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Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are a class of oral antihyperglycemic drugs recently added to clinical practice guidelines to manage type 2 diabetes mellitus (T2DM). Recent clinical trials have established significant benefits in using SGLT-2is to treat both heart failure and renal disease. This article aims to explain the clinical benefits of inhibiting sodium-glucose cotransporter-2 proteins in patients with T2DM, renal disease, and heart failure. These authors also seek to guide nurse practitioners in prescribing SGLT-2is. Evidence-based guidance for nurse practitioners to treat T2DM, heart failure, and renal disease is likely to improve patients’ clinical outcomes and decrease associated morbidities.

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage., Lay summary SGLT2 inhibitors have cardiovascular benefits that include HF outcomes in patients with and without diabetes. Because the underlying mechanisms are only partly explained by improvements in BP, body weight, or glucose control, other mechanisms have been proposed. We focus here on a central role for effects on sodium as underlying the positive benefits of SGLT2 inhibitors in HF. We explore the new (although still unconfirmed) idea that SGLT2 inhibitors exert some of their positive effects by affecting nonosmotic sodium (ie, sodium bound to muscles and skin and not dissolved in the blood). SGLT2 inhibitors have emerged as a class of drugs, previously prescribed for patients with T2D, that have in more recent years been shown to have substantial heart and kidney clinical benefits in patients with and without T2D.The degree to which these benefits are related to kidney-independent changes in sodium homeostasis is currently unknown.A better understanding of the nonosmotic mechanisms underpinning the benefits of SGLT2 inhibition on HF (with reduced or preserved left ventricular ejection fraction) may allow researchers to assess the effects of SGLT2 inhibitors in combination with other treatments that affect sodium balance.

Heart failure (HF) is a common cause of cardiovascular mortality and morbidity. Despite advances in treatment, the prognosis remains poor. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors decrease HF events by 27–39% in high-risk patients with type 2 diabetes mellitus (T2DM). Moreover, the DAPA-HF and EMPEROR-Reduced studies randomized patients with HF with reduced ejection fraction (HFrEF) with or without diabetes mellitus to receive guideline-directed medical therapy versus guideline-directed medical therapy plus an SGLT-2 inhibitor. Both studies showed the benefits of SGLT-2 inhibitors. In addition, SGLT-2 inhibitors have shown improvement according to the EMPEROR-Preserved study of HF with preserved ejection fraction (HFpEF). Therefore, a panel of cardiology experts from the Egyptian Atherosclerosis and Vascular Biology Association (EAVA) revised the literature for SGLT-2 inhibitors in HF, along with the recommended indications and contraindications, and this article presents their consensus on the topic. The panel concluded that SGLT-2 inhibitors have significantly benefited patients with chronic HFrEF, as indicated through the DAPA-HF and EMPEROR-Reduced trials. The panel recommended early use of dapagliflozin 10 mg or empagliflozin 10 mg in patients with symptomatic chronic HFrEF, whether diabetic or non-diabetic, to ameliorate HF hospitalization rate, mortality, symptoms, and decline in renal function.

Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

Summary Cardiovascular and renal outcome trials (CVOTs) for glucagon-like-peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) highlight new options for people with and without type 2 diabetes (T2D). Drugs within these classes reduce rates of major adverse cardiovascular events (MACE), with SGLT2i simultaneously attenuating decline in kidney function. SGLT2i reduce rates of heart failure in people with and without T2D, whereas GLP1RA lower rates of myocardial infarction and stroke in people with T2D with or without preexisting cardiovascular disease. Mechanistically, SGLT2 and the GLP-1 receptor are expressed at low levels in the heart, and within some blood vessels and immune cells, implying indirect mechanisms of action for the preservation of ventricular function, and reduction of atherosclerosis. SGLT2i likely preserve renal function through the alteration of glomerular hemodynamics. These two drug classes enable organ protection and reduced mortality in people with T2D and represent promising therapies for some people without T2D.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially born as anti-diabetic drugs, have shown many beneficial effects on the cardiovascular system, in particular against heart failure (HF). HF is a complex and multifaceted disease that requires a comprehensive approach. It should not be considered as a simplistic cardiac disease, but a systemic disease that leads to multisystemic organ failure and death. Exploiting their pleiotropic effects, SGLT2i are a very valid tool for HF treatment. Beyond the indication to reduce HF hospitalization and death risk, in patients with diabetes mellitus at high cardiovascular risk or with established cardiovascular event, SGLT2i administration reported beneficial effects regarding the wide spectrum of HF manifestations and stages, independently by diabetes mellitus presence. Recent evidence focuses on HF rehospitalization, cardiac and all-cause death reduction, as well as symptoms and quality of life improvement, in patients with chronic HF or with a recent HF decompensation episode. Given the recent finding about the SGLT2i usefulness in HF patients, further studies are needed to define the best administration timing to maximize the SGLT2i-derived beneficial effects.

