Sodium-glucose Cotransporter Type 2 Inhibitors Research Articles

Empagliflozin restores cardiac metabolic flexibility in diet-induced obese C57BL6/J mice.

Sodium-glucose co-transporter type 2 (SGLT2) inhibitor therapy to treat type 2 diabetes unexpectedly reduced all-cause mortality and hospitalization due to heart failure in several large-scale clinical trials, and has since been shown to produce similar cardiovascular disease-protective effects in patients without diabetes. How SGLT2 inhibitor therapy improves cardiovascular disease outcomes remains incompletely understood. Metabolic flexibility refers to the ability of a cell or organ to adjust its use of metabolic substrates, such as glucose or fatty acids, in response to physiological or pathophysiological conditions, and is a feature of a healthy heart that may be lost during diabetic cardiomyopathy and in the failing heart. We therefore undertook studies to determine the effects of SGLT2 inhibitor therapy on cardiac metabolic flexibility in vivo in obese, insulin resistant mice using a [U13C]-glucose infusion during fasting and hyperinsulinemic euglycemic clamp. Relative rates of cardiac glucose versus fatty acid use during fasting were unaffected by EMPA, whereas insulin-stimulated rates of glucose use were significantly increased by EMPA, alongside significant improvements in cardiac insulin signaling. These metabolic effects of EMPA were associated with reduced cardiac hypertrophy and protection from ischemia. These observations suggest that the cardiovascular disease-protective effects of SGLT2 inhibitors may in part be explained by beneficial effects on cardiac metabolic substrate selection.

Real-World Assessment of Efficacy and Safety Parameters for Dapagliflozin in Management of Type 2 Diabetes Mellitus: REWARD Study

Introduction: While ample evidence on improved glycemic control, weight reduction, and lowered blood pressure (BP) with sodium-glucose cotransporter type 2 inhibitors (SGLT2is) exists, real-world data on the potential benefit of SGLT2i on the diabetic population in the Middle East are lacking. The aim of our study was to describe the glycemic control, changes in body weight, body mass index (BMI), lipid profile, and BPs in patients receiving dapagliflozin with other antidiabetic medication. Methods: The REWARD study was a multicenter, post-authorization, prospective, open-label, noninterventional, real-world, cohort study. We enrolled 511 adult, type 2 diabetes mellitus patients on antidiabetic medications. These patients were started on dapagliflozin and followed up for 1 year to assess changes in their clinical and laboratory outcomes. Results: The mean HbA1c decreased significantly from 8.5 ± 1.6% at baseline to 7.6 ± 1.3% after 12 months (p value <0.001), with an absolute change of 0.9%. Of the study population, 41.6% of patients reached an HbA1c level less than 7% (53 mmol/mol). The systolic pressure improved (mean change = −1.9 mm Hg, p value = 0.003), yet no change in the diastolic pressure was observed. Both body weight and BMI significantly decreased by 0.7 kg and 0.2 kg/m², respectively (p value <0.001). About 84.5% of patients were on antidyslipidemic agents, while 57.4% were on antihypertensives. Approximately 83.6% of adverse events were mild. A total of 90 hypoglycemic episodes were reported; none were severe. Conclusion: In a real-world setting, dapagliflozin in combination with other antidiabetic medications exhibited significant improvement in glycemic control, weight, BMI, and systolic BP. Additionally, it demonstrated a well-tolerated safety profile.

