scholarly journals The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?

2021 ◽  
Author(s):  
Jiang Liu ◽  
Jiang Tian ◽  
Komal Sodhi ◽  
Joseph I. Shapiro
Keyword(s):  
Large Scale ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Sodium Potassium ◽  
Glucose Lowering ◽  
Ion Transporter ◽  
Signaling Function

AbstractIn different large-scale clinic outcome trials, sodium (Na+)/glucose co-transporter 2 (SGLT2) inhibitors showed profound cardiac- and renal-protective effects, making them revolutionary treatments for heart failure and kidney disease. Different theories are proposed according to the emerging protective effects other than the original purpose of glucose-lowering in diabetic patients. As the ATP-dependent primary ion transporter providing the Na+ gradient to drive other Na+-dependent transporters, the possible role of the sodium–potassium adenosine triphosphatase (Na/K-ATPase) as the primary ion transporter and its signaling function is not explored. Graphic Abstract

scholarly journals Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1166
Author(s):  
Kai-Fan Tsai ◽  
Yung-Lung Chen ◽  
Terry Ting-Yu Chiou ◽  
Tian-Huei Chu ◽  
Lung-Chih Li ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Redox Homeostasis ◽  
Sglt2 Inhibitors ◽  
Human Diseases ◽  
Oral Glucose ◽  
Diabetic Patients ◽  
Protective Effects ◽  
Glucose Lowering ◽  
Therapeutic Benefits ◽  
Neural Disorders

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral glucose-lowering agents. Apart from their glucose-lowering effects, large clinical trials assessing certain SGLT2 inhibitors have revealed cardiac and renal protective effects in non-diabetic patients. These excellent outcomes motivated scientists and clinical professionals to revisit their underlying mechanisms. In addition to the heart and kidney, redox homeostasis is crucial in several human diseases, including liver diseases, neural disorders, and cancers, with accumulating preclinical studies demonstrating the therapeutic benefits of SGLT2 inhibitors. In the present review, we aimed to update recent advances in the antioxidant roles of SGLT2 inhibitors in common but debilitating human diseases. We anticipate that this review will guide new research directions and novel therapeutic strategies for diabetes, cardiovascular diseases, nephropathies, liver diseases, neural disorders, and cancers in the era of SGLT2 inhibitors.

Cardio-protective effects of sodium-glucose co-transporter 2 inhibitors: focus on heart failure

2020 ◽  
Vol 26 ◽  
Author(s):  
Dimos Karangelis ◽  
C. David Mazer ◽  
Dimitrios Stakos ◽  
Aphrodite Tzifa ◽  
Spiros Loggos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Mechanisms Of Action ◽  
Sglt2 Inhibitors ◽  
Protective Effects ◽  
Reduced Ejection Fraction ◽  
Risk Of Death ◽  
Sodium Glucose Cotransporter ◽  
Myocardial Energetics

Background: Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal disease, including heart failure. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Objective: Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. Methods: PubMed, Embase and Google Scholar databases were searched to identify eligible articles which are comprehensively summarized and discussed. Results: The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Conclusion: Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.

scholarly journals Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity

2017 ◽  
Vol 313 (4) ◽  
pp. F951-F954 ◽  
Author(s):  
Danielle L. Saly ◽  
Mark A. Perazella
Keyword(s):  
Early Stage ◽  
Functional Decline ◽  
Healthcare Providers ◽  
Sglt2 Inhibitor ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Chip Technology ◽  
Urinary Glucose

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported “AKI” actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers.

scholarly journals Potential Impact on Lipoprotein Subfractions in Type 2 Diabetes

2019 ◽  
Vol 12 ◽  
pp. 117955141986681 ◽  
Author(s):  
Yuka Kamijo ◽  
Hideto Ishii ◽  
Tomohiko Yamamoto ◽  
Kunihisa Kobayashi ◽  
Hiroyuki Asano ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Sglt2 Inhibitor ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Lipoprotein Subfractions ◽  
Cholesterol Levels