Background: Patients with type II diabetes are at major risk for cardiovascular disease. Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have demonstrated benefit for these patients. The purpose of this study is to determine whether SGLT-2 inhibitors significantly reduce heart failure readmission rates and improve outcomes in patients with congestive heart failure (CHF). Methods: Patient data was pulled on CHF patients with an active prescription for an SGLT-2 inhibitor, and it was analyzed using Fischer’s Exact tests and two-tailed t-tests. The primary outcome was a 6-month hospital readmission rate due to CHF while taking SGLT-2 inhibitors. Secondary outcomes included 6-month all-cause hospital readmissions, renal function as measured by an estimated glomerular filtration rate change between admissions, mortality rates, and ejection fraction. Results: Of the 138 patients that met inclusion criteria for the first admission, the 6-month all-cause readmission rate for CHF patients still taking SGLT-2 inhibitors at readmission was 21 percent vs 16 percent (p=0.6) for the control group not taking SGLT-2 inhibitors. The 6-month CHF readmission rate in patients taking SGLT-2 inhibitors was 7.2 percent, and a CHF specific readmission rate was not collected for the control group. In patients with an eGFR less than 90, the average eGFR for the SGLT-2 group declined slightly but was not significant between patients at first admission and those with readmission (p=0.21). Conclusion: The use of SGLT-2 inhibitors in patients with CHF did not change the overall hospital readmission rate; however, larger randomized controlled trials are needed for further evaluation of the potential benefit. Key words: Cardiovascular Outcomes, Chronic Heart Failure, Heart Failure Hospitalization, SGLT2 Inhibition, Type II Diabetes.

The findings of large-scale cardiovascular outcome trials have been demonstrated that sodium-glucose cotransporter 2 ­inhibitors (iSGLT-2) have shown beneficial cardiovascular effects. In this review proposed mechanisms underlying iSGLT-2-associated cardiovascular benefits have been discussed: haemodynamic and intracellular effects, including metabolic effects and electrolyte changes; and also, the effect on markers of cardiovascular disease (CVD). The hemodynamic effects of SGLT-2 are characterized by reduction of cardiac preload and afterload as a result of osmotic diuresis, a decrease in blood pressure and arterial stiffness. The metabolic effects of this medicine are accompanied by an increase the production of ketone bodies, followed by improving ATP production and myocardial energetics. Also, iSGLT-2 modulate ion transporters (NHE1 and NHE3). A reduction of cytoplasmic sodium and calcium levels and increasing mitochondrial calcium levels in the cardiomyocytes enhances the synthesis of ATP and increases cell viability. Effect of iSGLT-2 on CVD markers showed a decrease in the levels of the N-terminal pro-B-type natriuretic peptide and highly sensitive troponin I in elderly patients with type 2 diabetes mellitus (T2DM). Thus, this class of agents has a multifactorial effect on the functioning of cardiovascular system. Further studies will help to explain the all possible cardioprotective effects of iSGLT-2 in individuals with and without T2DM.