Longer-term Benefits and Risks of Sodium-Glucose Cotransporter-2 Inhibitors in Type 2 Diabetes: a Systematic Review and Meta-analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are a recent class of medication approved for the treatment of type 2 diabetes (T2D). Previous meta-analyses have quantified the benefits and harms of SGLT2Is; however, these analyses have been limited to specific outcomes and comparisons and included trials of short duration. We comprehensively reviewed the longer-term benefits and harms of SGLT2Is compared to placebo or other anti-hyperglycemic medications. We searched PubMed, Scopus, and clinicaltrials.gov from inception to July 2019 for randomized controlled trials of minimum 52weeks' duration that enrolled adults with T2D, compared an SGLT2I to either placebo or other anti-hyperglycemic medications, and reported at least one outcome of interest including cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events. We conducted random effects meta-analyses to provide summary estimates using weighted mean differences (MD) and pooled relative risks (RR). The study was registered a priori with PROSPERO (CRD42018090506). Fifty articles describing 39 trials (vs. placebo, n = 28; vs. other anti-hyperglycemic medication, n = 12; vs. both, n = 1) and 112,128 patients were included in our analyses. Compared to placebo, SGLT2Is reduced cardiovascular risk factors (e.g., hemoglobin A1c, MD - 0.55%, 95% CI - 0.62, - 0.49), macrovascular outcomes (e.g., hospitalization for heart failure, RR 0.70, 95% CI 0.62, 0.78), and mortality (RR 0.87, 95% CI 0.80, 0.94). Compared to other anti-hyperglycemic medications, SGLT2Is reduced cardiovascular risk factors, but insufficient data existed for other outcomes. About a fourfold increased risk of genital yeast infections for both genders was observed for comparisons vs. placebo and other anti-hyperglycemic medications. We found that SGLT2Is led to durable reductions in cardiovascular risk factors compared to both placebo and other anti-hyperglycemic medications. Reductions in macrovascular complications and mortality were only observed in comparisons with placebo, although trials comparing SGLT2Is vs. other anti-hyperglycemic medications were not designed to assess longer-term outcomes.

Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A potential rescue strategy

BackgroundPonatinib (PON), a third-generation tyrosine kinase inhibitor (TKI), has proven cardiovascular toxicity, with no known preventing agents usable to limit such side effect. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a new class of glucose-lowering agents, featuring favorable cardiac and vascular effects. AimsWe assessed the effects of the SGLT2 inhibitors empagliflozin (EMPA) and dapagliflozin (DAPA) on human aortic endothelial cells (HAECs) and underlying vasculo-protective mechanisms in an in vitro model of PON-induced endothelial toxicity. Methods and resultsWe exposed HAECs to PON or vehicle (DMSO) in the presence or absence of EMPA (100 and 500 nmol/L) or dapagliflozin (DAPA) for 0–48 h exposure times. Compared with vehicle, incubations of HAECs with PON significantly reduced cell viability (0.56 ± 0.11 vs 0.23 ± 0.05 absorbance units, p < 0.01), increased the number of senescent cells at β-gal-assay (PON 9 ± 4 vs basal DMSO 3 ± 1 β-Gal+ cells/field, p < 0.01), decreased tubulization in Matrigel (PON PON: 6 ± 1 vs basal DMSO 12 ± 1 tubuli number/field, p < 0.05) with a non-statistically significant trend of PON to decrease the number of autophagic cells at immunofluorescence assay and flow cytometry. EMPA reverted the effects of PON on cell viability (E 500 + PON 0.24 ± 0.05 vs PON 0.56 ± 0.11 absorbance units, p < 0.01) and induced autophagy (E 500 7 ± 4.3 vs basal DMSO 2.6 ± 2.3 mean fluorescence vs PON 2.6 ± 2.4 mean fluorescence, p < 0.05). EMPA and DAPA also reversed the effects of PON on cell senescence (E 500 + PON 4 ± 1 and DAPA 100 4 ± 2 vs PON 9 ± 4 β-Gal+ cells/field, p < 0.01) and improved cell tubulization (E 500 + PON 21 ± 3 vs PON 6 ± 1 tubuli number/field, p < 0.05; DAPA 100 + PON 16 ± 2 vs PON 6 ± 1 tubuli number/field, p < 0.05). ConclusionEMPA and DAPA attenuate the vasculo-toxic effect exerted by PON by reverting endothelial cell senescence and dysfunction. These findings support the design of clinical studies exploring the vasculo-protective effects of EMPA or DAPA on PON-induced vascular toxicity.

