scholarly journals Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors

2020 ◽  
Vol 13 (9) ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Experimental Models ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Nutrient Deprivation ◽  
Fibroblast Growth Factor 21 ◽  
Downstream Effectors ◽  
Sodium Glucose Cotransporter ◽  
Cardioprotective Effects ◽  
Amp Activated Protein Kinase

The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy—a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

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

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 Mitigation of the Adverse Consequences of Nutrient Excess on the Kidney: A Unified Hypothesis to Explain the Renoprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors

2020 ◽  
Vol 51 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Renin Angiotensin System ◽  
Tissue Expansion ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Glomerular Hyperfiltration ◽  
Sodium Glucose Cotransporter

The 2 most common causes of chronic kidney disease worldwide (type 2 diabetes and obesity) are states of nutrient excess, suggesting that fuel overabundance leads to deleterious effects on the structure and function of the kidneys. Three pathophysiological pathways may potentially explain this linkage. First, both obesity and type 2 diabetes are characterized by glomerular hyperfiltration, which may result from increased proximal tubular reabsorption of sodium (due to enhanced glucose and sodium transport) coupled with activation of the renin-angiotensin system. Second, both obesity and type 2 diabetes are characterized by adipose tissue expansion and inflammation, followed by the augmented synthesis and release of lipid intermediates and proinflammatory adipocytokines that can have deleterious effects on the kidney. Third, states of nutrient excess cause a diminution in the activation of the energy sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). The result is a suppression of autophagy, a lysosomal degradative pathway that is responsible for the clearance of damaged organelles that are an important source of oxidative and endoplasmic reticulum stress and inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors induces a transcriptional paradigm that mimics fasting, which leads to the amelioration of glomerular hyperfiltration and adipose tissue inflammation as well as augmentation of AMPK/SIRT1 signaling and autophagy, thereby acting to mute organellar and cellular stress in the kidney. Therefore, SGLT2 inhibitors are positioned to antagonize all 3 pathways by which nutrient excess can lead to nephropathy.

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 Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance

Circulation ◽  
2020 ◽  
Vol 141 (25) ◽  
pp. 2095-2105 ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Close Association ◽  
Sglt2 Inhibitors ◽  
Sirtuin 1 ◽  
Acid Oxidation ◽  
Autophagic Flux ◽  
Inflammasome Activation ◽  
Cellular Homeostasis ◽  
Energy Deprivation

Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by 2 intriguing features: ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia inducible factors (HIFs; especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeogenesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. HIFs act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. The activation of SIRT1, AMPK, and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. It is interesting that type 2 diabetes mellitus, obesity, chronic heart failure, and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by downregulating SIRT1, AMPK, and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK, and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.

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 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.

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.

Focused Updates: SGLT2 Inhibitors in Patients With Heart Failure and/or Chronic Kidney Disease

2020 ◽  
Vol 55 (2) ◽  
pp. 252-260
Author(s):  
Judy W. M. Cheng ◽  
Vincent Colucci ◽  
James S. Kalus ◽  
Sarah A. Spinler
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Kidney Diseases ◽  
Sglt2 Inhibitors ◽  
Renal Protection ◽  
Chronic Kidney Diseases ◽  
Sodium Glucose Cotransporter ◽  
Patients With Heart Failure ◽  
Cv Disease

Sodium-glucose cotransporter (SGLT2) inhibitors have demonstrated cardiovascular (CV) benefits in large-scale clinical trials of people who have type 2 diabetes and either established CV disease or multiple CV risk factors. These studies also indicated early signals in benefiting heart failure (HF) patients and those with chronic kidney diseases. This article reviews recent and future clinical studies that focus on evaluation of the use of SGLT2 inhibitors in HF management and renal protection.

scholarly journals Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Adverse Outcomes ◽  
Lessons Learned ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Artery Disease

Abstract Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

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