Aims/Introduction The aim of this study was to elucidate whether sodium–glucose cotransporter 2 inhibitors (SGLT2is) treatment has any renoprotective effect for type 2 diabetes mellitus patients with an estimated glomerular filtration rate (eGFR) of, Administration of sodium–glucose cotransporter 2 inhibitors slowed the annual estimated glomerular filtration rate decline in type 2 diabetes patients with an estimated glomerular filtration rate of

Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the progression of diabetic kidney disease. However, the mechanisms underlying this renoprotective benefit are not completely understood. We evaluated whether SGLT2 inhibition reduces cellular senescence in the kidney and investigated the molecular pathways involved in the renoprotective effect. Materials and methods Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg), or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real-time RT-PCR, immunohistochemistry, and western blot analysis. For in vitro analysis, HK-2 cells, a human renal tubular epithelial cell line, were pretreated with H2 O2 to induce cellular senescence, and the levels of ageing markers were measured after treatment with β-hydroxybutyrate (β-HB) or NRF2-specific siRNA. Results Expression levels of ageing marker genes (p21, p16, and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db+vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db+SGLT2i) group, but not in the glimepiride-treated db/db (db/db+SU) group. In the kidneys of mice in the db/db+SGLT2i group, oxidative stress and DNA damage were also reduced compared with those in the db/db+vehicle and db/db+SU groups. Dapagliflozin increased plasma β-HB, which reduced H2 O2 -induced DNA damage and senescence in HK-2 cells. β-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways. Conclusions Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation. This article is protected by copyright. All rights reserved.

Diabetes is a known risk factor for the development of cardiovascular and chronic kidney disease. Sodium–glucose cotransporter 2 inhibitors are glucose-lowering medications that have been demonstrated to improve clinical cardiovascular and renal outcomes. This article reviews recent large clinical trials involving these medications and explains their impact on type 2 diabetes treatment guidelines.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antidiabetic drugs that reduce hyperglycemia by inhibiting the glucose reabsorption in renal proximal tubules. Clinical studies have shown that SGLT2 inhibitors not only improve glycemic control but also reduce major adverse cardiovascular events (MACE, cardiovascular and total mortality, fatal or nonfatal myocardial infarction or stroke) and hospitalization for heart failure (HF), and improve outcome in chronic kidney disease. These cardiovascular and renal benefits have now been confirmed in both diabetes and non-diabetes patients. The precise mechanism(s) responsible for the protective effects are under intensive investigation. This review examines current evidence on the cardiovascular benefits of SGLT2 inhibitors, with a special emphasis on the vascular actions and their potential mechanisms.

Solid organ transplantation offers life-saving treatment for patients with end-organ dysfunction. Patient survival and quality of life have improved over the past few decades as a result of pharmacological development, expansion of the donor pool, technological advances and standardization of practices related to transplantation. Still, transplantation is associated with cardiovascular complications, of which post-transplant diabetes mellitus (PTDM) is one of the most important. PTDM increases mortality, which is best documented in patients who have received kidney and heart transplants. PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus, but also from specific post-transplant risk factors such as metabolic side effects of immunosuppressive drugs, post-transplant viral infections and hypomagnesemia. Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients. However, the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited. The favourable risk/benefit ratio, which is suggested by large-scale and long-term studies on new glucose-lowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, makes studies warranted to assess the potential role of these agents in the management of PTDM.

Les inhibiteurs du cotransporteur sodium-glucose de type 2 (iSGLT2) sont de plus en plus recommandes comme traitement de l’insuffisance cardiaque en raison d’un benefice cardio-renal et d’un effet favorable sur la mortabilite. L’utilisation de biomarqueurs pour suivre l’efficacite de ce traitement pourrait s’averer utile et notamment le Fibroblaste Growth Factor 23 (FGF-23) en raison de la relation entre ses taux circulants et le pronostic cardiovasculaire. D’autre part, la mesure de FGF-23 lors du traitement par un iSGLT2 pourrait permettre de suivre les repercussions sur le metabolisme phosphocalcique.