Efficiency of empagliflosin in combined nephroprotective therapy in patients with type 2 diabetes mellitus

INTRODUCTION. The data obtained in clinical studies of recent years of the possible inhibitors of sodium-glucose cotransporter type 2 (SGLT2) nephroprotective effect in type 2 diabetes mellitus necessitate the further study of these drug's effect on kidney injury risk factors.THE AIM: to study the effect of SGLT2 inhibitor empagliflozin as part of combination therapy on the main mechanisms of kidney damage in patients with type 2 diabetes.PATIENTS AND METHODS. We have completed a clinical randomized study in parallel groups in patients with type 2 diabetes of nephroprotective effects of SGLT2 inhibitor empagliflozin during 2 years. The study included 244 patients with type 2 diabetes with a preserved glomerular filtration rate (GFR) and moderate arterial hypertension (AH), who had previously taken perindopril and indapamide, but did not reach target blood pressure (BP) values. Patients were randomized into 2 groups: Group I (n = 120) took Perindopril 10 mg per day, Indapamide retard 1.5 mg per day, β-blocker Carvedilol 12.5-25 mg 2 times a day; Group II (n = 124) was additionally prescribed empagliflozin 25 mg per day. The study endpoints were GFR changes, albuminuria, and renal blood flow as measured by Doppler imaging. Also studied the dynamics of blood pressure and glycemic control.RESULTS. It was found that empagliflozin as part of complex therapy for type 2 diabetes is able to reduce albuminuria and prevent a decrease in GFR within a 2-year follow-up period. The use of empagliflozin promoted an increase in the rate of renal blood flow and a decrease in intrarenal vascular resistance and had a corrective effect on the daily dynamics of blood pressure and glycemic control.CONCLUSION. Empagliflozin improves intrarenal and systemic hemodynamics, prevents a decrease in GFR, reduces albuminuria, and improves glycemic control in type 2 diabetes.

Women and Diabetes: Preventing Heart Disease in a New Era of Therapies.

Despite major advances in cardiovascular research over the past decade, women with type 2 diabetes have a high risk of cardiovascular events. Several factors contribute to the poor prognosis for women, including higher levels of frailty and comorbidities, but their cardiovascular risk is underestimated and there is suboptimal implementation and uptitration of new evidence-based therapies, leading to high morbidity and mortality. Recent studies highlight the need for better management of diabetes in women that can be pursued and achieved in light of recent results from randomised controlled trials demonstrating evidence of the benefits of new therapeutic strategies in improving cardiovascular outcomes and quality of life of women covering the entire cardiovascular continuum. This review critically discusses the multiple benefits for women of new pharmacological treatments, such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter type 2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, icosapent ethyl and bempedoic acid in preventing cardiovascular events, and treatments, such as angiotensin receptor neprilysin inhibitors, SGLT2i, vericiguat and omecamtiv mecarbil, for preventing heart failure.

Cardiovascular Benefit of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Type 2 Diabetes: A Systematic Review.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide yet, despite advances in treatment, CVD remains an underestimated and undermanaged condition, with an even greater risk in Type 2 Diabetes Mellitus (T2DM). Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are a promising novel drug class reported to improve Cardiovascular (CV) and renal outcomes in T2DM. Recent large-scale trials have assessed their CV safety with unexpected findings of multiple systemic benefits that could potentially reverse CVD. In this systematic review, we examined ten Randomized Controlled Trials (RCTs) that looked at cardiovascular outcomes in Type 2 diabetics and SGLT-2i. The RCTs were appropriately screened, looking for clear primary or secondary outcomes on CV events, and compared with placebo or other antidiabetic drugs. The RCTs had an average sample population studied of 5,549 participants with a mean follow-up time of 2.66 years. Three of the studies focused on CV parameters and risk factors. The remaining had defined CV composite events, and all consistently observed at least one CV benefit when using SGLT-2i. Our review of SGLT-2i in Type 2 diabetics showed the greatest benefit in reducing Heart Failure (HF) exacerbation and modest lowering of CV complications in high CV risk participants. Overall, there is still uncertainty about the exact mechanisms of SGLT-2i in their CV benefit, and whether they would favor pre-diabetic populations and those at earlier stages of CVD.

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure

PurposeThe use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study.MethodsTwenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up.ResultsThree months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001).ConclusionsSwitch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

Use of Sodium Glucose Co-Transporter 2 Inhibitor (SGLT2i) in Geriatric Population

