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 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 Sodium-Glucose Cotransporter-2 Inhibitors Improve Cardiovascular Dysfunction in Type 2 Diabetic East Asians

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 794
Author(s):  
Muhammad Afzal ◽  
Fahad A. Al-Abbasi ◽  
Muhammad Shahid Nadeem ◽  
Sultan Alshehri ◽  
Mohammed M. Ghoneim ◽  
...  
Keyword(s):  
Glycemic Control ◽  
Diabetes Management ◽  
Cardiovascular Effects ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
East Asians ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Renal Glucose Reabsorption

In East Asians, the incidence of type 2 DM (T2DM) has increased as a result of major alterations in life. Cardiovascular problems are more likely in those with T2DM. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel insulin-independent antihyperglycemic drugs that limit renal glucose reabsorption and thereby improve glycemic control. They are used alone or in combination with insulin and other antihyperglycemic medications to treat diabetes, and they are also helpful in protecting against the progression of complications. This review has evaluated the available evidence not only on the efficacy of SGLT2 inhibitors in T2DM, but also on their favourable cardiovascular events in East Asians. DM is an independent risk factor for cardiovascular diseases. As a result, in addition to glycemic control in diabetes management, the therapeutic goal in East Asian diabetic patients should be to improve adverse cardiovascular outcomes. Besides establishing antidiabetic effects, several studies have reported cardioprotective benefits of SGLT2 inhibitors via numerous pathways. SGLT2 inhibitors show promising antidiabetic drugs with potential cardiovascular advantages, given that a high number of diabetic patients in East Asia have co-existing cardiovascular disorders. Despite significant positive results in favour of SGLT2, more research is needed to determine how SGLT2 inhibitors exert these impressive cardiovascular effects.

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.

Effects of SGLT2 Inhibitors on the Risks of Hypertension and Heart Failure in Diabetic Patients: A Systematic Review

2021 ◽  
Vol 1 ◽  
pp. 73-80
Author(s):  
Harzhin Hiwa Ali ◽  
Naza Mohammed Ali Mahmood ◽  
Saad Abdulrahman Hussain
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Blood Sugar ◽  
Animal Studies ◽  
Cardiovascular Effects ◽  
Pressure Control ◽  
Sglt2 Inhibitors ◽  
Diabetic Patients ◽  
Good Glycemic Control ◽  
Artery Disease

Diabetes mellitus (DM) with uncontrolled blood sugar causes a variety of problems, including coronary artery disease, stroke, heart failure, hypertension, nephropathy, neuropathy, and retinopathy. These consequences harm the diabetic patients' lives. Many studies have shown that diabetic patients have a higher rate of heart failure and a worse prognosis than non-diabetic people. Sodium and glucose co-transporter receptor-2 (SGLT2) inhibitors are a relatively new class of anti-diabetic drugs. They not only regulate blood sugar but also have positive cardiovascular effects via a variety of mechanisms. This review intends to show that SGLT2 inhibitors, in addition to good glycemic control, possess a cardioprotective role. We conducted a literature review and identified 20 adequately powered clinical trials and animal studies in type 2 DM that investigated the cardiovascular (CV) effects of SGLT2 inhibitors (particularly heart failure and hypertension). These studies looked at the cardiovascular effects of three SGLT2 inhibitors: Empagliflozin, Canagliflozin, and Dapagliflozin. In diabetic patients, these three inhibitors of SGLT2 significantly lowered the risk of heart failure and hypertension, making them valuable therapy for lowering CV risks in high cardiovascular-risk individuals with T2DM. Finally, the use of SGLT2 inhibitors in patients without diabetes mellitus showed positive metabolic outcomes in weight and blood pressure control.

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 Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Hiraku Kameda ◽  
Kumiko Yamashita ◽  
Yoshio Kurihara
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Creatinine Ratio ◽  
Sodium Glucose Cotransporter ◽  
Clinical Records

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018

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