Fluctuations in the concentration of glucose in the blood is more detrimental than a constantly high level of glucose with respect to the development of cardiovascular complications associated with diabetes mellitus (DM). Sodium glucose cotransporter 2 (SGLT2) inhibitors have been developed as antidiabetic drugs with cardiovascular benefits; however, whether inhibition of SGLT1 protects the diabetic heart remains to be determined. This study investigated the role of SGLT1 in rat H9c2 cardiomyocytes subjected to fluctuating levels of glucose and the underlying mechanisms. The results indicated that knockdown of SGLT1 restored cell proliferation and suppressed the cytotoxicity associated with fluctuating glucose levels. Oxidative stress was induced in H9c2 cells subjected to fluctuating glucose levels, but these changes were effectively reversed by knockdown of SGLT1, as manifested by reductions in the level of intracellular reactive oxygen species and increased antioxidant activity. Further study demonstrated that knockdown of SGLT1 attenuated the mitochondrial dysfunction in H9c2 cells exposed to fluctuating glucose levels, by restoring mitochondrial membrane potential and promoting mitochondrial fusion. In addition, knockdown of SGLT1 downregulated the expression of Bax, upregulated the expression of Bcl-2, and reduced the activation of caspase-3 in H9c2 cells subjected to fluctuating levels of glucose. Collectively, our results show that knockdown of SGLT1 ameliorates the apoptosis of cardiomyocyte caused by fluctuating glucose levels via regulating oxidative stress and combatting mitochondrial dysfunction.

Sodium–glucose cotransporter-2 (SGLT2) inhibitors recently emerged as an effective therapy for heart failure (HF) with reduced ejection fraction. Recent published clinical trials have confirmed these agents substantially reduce mortality and HF hospitalization among patients with established HF with reduced ejection fraction, with or without type 2 diabetes. Ongoing studies are evaluating the effects of SGLT2 inhibitors on clinical outcomes for patients with HF with preserved ejection fraction. Nurse practitioners must understand the indications and mechanisms of SGLT2 inhibitors when prescribing. Thoughtful collaboration between cardiology and endocrine providers can guide management with the use of SGLT2 inhibitors in complicated HF patients.

Purpose of review Sodium-glucose cotransporter 2 (SGLT2) inhibitors have proven cardiorenal protection in patients with diabetes and chronic kidney disease (CKD) as seen in cardiovascular outcome trials (CVOTs) and CREDENCE. In this review, we aim to discuss the mechanisms of kidney protection with SGLT2 inhibition as well as review the results of multiple translational studies and clinical trials of SGLT2 inhibition in the nondiabetic kidney disease (non-DKD) population. Recent findings The application of SGLT2 inhibitors as dedicated kidney-protective agents continues to evolve with the publication of the dapagliflozin in patients with chronic kidney disease (DAPA CKD) trial, which extends their cardiorenal protection to patients with nondiabetic CKD. This trial was preceded by CREDENCE, a dedicated kidney outcome study in participants with DKD that demonstrated a 30% reduction in the risk of the composite kidney outcome. From a physiological perspective, mechanistic benefits of SGLT2 inhibitors are independent of their glucose-lowering effects as demonstrated in preclinical studies and post hoc analyses of dedicated CVOTs in participants with type 2 diabetes. From a clinical perspective, there is a growing body of evidence for kidney protection in nondiabetes mellitus patients. Summary There exists strong rationale for SGLT2 inhibition to be incorporated into standard of care for appropriate groups of patients with nondiabetic kidney disease.

Aims We aimed to assess whether the safety outcomes exerted by sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with different renal function at baseline. Data Synthesis We searched randomized controlled trials comparing SGLT2 inhibitors with placebo in participants simultaneously involving the entire range of estimated glomerular filtration rate (eGFR) levels at baseline in one study. According to eGFR, we divided the population into two subgroups with eGFR 0.05). For osmotic diuresis, SGLT2 inhibitors significantly increased the risk by 75% (p = 0.036), and subgroup analyses showed that this effect was completely attributed to the increase in patients with eGFR ≥60 ml/min/1.73 m2 (p-interaction Conclusion The indication of no risk of osmotic diuresis in patients with eGFR

Purpose of review Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antihyperglycemic drugs that show remarkable cardiorenal protective effects in patients with or without type 2 diabetes. Furthermore, they are effective among patients across a wide range of baseline renal and cardiac function. Numerous mechanisms have been evaluated to understand these remarkable clinical benefits. From an early stage, these agents were noted to affect the plasma lipid profile. Here we review lipid profile alterations attributable to SGLT2 inhibitors and also some mechanisms explored in model systems and human studies. Recent findings SGLT2 inhibitors given to patients with diabetes as monotherapy shift substrate utilization from carbohydrates to lipids, and have mild effects on the lipid profile. Increased LDL cholesterol appears to be associated with increased hepatic production and decreased catabolism. Increased HDL cholesterol and decreased triglycerides appear to be associated with improved insulin sensitivity and increased lipolysis. Lipid effects of SGLT2 inhibitors are further modulated by background therapy with other diabetes medications and statins. Summary The minor lipid profile alterations observed in patients treated with SGLT2 inhibitors are offset by the staggering range of beneficial pleiotropic mechanisms that likely explain the marked cardiorenal benefits of these agents.

