGLT2 inhibitors seem to be independent of their glucose-lowering effects, as shown in several post hoc analyses. In this review we discuss the alleged mechanisms of action that explain the beneficial effects of this novel class of drugs. Moreover, we discuss whether these findings indicate that this class of drugs may also be beneficial in non-diabetic chronic kidney diseases.

Role of Sodium-Glucose Cotransporter-2 Inhibition in the Treatment of Adults With Heart Failure.

Diabetes and heart failure (HF) independently contribute to significant cardiovascular (CV) morbidity and mortality. Both are tremendous burdens to health-care systems. Among patients with established HF, diabetes mellitus is one of the most common comorbidities, present in up to 45% of all patients. Although atherosclerotic CV disease outcomes are thought to be the major cause of morbidity and mortality among patients with diabetes, HF death and hospitalization has been recognized as being just as common. However, despite this evidence, HF as an outcome among trials of glucose-lowering therapies has been largely ignored. Now, there are 3 noninferiority CV outcome trials that have demonstrated the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors to reduce the risk of HF hospitalizations in patients with type 2 diabetes with CV risk factors and/or established atherosclerotic CV disease. The demonstration of a reduction in HF outcomes seen in these CV outcome trials represents a paradigm shift in the management of patients with type 2 diabetes mellitus and atherosclerotic CV disease or CV risk factors. Whether SGLT-2 inhibitors represent a therapeutic strategy to reduce the risk of CV events among patients with established HF remains to be explored. Furthermore, the benefit of SGLT-2 inhibitors in a population of patients with HF yet without diabetes remains to be demonstrated across multiple trials. This review aims to highlight the clinical trial and real-world evidence regarding the safety and efficacy of SGLT-2 inhibitors among patients with type 2 diabetes mellitus and established HF.