Introduction: Recently, the sodium-glucose cotransporter2 (SGLT2) inhibitor empagliflozin has been shown to lower cardiovascular risk among diabetic patients. It is intriguing that some SGLT2 inhibitors have been found to increase low-density lipoprotein (LDL) cholesterol levels, while the relevance to high-density lipoprotein (HDL) cholesterol is unknown. Although the inhibitory effect of SGLT2 inhibitors on glucose reabsorption may accelerate compensatory lipid metabolism and subsequently reduce body weight and affect the lipid profile, much remains unclear about this mechanism. Therefore, we conducted this study to investigate in detail how canagliflozin affects lipoprotein fractions including LDL and HDL subclasses. Materials and Methods: This study is a multicenter prospective study. The participants were patients with 22 type 2 diabetes (60.7 ± 11.6 years, 59.1% of men) who had HbA1c ⩾ 7.0% and consented to participate in the study. They were administered 100 mg canagliflozin orally once per day. Biochemistry test and cholesterol levels of 20 lipoprotein fractions (G1-G20) using high performance liquid chromatography methods were examined before and after 12 weeks of treatment period. Results: Significant decreases were observed in the participants’ body weight (69.7 to 67.9 kg, P < .001), systolic blood pressure (129.3 to 119.5 mm Hg, P < .01), and HbA1c (8.5% to 7.4%, P < .001). Cholesterol levels in the 20 lipoprotein fractions increased for very large HDL (G14, G15) and large HDL (G16) ( P < .05). Conclusions: Reduction in body weight, improvement of blood glucose levels, and increases in very large HDL and large HDL subclasses were observed after canagliflozin treatment. These beneficial changes might contribute to subsequent suppression of cardiovascular outcomes.

scholarly journals The expanding role of SGLT2 inhibitors beyond glucose-lowering to cardiorenal protection

2020 ◽  
pp. 1-32
Author(s):  
Emily Brown ◽  
John PH Wilding ◽  
Uazman Alam ◽  
Thomas M Barber ◽  
Janaka Karalliedde ◽  
...  
Keyword(s):  
Sglt2 Inhibitors ◽  
Glucose Lowering

scholarly journals Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

2021 ◽  
Vol 22 (18) ◽  
pp. 9852
Author(s):  
Alex Ali Sayour ◽  
Mihály Ruppert ◽  
Attila Oláh ◽  
Kálmán Benke ◽  
Bálint András Barta ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Large Scale ◽  
Sglt2 Inhibitor ◽  
Basic Research ◽  
Additional Benefit ◽  
Sglt2 Inhibitors ◽  
Preclinical Studies ◽  
Sodium Glucose Cotransporter

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

scholarly journals Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database

2021 ◽  
Author(s):  
Hajime Nagasu ◽  
Yuichiro Yano ◽  
Hiroshi Kanegae ◽  
Hiddo J.L. Heerspink ◽  
Masaomi Nangaku ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Practice ◽  
Kidney Disease ◽  
Kidney Function ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Glucose Lowering ◽  
Glucose Transporter 2 ◽  
Egfr Decline

<b>Objective: </b>Randomized controlled trials have shown kidney protective effects of sodium glucose transporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitors initiation modifies treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients is unknown. <p><b>Research Design and Methods: </b>Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. </p> <p><b>Results: </b>At baseline, mean age at initiation of the SGLT2 inhibitor (n=1,033) or other glucose-lowering drug (n=1,033) was 64.4 years; mean eGFR was 68.1 mL/min per 1.73 m²; and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other drugs 0.75 mL/min/1.73 m² per year (0.51 to 1.00). During a mean follow-up of 24 months, 103 c<a>omposite kidney outcomes </a>occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26 to 0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiating SGLT2 inhibitors (p<sub>heterogeneity</sub> ≥0.35). </p> <p><b>Conclusions: </b>The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.</p>

scholarly journals Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database

2021 ◽  
Author(s):  
Hajime Nagasu ◽  
Yuichiro Yano ◽  
Hiroshi Kanegae ◽  
Hiddo J.L. Heerspink ◽  
Masaomi Nangaku ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Clinical Practice ◽  
Kidney Disease ◽  
Kidney Function ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Glucose Lowering ◽  
Glucose Transporter 2 ◽  
Egfr Decline

<b>Objective: </b>Randomized controlled trials have shown kidney protective effects of sodium glucose transporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitors initiation modifies treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients is unknown. <p><b>Research Design and Methods: </b>Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. </p> <p><b>Results: </b>At baseline, mean age at initiation of the SGLT2 inhibitor (n=1,033) or other glucose-lowering drug (n=1,033) was 64.4 years; mean eGFR was 68.1 mL/min per 1.73 m²; and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other drugs 0.75 mL/min/1.73 m² per year (0.51 to 1.00). During a mean follow-up of 24 months, 103 c<a>omposite kidney outcomes </a>occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26 to 0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiating SGLT2 inhibitors (p<sub>heterogeneity</sub> ≥0.35). </p> <p><b>Conclusions: </b>The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.</p>

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