Purpose of review Controlling hypertension to the desired target is commonly unsuccessful and requires multi-drug regimen, which can lead to undesirable side effects. Resistant hypertension (RH) is more cumbersome to deal with and has robust morbidity and mortality burden even with current multiple medical options. Herein, we review the literature for the potential role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a treatment option for hypertension and RH. Recent findings With more recent randomized controlled trials (RCTs), SGLT2i have gained more recognition for their renal and cardiovascular protection as well as mortality benefit that are believed to be medication class-related effects. Multiple RCTs have evaluated blood pressure (BP) lowering properties of SGLT2i, as a primary or secondary end point, in diabetic and nondiabetic patients, yet trials are scarce in studying SGLT2i as first-line antihypertensives, or as add-on agents for treating RH. Summary Finding the right medical therapy in treating hypertension, especially RH, is commonly onerous when it comes to achieving BP targets, avoiding medication side effects, and aiming for the best outcomes. Utilizing existing drugs like SGLT2i or exploring other novel agents with more RCTs for these purposes will be beneficial. The addition of SGLT2i to the therapeutic armamentarium in patients with RH should be considered as a target for upcoming RCTs.

Sodium glucose cotransporter 2 (SGLT2), a type of membrane protein highly expressed in the kidney, can regulate plasma glucose through the glomerular filtration process by reabsorption from the kidney. SGLT2 inhibitors, which are newly developed oral antidiabetic drugs, can play a role in liver diseases by inhibiting SGLT2‐mediated renal glucose reabsorption and inducing glycosuria. Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, resulting in severe liver dysfunction. During the progression of NAFLD, there are some hallmark complications, including lipid metabolism disorders, inflammation induction, and hepatocyte death. Herein, we review several SGLT2 inhibitors that are capable of protecting individuals with NAFLD from severe complications by inhibiting de novo lipogenesis, oxidative responses, inflammation induction, and hepatocyte death.

New glucose-lowering agents reduce liver enzyme levels and blood pressure (BP). Whether this finding can be extended to non-alcoholic fatty liver disease (NAFLD) patients, in whom a bidirectional association of NAFLD measures and BP has been also demonstrated, remains by and large unknown.

On July 10, 2019, the Trump administration signed an Executive Order titled the “Advancing American Kidney Health” (AAKH) Initiative, which primarily aims to reduce the incidence of kidney failure by 25% by 2030 and shift kidney care from treating kidney failure to maximizing kidney health ([1][

Introduction: Ramadan is a holy month and the majority of Muslims fast in it, without considering background illnesses. SGLT-2 drugs were available for Pakistani patients recently, and this was the first year to fast in their presence.Objectives: To assess the risk of hypoglycemia in fasting diabetics using SGLT-2 drugs, comparing it with Sulphonylurea (SU) drugs. Also, a change in HbA1c and eGFR was checked. Hence, evidence was collected to recommend their use in fasting Diabetics with safety. Material and Methods: A total of 5500 patients from three different sites were included. Only 500 fulfilled the criteria of inclusion. Pregnant, lactating, advanced Chronic Kidney Disease (CKD), and those recording hypoglycemia frequently were not included. Ages between 20 to 70 years, HbA1c between 7 to 11, and patients taking SU or SGLT-2 were included. Conclusion: The eGFR was comparable in both groups post-Ramadan. HbA1c was significantly reduced in the SGLT-2 group. Bitter taste and thirst were common with the SU group. Hypoglycemia was comparable in both groups. We concluded that SGLT-2 drugs were safe during Ramadan, and caused more HbA1c reduction.

