Renal threshold for glucose reabsorption predicts diabetes improvement by sodium‐glucose cotransporter 2 inhibitor therapy

: Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. : The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

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SODIUM-GLUCOSE LINKED COTRANSPORTER 2 INHIBITOR: A NEW HORIZON IN THE TREATMENT OF TYPE-2 DIABETES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2021.v14i3.39667 ◽

2021 ◽

pp. 45-48

Author(s):

REKHA BISHT

Keyword(s):

Type 2 Diabetes ◽

Adverse Effects ◽

Antidiabetic Drugs ◽

Diabetic Patients ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Glycemic Targets

Hyperglycemia is a key therapeutic focus in the management of patients with type 2 diabetes (T2D) mellitus. The various therapeutic classes of antidiabetic drugs presently existing in the market are not sufficiently effective in maintaining long-term glycemic control in most of the diabetic patients, even when used in combination. The undesirable adverse effects of these drugs, such as hypoglycemia, weight gain, and hepatic and renal toxicity, have escalated the demand for the discovery of new and safer antidiabetic drugs. The progressive nature of T2D requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. Sodium-glucose cotransporter 2 inhibitors (SGLT2-is) are the new class of antidiabetic medications that are approved (2013) by the Food and Drug Administration recently for treating diabetes. These inhibitors block the SGLT2 protein involved in glucose reabsorption from the proximal renal tubule resulting in escalated glucose excretion and lower blood glucose levels. These inhibitors exhibit favorable effects beyond glucose control, such as consistent body weight, blood pressure, and serum uric acid reductions. This review highlighted the brief updates of SGLT2-i, their benefits, and adverse effects.

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How should we monitor the cardiovascular benefit of sodium–glucose cotransporter 2 inhibition?

Cardiovascular Diabetology ◽

10.1186/s12933-020-01191-5 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Atsushi Tanaka ◽

Koichi Node

Keyword(s):

Sglt2 Inhibitor ◽

Cardiovascular Outcomes ◽

Sglt2 Inhibitors ◽

Inhibitor Therapy ◽

Cardiovascular Outcome ◽

Cardiovascular Outcome Trials ◽

Amino Terminal ◽

Sodium Glucose Cotransporter ◽

Diabetes Status ◽

Cardiovascular Benefit

AbstractSodium–glucose cotransporter 2 (SGLT2) inhibitors are increasingly prescribed for the treatment of patients with type 2 diabetes to reduce the risk of cardiovascular events, including heart failure (HF). The mechanisms by which SGLT2 inhibitors reduce such risk are likely to be independent of diabetes status and improvement of glycemic control. In this commentary, based on recent mediation analyses of cardiovascular outcome trials with SGLT2 inhibitors, we discuss the prognostic role of a well-known HF-related biomarker, amino-terminal pro-B-type natriuretic peptide (NT-proBNP), in patients receiving SGLT2 inhibitors. Interestingly, the NT-proBNP concentration had a relatively small impact on the SGLT2 inhibitor-associated benefit on HF events, suggesting a limited value in measuring NT-proBNP concentrations to monitor effects on cardiovascular outcomes after initiation of SGLT2 inhibitor therapy. Instead, clinical factors, such as body weight and volume status, were prognostic for cardiovascular outcomes. As shown in some biomarker studies, short-term SGLT2 inhibitor treatment significantly improved volume and HF-related health status, despite the absence of a significant change in NT-proBNP concentration. Given the early and continuous risk reduction in HF events seen in the cardiovascular outcome trials with SGLT2 inhibitors, changes in these fundamental clinical parameters after initiation of SGLT2 inhibitor therapy, independent of NT-proBNP, could be more prognostic and could represent key determinants to identify responders or non-responders to SGLT2 inhibitors for cardiovascular outcomes. Thus, this commentary highlights the clinical importance of establishing how clinicians should monitor patients initiating SGLT2 inhibitor therapy to predict the expected cardiovascular benefit. Further detailed investigations and discussion to better understand this ‘‘black box’’ are urgently warranted.

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Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes

American Journal of Nephrology ◽

10.1159/000507272 ◽

2020 ◽

Vol 51 (5) ◽

pp. 349-356 ◽

Cited By ~ 1

Author(s):

Katerina P. Marathias ◽

Vaia A. Lambadiari ◽

Konstantinos P. Markakis ◽

Vassilios D. Vlahakos ◽

Dimitra Bacharaki ◽

...

Keyword(s):

Angiotensin Receptor Blockers ◽

Haemoglobin Concentration ◽

Renin Angiotensin System ◽

Sglt2 Inhibitors ◽

Common Finding ◽

Diabetic Patients ◽

Angiotensin System ◽

Renin Angiotensin ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption

Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2–3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

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Diabetes Research Open Access: Sodium Glucose Cotransporter2 (SGLT2) Inhibitors

10.36502/2020/droa.6157 ◽

2020 ◽

Vol 2 (S1) ◽

pp. 14

Author(s):

Kuşkonmaz SM

Keyword(s):

Sglt2 Inhibitors ◽

Diabetes Research ◽

Oral Antidiabetics ◽

First Line ◽

Glucose Lowering ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

New Guidelines ◽

Renal Glucose Reabsorption

Sodium glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are a group of glycosuric drugs approved in the management of type 2 diabetes mellitus. They act on the sodium glucose cotransporter and inhibit renal glucose reabsorption. Canagliflozin dapagliflozin and empagliflozin are members of the SGLT2i group. SGLT2 is supposed to be unique to the kidney. Recent studies showed the benefits of these agents beyond and independent from glucose lowering. New guidelines emphasize these pleiotropic effects such as cardioprotective and renoprotective effects of SGLT2i and suggest them as first line oral antidiabetics in patients with coronary heart disease.

