scholarly journals Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey

2021 ◽  
Vol 8 ◽  
Author(s):  
Donato Cappetta ◽  
Antonella De Angelis ◽  
Gabriella Bellocchio ◽  
Marialucia Telesca ◽  
Eleonora Cianflone ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ion Homeostasis ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Cellular Targets ◽  
Multifactorial Diseases ◽  
Positive Effects ◽  
Sodium Glucose Cotransporter ◽  
Underlying Mechanisms ◽  
The Moment

Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na+ levels with consequent positive effects on Ca2+ handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs.

scholarly journals Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e018097 ◽  
Author(s):  
Natalie A Mordi ◽  
Ify R Mordi ◽  
Jagdeep S Singh ◽  
Fatima Baig ◽  
Anna-Maria Choy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Effects ◽  
Sglt2 Inhibitors ◽  
Loop Diuretics ◽  
Diabetic Patients ◽  
Creatinine Ratio ◽  
Double Blind ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition ◽  
Secondary Outcomes

IntroductionType 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium–glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and analysisTo assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-blind, placebo-controlled, cross-over trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 and 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 and 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio and urinary albumin/creatinine ratio when compared with placebo.Ethics and disseminationEthics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03226457; Pre-results.

scholarly journals SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

2021 ◽  
Author(s):  
Steffen Pabel ◽  
Nazha Hamdani ◽  
Mark Luedde ◽  
Samuel Sossalla
Keyword(s):  
Heart Failure ◽  
Clinical Evidence ◽  
Ion Homeostasis ◽  
Cardiac Contractility ◽  
Sglt2 Inhibitors ◽  
New Drugs ◽  
Metabolic Effects ◽  
Patients With Heart Failure ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

Abstract Purpose of review SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

Characterization of myocardial sodium-glucose cotransporter 1 expression in humans with heart failure and reduced ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.A Sayour ◽  
A Olah ◽  
M Ruppert ◽  
I Hartyanszky ◽  
M Polos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Protein Expression ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Funding Source ◽  
Specific Inhibition ◽  
Sodium Glucose Cotransporter ◽  
Cardioprotective Effects ◽  
End Stage

Abstract Introduction In diabetic patients, multiple cardiovascular outcome trials consistently showed the robust cardioprotective effects of the novel antidiabetic agents, sodium glucose cotransporter 2 (SGLT2) inhibitors. However, the DAPA-HF study using the SGLT2 inhibitor dapagliflozin have extended these observations onto non-diabetic patients with heart failure (HF), urging previous hypotheses regarding the cardioprotective effects of SGLT2 inhibitors to be revised. This is further complicated by the fact that SGLT2 is not expressed in the human myocardium neither under normal nor diseased states. Hence, it has been postulated that SGLT2 inhibitors might exert direct cardioprotection via non-specific inhibition of SGLT1, which is in turn highly expressed in the myocardium. Purpose Because literature data is scarce regarding the expression profile of myocardial SGLT1, we aimed to characterize left ventricular SGLT1 expression in humans with end-stage HF accordingly to HF aetiology and to investigate whether cardiac resynchronization therapy (CRT) affects SGLT1 expression. Methods From patients undergoing mitral valve replacement with otherwise no myocardial disease and preserved LV function, we collected control papillary muscles (Control, n=9). From patients with end-stage HF undergoing heart transplantation (n=72), we obtained LV anterior wall samples according to the following HF aetiology groups: hypertrophic cardiomyopathy (HCM, n=7); idiopathic dilated cardiomyopathy (DCM, n=12); ischaemic heart disease (IHD, n=14), IHD with type 2 diabetes mellitus (IHD+T2DM, n=11); and patients with CRT (CRT-DCM, n=9; CRT-IHD, n=9; CRT-IHD+T2DM, n=10). We measured LV SGLT1 expression on the gene and protein expression levels using qRT-PCR and western blotting, respectively. Echocardiography-derived LV end-diastolic diameter (LVEDD) and LV ejection fraction (LVEF) were registered prior to surgery. Results Compared to controls, LV SGLT1 mRNA and protein expressions were significantly upregulated in patients with DCM, IHD and IHD+T2DM (all P<0.05), but not in HCM. In these patient groups, LV SGLT1 mRNA expression showed a significant positive correlation with LVEDD (r=0.493; P<0.001) and significant negative correlation with LVEF (r=−0.477; P<0.001). On the protein expression level, CRT was associated with significant reduction in LV SGLT1 only in patients with DCM and IHD, but not in IHD+T2DM. Conclusions Myocardial SGLT1 is upregulated in patients with HF (except HCM), and correlated strongly with parameters (LVEDD, LVEF) related to adverse LV remodelling. CRT was associated with reduced SGLT1 expression in DCM and IHD patients, but not in those with IHD+T2DM. Our results suggest that SGLT1 is upregulated in HF and might be implicated in adverse myocardial remodelling. Accordingly, whether SGLT2 inhibitors exert direct cardioprotection in HFrEF via non-specific inhibition of SGLT1 needs to be further elucidated. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary, Higher Education Institutional Excellence Programme of the Ministry of Human Capacities of Hungary

Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
Kevin S. Shah ◽  
James C. Fang
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Blood Glucose Control ◽  
Sglt2 Inhibitors ◽  
Annual Review ◽  
Diabetic Patients ◽  
Publication Date ◽  
Cardiovascular Outcome Trials ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve blood glucose control by blocking renal glucose reabsorption with little subsequent risk of hypoglycemia. Consequently, there are decreases in plasma volume, body weight, and blood pressure. Additional putative benefits include improved cardiovascular energetics, decreased systemic inflammation, and less renal dysfunction. Multiple cardiovascular outcome trials in diabetic patients have demonstrated this drug class reduces the risk of adverse cardiovascular events. Reductions in heart failure (HF) hospitalization suggested that SGLT2 inhibitors might prove useful for the primary treatment of HF. Two large subsequent trials studying SGLT2 inhibitors in heart failure with reduced ejection fraction (HFrEF) demonstrated a reduction in cardiovascular mortality, HF hospitalizations, and renal-specific adverse events. This medication class is now recognized as a new pillar of therapy for patients with HFrEF. The cardiovascular and HF community await the results of ongoing trials of SGLT2 inhibition in patients with HF with preserved ejection fraction. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

2019 ◽  
Vol 19 (20) ◽  
pp. 1818-1849 ◽  
Author(s):  
Ban Liu ◽  
Yuliang Wang ◽  
Yangyang Zhang ◽  
Biao Yan
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Renal Dysfunction ◽  
Sglt2 Inhibitors ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

: 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.

scholarly journals Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

2021 ◽  
Vol 22 (9) ◽  
pp. 4374
Author(s):  
Tomoaki Takata ◽  
Hajime Isomoto
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glycemic Control ◽  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Pleiotropic Effects ◽  
Future Research ◽  
Diabetic Patients ◽  
Sodium Glucose Cotransporter ◽  
Stage Renal Disease

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) as a Primary Preventative Agent in the Healthy Individual: A Need of a Future Randomised Clinical Trial?

2021 ◽  
Vol 8 ◽  
Author(s):  
Dan Xu ◽  
Owain Chandler ◽  
Cleo Wee ◽  
Chau Ho ◽  
Jacquita S. Affandi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Clinical Trial ◽  
Diabetic Patients ◽  
Atherosclerotic Cardiovascular Disease ◽  
Healthy Individuals ◽  
Type 2 Diabetic Patients ◽  
Sodium Glucose Cotransporter ◽  
Type 2 Diabetic

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a relatively novel class of drug for treating type 2 diabetes mellitus (T2DM) that inhibits glucose reabsorption in the renal proximal tubule to promote glycosuria and reduce blood glucose levels. SGLT2i has been clinically indicated for treating T2DM, with numerous recent publications focussing on both primary and secondary prevention of cardiovascular and renal events in Type 2 diabetic patients. The most recent clinical trials showed that SGLT2i have moderately significant beneficial effects on atherosclerotic major adverse cardiovascular events (MACE) in patients with histories of atherosclerotic cardiovascular disease. In this review and analysis, SGLT2i have however demonstrated clinically significant benefits in reducing hospitalisation for heart failure and worsening of chronic kidney disease (CKD) irrespective of pre-existing atherosclerotic cardiovascular disease or previous heart failure history. A meta-analysis suggests that all SGLT2 inhibitors demonstrated the therapeutic benefit on all-cause and cardiovascular mortality, as shown in EMPAREG OUTCOME study with a significant decrease in myocardial infarction, without increased stroke risk. All the above clinical trial recruited type 2 diabetic patients. This article aims to postulate and review the possible primary prevention role of SGLT2i in healthy individuals by reviewing the current literature and provide a prospective overview. The emphasis will include primary prevention of Type 2 Diabetes, Heart Failure, CKD, Hypertension, Obesity and Dyslipidaemia in healthy individuals, whom are defined as healthy, low or intermediate risks patients.

scholarly journals Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients

2018 ◽  
Vol 9 ◽  
Author(s):  
Laween Uthman ◽  
Antonius Baartscheer ◽  
Cees A. Schumacher ◽  
Jan W. T. Fiolet ◽  
Marius C. Kuschma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diabetic Patients ◽  
Pathogenic Mechanisms ◽  
Sodium Glucose Cotransporter

scholarly journals Molecular, Cellular, and Clinical Evidence That Sodium‐Glucose Cotransporter 2 Inhibitors Act as Neurohormonal Antagonists When Used for the Treatment of Chronic Heart Failure

2020 ◽  
Vol 9 (16) ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Mineralocorticoid Receptor ◽  
Sglt2 Inhibitors ◽  
Autophagic Flux ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists ◽  
Cellular Effects ◽  
Sodium Glucose Cotransporter ◽  
Β Blockers

Abstract Sodium‐glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin‐angiotensin system, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.

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

2020 ◽  
Vol 51 (5) ◽  
pp. 349-356 ◽  
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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