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 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 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 112 Safety and biochemical efficacy of sodium–glucose cotransporter 2 inhibitors based on cardiovascular risk profile and volume status in a real-world diabetic population

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Mauro Gitto ◽  
Alexios Kotinas ◽  
Riccardo Terzi ◽  
Angelo Oliva ◽  
Jorgele Zagoreo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Risk ◽  
Glycaemic Control ◽  
Real World ◽  
Glycated Haemoglobin ◽  
Diabetic Patients ◽  
World Population ◽  
High Cardiovascular Risk ◽  
Sodium Glucose Cotransporter ◽  
Tract Infections

Abstract Aims Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have become a first-line cardiovascular medication. However, their potential side effects still limit a widespread use in real-world clinical practice. Further, there is uncertainty about the mechanisms mediating SGLT2i-associated cardiovascular benefit. Methods We performed a retrospective analysis on consecutive diabetic patients who were prescribed a SGLT2i in a tertiary referral centre. Patients who completed at least 1 year of treatment were included in the data analysis. Changes in glycated haemoglobin, weight and haematocrit were evaluated and compared across two cardiovascular risk categories, defined through the inclusion criteria of three large randomized clinical trials. Additionally, a modified clinical score (mH2FPEF) was applied to detect the probability of heart failure with preserved ejection fraction (HFpEF). Results Of the 459 patients screened from 2015 to 2020, 312 completed 1 year of treatment (68.0%), 92 interrupted the treatment prematurely (20.0%) and 55 were lost to follow-up (12.0%). The most common causes of drug discontinuation were genital or urinary tract infections (9.4%) and poor glycaemic control (5%). At 1 year, a significant reduction in glycated haemoglobin concentration (−0.6 ± 1.4%, P < 0.001) and body weight (2.4 ± 4.6 Kg, P < 0.001) was observed and was comparable between patients at high vs. low cardiovascular risk. Haematocrit increase at 1 year (2.3 ± 3.3%, P < 0.001) was more marked in patients with high cardiovascular risk and low baseline haematocrit. Among patients with no established heart failure (N = 295), 156 (52.9%) had >50% probability of HFpEF (mH2FPEF ≥3). Conclusions In a real-world population of diabetic patients, SGLT2i were well-tolerated at 1 year and led to improved glycaemic control and weight loss. Haematocrit increase was more consistent in patients with high cardiovascular risk and signs of fluid overload, indicating the potentially beneficial role of euvolemic restoration. More than half of these diabetic patients had a high likelihood of unrecognized HFpEF.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitors and Cardiovascular Disease: Lessons and the Future

2020 ◽  
Vol 4 (1) ◽  
pp. 10-12
Author(s):  
Abdulhalim J. A. Kinsara ◽  
◽  
Atif Al Qubbany ◽  
Wail Alkashkar ◽  
◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Communicable Disease ◽  
Therapeutic Option ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Diabetic Patients ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter ◽  
Related Hospitalisation

Diabetes mellitus (DM), an epidemic non-communicable disease, is associated with macro- and micro-vascular complications which may result in sudden cardiac death at a young age. Sodium-glucose cotransporter-2 inhibitors (SGLT2-I) emerged as a new therapeutic option for managing DM with cardiovascular complications as well as diabetic patients with multiple risk factors. Three drugs in this class significantly reduced cardiovascular mortality and heart failure events, in both type 2 diabetes mellitus and non-diabetic patients with a reduced ejection fraction, to prevent heart failure-related hospitalisation. Evidence of kidney protection was another major advantage provided in more than one study. We reviewed recent SGLT2-I related literature and discuss the benefits beyond the cardiac system.

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.

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