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Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review

Frontiers in Medicine ◽

10.3389/fmed.2021.777861 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jorge I. Fonseca-Correa ◽

Ricardo Correa-Rotter

Keyword(s):

Oxygen Demand ◽

Mechanisms Of Action ◽

Tubuloglomerular Feedback ◽

Podocyte Injury ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Sympathetic Nervous ◽

Renal Glucose Reabsorption ◽

Intraglomerular Pressure ◽

Sodium And Water Balance

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.

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Periprocedural Euglycemic Diabetic Ketoacidosis Associated With Sodium–Glucose Cotransporter 2 Inhibitor Therapy During Colonoscopy

Diabetes Care ◽

10.2337/dc20-1244 ◽

2020 ◽

Vol 43 (11) ◽

pp. e181-e184

Author(s):

Emily J. Meyer ◽

Edward Mignone ◽

Anthony Hade ◽

Venkatesan Thiruvenkatarajan ◽

Robert V. Bryant ◽

...

Keyword(s):

Diabetic Ketoacidosis ◽

Inhibitor Therapy ◽

Sodium Glucose Cotransporter ◽

Euglycemic Diabetic Ketoacidosis

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The Possible Effects of Dapagliflozin on 12-derived Electrocardiogram in Patients with Type 2 Diabetes Mellitus

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666181218121508 ◽

2019 ◽

Vol 19 (2) ◽

pp. 207-213 ◽

Cited By ~ 1

Author(s):

Oğuz Akkuş ◽

Gamze Akkuş ◽

Onur Kaypaklı

Keyword(s):

Linear Regression Analysis ◽

Electrolyte Imbalance ◽

Type 2 Dm ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Blood Pressures ◽

Male Patients ◽

Electrocardiogram Ecg ◽

Inadequate Glycemic Control

Background: Dapagliflozin, sodium glucose cotransporter 2 inhibitor, has potential side effects on electrolyte imbalance as it has diuretic effects which include decreasing glucose reabsorption, increasing glucosuria and natriuresis. We aimed to determine the possible effects of dapagliflozin on electrocardiogram (ECG) in patients with type 2 DM. </P><P> Material and Methods: This retrospective study consisted of 49 patients (25 female, 24 male). Patients who had inadequate glycemic control besides using several oral antidiabetics, subsequently endorsed with dapagliflozin, were included in the current study. Results: Meantime interval from treatment initiation to control was 10.5 ± 5.03 weeks. Body mass index, glucose, HbA1C, eGFR, LDL-C, heart rate, systolic and diastolic blood pressures were found to be significantly lower at control admission (p<0.05). Creatinine and QT interval were significantly higher at control admission (p<0.05). Baseline Tpe duration and baseline Tpe/QT ratio were found to be significantly correlated with Tpe/QT difference (p<0.05). In linear regression analysis, baseline Tpe/QT ratio was found to be the sole independent predictor of Tpe/QT difference (p<0.05). Conclusion: Initiation of dapagliflozin treatment seems to be safe, up to several months, in terms of serum electrolytes and ECG findings in patients with type 2 DM with a probable improvement.

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Faculty Opinions recommendation of Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1048263.500176 ◽

2006 ◽

Author(s):

Thomas W von Geldern

Keyword(s):

Glucose Level ◽

Plasma Glucose ◽

Plasma Glucose Level ◽

Critical Role ◽

Selective Inhibitor ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Renal Glucose Reabsorption

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Sodium-glucose cotransporter-2 inhibitors: updated evidence on their efficacy and safety in patients with type-2 diabetes

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20201102 ◽

2020 ◽

Vol 9 (4) ◽

pp. 666

Author(s):

Vipul Gupta ◽

Girish Khurana

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Initial Therapy ◽

Sodium Glucose Cotransporter ◽

Lower Glucose ◽

Glucose Reabsorption ◽

Metabolic Aspect ◽

Treatment Of Diabetes ◽

Renal Tubular

Management of type-2 diabetes mellitus (T2DM) is challenging. The scope of existing therapies toward T2DM has transformed remarkably. These large assortments of therapies have produced evidence-based data. Sodium-glucose cotransporter-2 inhibitor (SGLT-2i) is the most recent class of oral anti-hyperglycemic agents. They are approved by Food and Drug Administration for the treatment of diabetes mellitus. SGLT-2i has a unique mechanism of action and that lower glucose independent of insulin. They reduce renal tubular glucose reabsorption, thereby lowering blood glucose without stimulating the release of insulin. Additional advantages involve suitable effects on blood pressure and weight. According to guidelines of the American Association of Clinical Endocrinologists/ the American College of Endocrinology 2016, SGLT-2i (in the form of canagliflozin, dapagliflozin, and empagliflozin) is one of the acceptable alternatives to metformin as initial therapy towards T2DM. Canagliflozin, dapagliflozin, and empagliflozin reduce the cardiovascular risk in comparison to placebo as the part of standard care. This review article focuses on the clinical trials published over the past year and specifically the metabolic aspect of SGLT-2i and the adverse effects related to SGLT-2 inhibitors.

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