To assess real-world data on the clinical implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in cardiovascular patients and to investigate barriers to prescribe these agents. Patients presenting with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) between 01/2014 and 04/2020 were included in the present analysis and followed prospectively. All first-time prescriptions of SGLT2i and GLP-1RA were identified. Among 1498 patients with CAD and T2DM, 17.6% of patients received an SGLT2i and 5.5% a GLP-1RA. The prescription of SGLT2i (+38.7%; p < 0.001) and GLP-1RA (+8%; p = 0.007) significantly increased during the observation period. Considering remuneration criteria for SGLT2i therapy, lowering the GFR cut-off to 30 ml/min/1.73 m2 would allow additional 26.6% of patients to qualify for an SGLT2i therapy. While SGLT2i therapy was inversely associated with CV mortality (adjusted hazard ratio of 0.18 [95% CI: 0.05–0.76]; p = 0.019), GLP-1RA therapy showed a trend for risk reduction. The present analysis revealed an infrequent prescription of SGLT2i and GLP-1RAs in patients with T2DM and CAD in clinical practice. Remuneration regulations that better reflect the inclusion criteria of the CV outcome trials would allow more patients at high risk to receive these CV protective drugs. Most importantly, while GLP-1RA therapy showed a trend for risk reduction of cardiovascular mortality, the use of SGLT2i had a strong inverse impact on cardiovascular mortality from a long-term perspective.

Aims/Introduction Increased blood glucose or increased weight is often observed in patients who are prescribed sodium–glucose cotransporter 2 inhibitors (SGLT2i). The aim of this study was to determine in advance which patients, among those prescribed a SGLT2i, would be likely to have improved or worsened blood glucose levels and gain or loss of weight through the use of real‐world data‐based prescriptions. Materials and Methods After 3 months of dapagliflozin prescription, patients were divided into four groups: H(+)W(+) for improved glucose and weight loss; H(+)W(−) for improved blood glucose and weight gain; H(−)W(+) for worsened glucose and weight loss; and H(−)W(−) for worsened glucose and weight gain. Results The proportion of patients in the H(+)W(+) group was 53.5% (325/608 patients), H(+)W(−) was 19.7% (120/608), H(−)W(+) was 26.8% (114/608) and H(−)W(−) was 8.1% (49/608). The odds of proceeding to H(+)W(−) compared with H(+)W(+), which served as the reference, were 144% in baseline hemoglobin A1c (HbA1c) 7.0–8.0%, 233% in baseline HbA1c 8.0–9.0% and 359% in baseline HbA1c ≥ 9.0% (odds ratio 3.59, P, Increased blood glucose or increased weight is often observed in patients who are prescribed sodium–glucose cotransporter 2 inhibitors. Many other studies have shown that the glucose‐lowering effect seen in real‐world evidence studies is relatively low compared with that seen in conventional randomized controlled trials, even if the same drugs are used. When first prescribing dapagliflozin, a physician should be aware of the weight gain rather than glucose change if the baseline glycated hemoglobin is high, and might concentrate on weight‐related lifestyle training, such as diet and exercise.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are the latest introduction into the armamentarium of diabetes care in the present decade. By virtue of their beneficial effects, such as blood pressure-lowering, bodyweight reduction and significant renal and cardioprotective effects which extends beyond their glycaemic control effects, SGLT2i have become one of the most preferred oral antihyperglycaemic agents of recent times. However, they can influence tubular handling of electrolytes that can result in some electrolyte disturbances such as alteration in the serum levels of magnesium, potassium and phosphate levels. Some of these changes are mild or transient and may not have significant clinical implications. The underlying putative mechanism(s) responsible for disturbances of electrolytes are yet to be deciphered. In this review, we aim to describe electrolytes and acid–base abnormalities due to SGLT2i as well as to elucidate the underlying mechanism.

Background Prior reports have suggested that pancreatic fat is related to type 2 diabetes. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors are expected to reduce ectopic fat accumulation. Aim This study assessed the effect of SGLT‐2 inhibitors on pancreatic and liver fat accumulations in patients with type 2 diabetes. Materials and Methods Retrospective analyses of indices of pancreatic and liver fat accumulations were conducted in 22 type 2 diabetes outpatients who were receiving SGLT‐2 inhibitors for more than 12 weeks. The differences between the pancreatic (P) or liver (L) and splenic (S) computed tomography values were evaluated. Results Fatty pancreas was defined as P−S

Aim: Sodium–glucose cotransporter 2 inhibitors (SGLT2is) provide renal protection in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to elucidate the renal effects of long-...