Aim: Diabetes treatment and follow-up is more difficult and sensitive in the elderly. Sodium glucose co-transporter type 2 (SGLT2) inhibitors are newly developed antidiabetic agents. In the geriatric age group, the use of SGLT2 inhibitors may be riskier in terms of side effects. We planned to evaluate the effect and tolerability of using SGLT2 inhibitors in geriatric patients. Material and Methods: Patients over 65 years of age with a diagnosis of type 2 DM who were started on empagliflozin or dapagliflozin in our center were included in the study. A total of 52 patients were included in the study. The study was designed as a retrospective file scan. Before and after SGLT2 inhibitor treatment, biochemical data, drug-related side effects and drug withdrawal information were recorded. Results: A statistically significant decrease was observed in the fasting blood glucose (FBG), postprandial blood glucose (PPBG), and HbA1c values of the patients after the SGLT2 inhibitor was started. While the urea and creatinine values of the patients increased after the treatment, a decrease was observed in the eGFR value. After treatment, a decrease in albumin/creatinine ratio in spot urine and an increase in hemoglobin and hematocrit values were observed. No complaints were reported in 31 patients (59.6%) and no side effects were detected. Side effects associated with SGLT2 inhibitor were observed in 21 patients (40.3%). In total, treatment was continued in 41 patients (78.8%) out of 52 patients, while treatment was discontinued in 11 patients (21.2%). Conclusion: In type 2 DM population over 65 years of age, glycemic control with SGLT 2 inhibitor treatment is successful, side effects and drug withdrawal rates are within acceptable limits.

Sodium and glucose cotransporter type 2 inhibitors: a new class of drugs for the treatment of diabetic and non-diabetic nephropathy

Inhibitors of renal sodium-glucose cotransporter type 2 (SGLT2) are a new class of antidiabetic drugs that have recently been introduced into clinical practice for the treatment of patients with type 2 diabetes mellitus. According to CREDENCE study, the inclusion of canagliflozin in drug therapy for patients with type 2 diabetes mellitus not only provides adequate control of blood glucose but also has a pronounced nephroprotective effect, which manifests in a significant reduction in the risk of progression of renal dysfunction in patients with stages 2, 3a and 3b CKD. The identification of nephroprotective effects in SGLT2 inhibitors, which is not related to their antihyperglycemic effect, suggests the possibility of using drugs of this class for drug therapy of patients with CKD of non-diabetic etiology. The review presents the data of clinical studies devoted to elucidating the participation of diuretic action and the associated decrease in blood pressure and venous stasis in the kidneys, improving glomerular hemodynamics and inhibiting the activity of intrarenal RAS in the mechanism of nephroprotective action of these drugs. Large-scale DAPA-CKD and EMPA-KIDNEY studies are currently underway, the results of which will provide information on the clinical efficacy and safety of dapagliflozin and empagliflozin in non-diabetic patients with the impaired renal function of varying severity, including those with stage 4 CKD. Initial data obtained in the DAPA-CKD trial indicated that dapagliflozin, when added to nephroprotective therapy, significantly improves renal outcomes not only in patients with type 2 diabetes but also in patients with CKD of non-diabetic origin, including those with glomerulonephritis, hypertensive nephropathy, and other kidney damage.

Sodium-glucose cotransporter type 2 inhibitors: successful running after two hares

The review is devoted to the clinical efficacy of sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Information on the mechanisms of drug action is given, as well as rationale for their use in the management of patients with diabetes and heart failure (HF) is provided. The results of large-scale randomized clinical trials evaluating the efficacy of SGLT2 inhibitors are discussed. We showed the beneficial effect of SGLT-2 inhibitors on the risk of cardiovascular events in patients with type 2 diabetes. In addition, an evidence of the ability of dapagliflozin and empagliflozin to improve the prognosis of patients with HF with reduced ejection fraction without diabetes are presented. The evidence and mechanisms of the nephroprotective action of SGLT2 inhibitors in patients with diabetes and HF are considered.

Clinician’s guide for dapagliflozin use in heart failure with reduced ejection fraction

Dapagliflozin belongs to a new class of drugs used for the treatment of heart failure — sodium-glucose cotransporter type 2 inhibitors (SGLT2i). Based on the DAPA-HF study results, dapagliflozin has become the first SGLT2i approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction. The present review summarizes the most important clinical issues related to the treatment with this drug.

Effects of Canagliflozin on Hepatic Steatosis, Visceral Fat and Skeletal Muscle among Patients with Type 2 Diabetes and Non-alcoholic Fatty Liver Disease.