Background and Aim Sodium glucose cotransporter 2 inhibitors (SGLT‐2i), by way of their unique mode of action, present an attractive strategy for the treatment of type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD), which often coexist and may lead to severe complications. However, the evidence for treatment with SGLT‐2i is limited to small heterogeneous studies. Therefore, this meta‐analysis was conducted to deduce the effects of SGLT‐2i in NAFLD with type 2 diabetes (T2D). Methods A web‐based search identified nine randomized controlled trials from the Cochrane Library, Embase, and PubMed for this meta‐analysis. The Comprehensive Meta‐Analysis Software version 3 was used to calculate the effect size. Result The outcomes of interest were analyzed from a pooled population of 11 369 patients—7281 on SGLT‐2i and 4088 in the control arm. SGLT‐2i therapy produced a statistically significant improvement in alanine aminotransferase [standardised mean difference (SDM), −0.21, 95% confidence interval (CI), −0.32 to −0.10, P, Sodium glucose cotransporter 2 inhibitors possess the capability to improve glycemic status along with weight reduction in patients with type 2 diabetes with non‐alcoholic fatty liver disease. As a result, there is a possibility that it may effect an improvement in preexisting hepatic inflammatory states. This meta‐analysis assessed such a possibility and found a positive influence.

Diabetes mellitus is a well-known risk factor for heart failure, and the reasons why are well understood. The incidence of diabetes mellitus is continuing to rise, posing a major concern in the medical world. The comorbidities associated with diabetes mellitus create a major hindrance on daily living, and promote the development of a plethora of other diseases. It is known that by controlling modifiable risk factors, such as glycemic control and body mass index, patients achieve more favorable outcomes. But, this is not always realistic and controlling modifiable risk factors should be balanced with a pharmacologic option. A relatively new drug class, which acts as an inhibitor of the sodium glucose cotransporter-2 receptor, has shown favorable outcomes in the treatment of heart failure associated with diabetes. However, the mechanism of action of this new drug class is not fully understood. There are several different proposed mechanisms of action for how sodium glucose cotransporter-2 inhibitors work in regards to the treatment of heart failure. This review will elaborate on those proposed mechanisms of action and offer insight into future implications of this relatively new drug class.

Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes. Materials and Methods Patients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. Results A total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6–38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P, The purpose of this study was to determine the efficacy and safety of sodium–glucose cotransporter 2 inhibitors in patients with type 1 diabetes. The changes in day‐to‐day glucose variability, as the primary end‐point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. Sodium–glucose cotransporter 2 inhibitors improved day‐to‐day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.

Clinical parameters with correlation to diuretic effects after initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors are unclear. We aimed to identify the factors associated with the diuretic effect observed following the initiation of SGLT2 inhibitors in patients with diabetes having an acute heart failure (HF). Fifty-six patients included were hospitalized for acute HF with diabetes and started on SGLT2 inhibitors. Changes in urine volume (ΔUV) and blood/urine laboratory parameters before and during the first 4 days of therapy were evaluated. Data were prospectively obtained under clinically stable conditions after initial HF treatment. UV increased following the initiation of SGLT2 inhibitors [UV at baseline (BL): 1383 ± 479 mL/day; ΔUV over 4 days: + 189 ± 358 mL/day]. Multivariate analysis revealed no association between BL-hemoglobin A1c or BL-estimated glomerular filtration rate and ΔUV. Conversely, higher BL-fasting plasma glucose (FPG) and higher BL-urine N-acetyl-β-D-glucosaminidase (NAG) were associated with a higher ΔUV. ΔUV was inversely associated with ΔFPG and ΔNAG, and positively associated with Δurinary sodium excretion. Elevated FPG and NAG both improved over 4 days of treatment. In conclusion, the diuretic effect of SGLT2 inhibitors was glycemia-dependent, and was associated with a reduction in elevated renal-tubular markers in hospitalized HF complicated with diabetes.

Modestly elevated circulating levels of the ketone β-hydroxybutyrate (βOHB) during treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors cause different beneficial effects on organs and cells, depending on the succinyl-CoA:3-ketoacid CoA transferase (SCOT) level. In the failing heart, SCOT is highly expressed/up-regulated, and thus, βOHB may be an energy source, in addition to fat and glucose oxidation. However, SCOT is not highly expressed/down-regulated in the kidney, and thus, βOHB may cause different beneficial effects, rather than acting as an alternative energy source in patients with chronic kidney disease (CKD). βOHB is an endogenous and specific inhibitor of class I histone deacetylases (HDACs) and the NLRP3 inflammasome, accumulates in the kidney because of its decreased utilization as an energy source due to the down-regulation of SCOT, and may induce beneficial effects such as inhibiting inflammation, oxidative stress, and fibrosis. In addition to restoring tubulo-glomerular feedback and improving renal proximal tubule oxygenation, SGLT2 inhibitors may play a renoprotective role by way of βOHB in patients with CKD.

Objective: To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM). Data Sources: We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction. Study Selection and Data Extraction: To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario. Data Synthesis: There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor. Relevance to Patient Care and Clinical Practice: The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes. Conclusions: SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) impede glucose reabsorption in kidney proximal tubules, which in turn can stimulate osmotic diuresis, natriuresis, and the renin-angiotensin system. This mechanism may enhance potassium secretion via increased distal sodium and water delivery and

In type 2 diabetes mellitus (T2DM), the development and progression of cardiovascular diseases occurs, which allows it to be considered as a cardiorenal metabolic syndrome. This should be taken into account when choosing hypoglycemic drugs. Patients with T2DM receiving insulin therapy often have a long history of diabetes, cardiovascular disease, chronic kidney disease, obesity, and need to be prescribed high doses of insulin and/or complex insulin therapy regimens to maintain glycemic control, which does not always lead to the achievement of target levels of glycemia and glycated hemoglobin (HbA1c). Adding to any insulin therapy regimen drugs from the class of sodium-glucose cotransporter type 2 inhibitors (SGLT-2), which have proven their cardio- and renoprotective properties, seems to be a rational combination in patients with T2DM and may have a number of advantages. The article presents 4 clinical examples of dapagliflozin administration, a drug from the SGLT2 class, to patients who are on insulin therapy, having T2DM with a long history (10–26 years), as well as cardiovascular diseases, chronic kidney disease, and obesity. Dapagliflozin administration allowed to improve glycemic control, to stabilize the insulin dose, as well as reduce body weight without increasing the frequency of serious episodes of hypoglycemia in patients who initially received large doses of insulin. In the long term, we can expect reduction of the progression of cardiovascular risks and the risks of hospitalization due to existing complications of the disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) are a new type of drug for the treatment of diabetes, and they have been proven to have a good hypoglycemic effect. Several lines of clinical evidence have shown that SGLT2 inhibitors can significantly reduce the risks of atherosclerosis, hospitalization for heart failure, cardiovascular death, and all-cause mortality and delay the progression of chronic kidney disease. Because of the protective effects of SGLT2 inhibitors on the heart and kidney, they are being studied for the treatment of heart failure and chronic kidney disease in patients without diabetes. Therefore, it is necessary for cardiologists, patients with diabetes, and nephrologists to fully understand this type of drug. In this review, we summarize the following three aspects of SGLT2 inhibitors: the recent clinical evidence of their cardiovascular benefits, their mechanisms of action, and their safety.

Inhibitors of sodium–glucose cotransporter 2 (SGLT2) have undoubtedly shifted the paradigm for diabetes medicine and research and, especially, diabetic kidney disease (DKD). The pharmacological action of SGLT2 inhibitors is simply the release of glucose into urine; however, precisely how SGLT2 inhibitors contribute to the health of those with diabetes has still not been completely elucidated. Towards this end, the present review provides a novel insight into the action of SGLT2 inhibitors by highlighting a neglected fuel-burning system found in proximal tubular cells—‘glycolysis’. In addition, exploring the details of the molecular mechanisms and clinical biomarkers of the organ protection conferred by SGLT2 inhibitors is now required to prepare for the next stage of clinical diabetes medicine—the ‘post-SGLT2 inhibitor era’.