Objective We assessed the effect of canagliflozin, an sodium-glucose co-transporter type-2 inhibitor, on hepatic steatosis using three imaging modalities: magnetic resonance imaging (MRI), computed tomography, and transient elastography. We further determined factors associated with improving hepatic steatosis by canagliflozin among patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Methods We conducted a six-month prospective single-arm study between August 2015 and June 2017. The primary outcome was the change in hepatic steatosis assessed using the hepatic proton density fat fraction (PDFF) on MRI before and after treatment with canagliflozin. The secondary outcomes were changes in measures of glucose metabolism, including the hepatic glucose uptake on fluorodeoxyglucose-positron emission tomography, and the inflammation and volumes of visceral and subcutaneous adipose tissue and skeletal muscle. Patients Nine patients with type 2 diabetes and NAFLD completed this study. All participants received canagliflozin at a dose of 100 mg daily. Results Canagliflozin caused a significant reduction in hepatic PDFF from baseline [median 20.6% (interquartile range 11.7%, 29.8%)] after 6 months [10.6% (5.4%, 22.6%), p=0.008]. Canagliflozin also significantly reduced the body weight, glycated hemoglobin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), and volumes of adipose tissue and skeletal muscle (all p<0.05). The reduction in hepatic PDFF was not correlated with changes in the body weight, HOMA-IR, hs-CRP, or volume of adipose tissue and skeletal muscle from baseline after six months. Conclusion Among patients with type 2 diabetes and NAFLD, canagliflozin improved hepatic steatosis. The effect may be independent of reducing adiposity, insulin resistance, inflammation, and skeletal muscle volume.

Effects of sodium\u2010glucose cotransporter type 2 inhibitors on cardiovascular, renal, and safety outcomes in patients with cardiovascular disease: a meta\u2010analysis of randomized controlled trials

BackgroundControlled studies and observational studies have shown that sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for the survival of patients with heart failure (HF). However, it is unclear whether SGLT-2i can provide benefit in patients with other cardiovascular diseases. Here, we conducted a systematic review and meta-analysis to determine the outcomes of cardiovascular, renal, and safety outcomes of SGLT-2i administration in patients with cardiovascular diseases.MethodsWe searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and ClinicalTrials.gov databases for randomised controlled trials written in English from inception until November 1, 2020. Two reviewers independently identified randomised controlled trials comparing the effects of SGLT-2i in patients with cardiovascular disease with or without diabetes. Primary outcomes were cardiovascular outcomes and renal outcomes. Secondary outcomes were safety outcomes, including adverse endocrine outcomes and adverse infection outcomes. The effects of SGLT-2i were evaluated using RevMan5.3 software. The Cochrane risk of bias tool was used to assess study quality.ResultsWe identified 10 randomised controlled trials (25,108 patients in the SGLT-2i group and 18,574 patients in the placebo group). Meta-analysis revealed that SGLT-2i treatment significantly reduced all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (HHF) in patients with cardiovascular disease (all-cause mortality relative risk [RR]: 0.86; 95% confidence interval [CI] 0.81–0.91; P < 0.00001; I2 = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79–0.92; P < 0.0001; I2 = 26%; HHF RR: 0.69; 95% CI 0.64–0.81; P < 0.00001; I2 = 0%). In patients with HF, mortality and HHF after SGLT-2i treatment for HF with reduced ejection fraction were significantly reduced, whereas HF with preserved ejection fraction did not differ compared with placebo treatment. Moreover, SGLT-2i induced a lower incidence of renal damage and myocardial infarction than the placebo group; however, the risk of infection, amputation, volume depletion, and diabetic ketoacidosis was higher.ConclusionsSGLT-2i had significant clinical effects on cardiovascular outcomes and significantly influenced acute kidney injury. The effects of SGLT-2i on cardiovascular disease were independent of diabetic status. Sotagliflozin could have advantages over other SGLT-2i in lowering HHF.

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis.

Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

Current status of Sodium-Glucose Co-Transporter Type 2 (SGLT2) inhibitors in treating diabetes mellitus

Background: Diabetes Mellitus is a spreading pandemic to the countries around the globe, despite of scientific breakthroughs and better healthcare facilities. Sodium-Glucose Co-Transporter Type 2 inhibitors (SGLT2i) are the latest class of oral anti-hyperglycemic agents that have been approved for the treatment of type II diabetes mellitus. Aim: In this review, we have comprehended the evidence for antidiabetic and extra-glycaemic effects of SGLT2i. Materials and Methods: The information is collected based on safety trials, randomized controlled trials (RCT), meta-analyses and real-world data. Results: SGLT2i are rapidly establishing their role in the treatment of diabetes mellitus. The beneficial effects extend beyond glycaemic control, impressive cardio protective and Reno protective effects and included improvement in blood pressure, uric acid concentrations, body weight and oxidative stress. Conclusion: Especially in patients with type 2 diabetes, SGLT2 inhibitors may be another option in those patients requiring additional glucose lowering and in those with acceptable risk factors. More research on the long term outcomes of SGLT2i is warranted. Keywords: Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Sodium-glucose cotransporter-2 inhibitors, Sotagliflozin, Type 2 diabetes mellitus.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors in heart transplant patients with type 2 diabetes: Initial report from a cardiometabolic center of excellence

Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

Role of SGLT2 inhibitors in the treatment of visceral obesity

The increasing prevalence of obesity limits the prevention of the development and progression of chronic non-communicable diseases. The central methods of risk correction associated with obesity are lifestyle changes and prescribing medications for obesity. Sodium-glucose co-transporter type-2 (SGLT2) inhibitors, also called gliflozins, which are used for type 2 diabetes, have shown additional positive effects on surrogate and hard endpoints in numerous studies. This became the basis for a detailed study of their cardio- and neuroprotective effects and for conducting studies with such drugs in other cohorts of patients. This review presents the results of studies that examined the effect of SGLT2 inhibitors on body weight in overweight and obese individuals, the quantitative characteristics and functional activity of visceral adipose tissue, as well as other components of visceral obesity, and discusses the potential of using these drugs in the management of such patients.

Impact of dapagliflozin on left ventricular diastolic function in diabetic patients with heart failure complicating cardiovascular risk factors

Abstract Funding Acknowledgements Type of funding sources: None. Background Type 2 diabetes mellitus (T2DM) is a well-known risk factor for heart failure (HF), even in patients without a structural heart disease or a symptom of HF. Diabetes-related cardiomyopathy is presented as an left ventricular (LV) diastolic dysfunction, which, like cardiovascular disease, is a contributor of the development of HF in both patients with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Furthermore, comorbid factors other than T2DM also have been identified as high risk factors for of progression to HF. Dapagliflozin is a sodium glucose cotransporter type 2 (SGLT2) inhibitor, and represents a new class of anti-hyperglycemic agents for T2DM. A result from a recent large clinical trial showed that dapagliflozin reduced risk of worsening HF or death from cardiovascular causes for patients with HFrEF compared to those who received a placebo, regardless of the presence or absence of T2DM. However, the effect of SGLT2 inhibitors on LV diastolic function in T2DM patients with HF who had cardiovascular risk factors other than T2DM remains uncertain. Purpose Our purpose was to investigate the impact of dapagliflozin on LV diastolic function in T2DM patients with stable HF complicating cardiovascular risk factors. Methods We analyzed data from our previous prospective multicenter study, which investigate the effect of dapagliflozin on LV diastolic function of 53 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitor started the administration of dapagliflozin. Cardiovascular risk factors other than T2DM was determined as age, gender, hypertension, dyslipidemia, history of cardiovascular events and overweight. Results E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described. Multivariate logistic regression analysis showed that dyslipidemia was the only independent determinant of an improvement of E/e’ among cardiovascular risk factors. Furthermore, relative changes in E/e’ from baseline to 6 months after administration of dapagliflozin seen in HFpEF patients with dyslipidemia were significantly larger than those in HFpEF patients without dyslipidemia (-15.2% vs. 29.6%, p = 0.014), but such a difference was not observed in non-HFpEF patients. In addition, relative changes in high-density lipoprotein cholesterol (HDL-C) from baseline to 6 months after administration of dapagliflozin had significant correlation with those in E/e’ (r=-0.300, p = 0.038). However, such correlations were not observed in low-density lipoprotein cholesterol (LDL-C) and triglyceride (r = 0.05, p = 0.72 and r = 0.05, p = 0.73). Conclusion: Dapagliflozin was more beneficial effect on LV diastolic function for T2DM patients with stable HF, especially those with complicating dyslipidemia. Our findings may thus offer a new insight into the management of T2DM patients with HF. Abstract Figure.