SGLT2 inhibition diabetic kidney disease

We investigated for the first time the effect of combination therapy of renin-angiotensin system inhibition (RASi) and sodium-glucose co-transporter-2 inhibitors (SGLT2is) on endotrophin (ETP), a pro-fibrotic signaling molecule reflecting collagen type VI formation, measured in the plasma of persons with type 2 diabetes (T2D). ETP was measured using the PRO-C6 ELISA in 294 individuals from the "Drug combinations for rewriting trajectories of renal pathologies in type 2 diabetes" (DC-ren) project. In the DC-ren study, kidney disease progression was defined as a >10% decline in the estimated glomerular filtration rate (eGFR) to an eGFR < 60 mL/min/1...

BACKGROUND: Heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM) are common and interrelated conditions, each with a significant burden of disease. HF and kidney disease progress through pathophysiologic pathways that culminate in end-stage disease, for which T2DM is a major risk factor. Intervention within these pathways can disrupt disease processes and improve patient outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been investigated in patient populations with combinations of T2DM, CKD, and/or HF...

Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic kidney disease is the leading cause of end-stage kidney disease worldwide. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to be effective in glucose control, improving cardiovascular outcomes and the progression of kidney disease. However, the protective role of SGLT2 inhibition on kidney metabolism is not fully understood. To explore these mechanisms further, we conducted analysis of publicly available single-cell RNA sequencing data of db/db mice treated with an SGLT2 inhibitor(dapagliflozin) and accompanying controls...

Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia...

Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA-approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be re-purposed for lung cancer. Despite the anti-tumor effects of SGLT2 inhibition, tumors eventually escape treatment...

BACKGROUND: Hypothalamic neuroinflammation is associated with disorders of lipid metabolism. Considering the anti-neuroinflammation effects of sodium-glucose cotransporter 2(SGLT2) inhibitors, a central administration of Dapagliflozin is postulated to provide hypothalamic protection and change lipid metabolism in kidney against diabetic kidney disease (DKD). METHODS: Blood samples of DKD patients were collected. Male Sprague-Dawley (SD) rats with 30 mg/kg streptozotocin and a high-fat diet, db/db mice and palmitic acid (PA)-stimulated BV2 microglia were used for study models...

Diabetes mellitus, a disease that affects hundreds of millions of people worldwide, is increasing in prevalence in all age groups, including children and adolescents. Much of the morbidity and mortality associated with diabetes is closely related to hypertension, often coincident with diabetes. Comorbid hypertension and diabetes often worsen the outcomes of each other, likely rooted in some overlapping pathogenic mechanisms. In this educational review, we will discuss the shared pathophysiology of diabetes and hypertension, particularly in regard to inflammation and oxidative stress, the sympathetic nervous system, vascular remodeling, and the renin-angiotensin-aldosterone system (RAAS)...

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by hyperglycaemia. T2DM is a highly heterogeneous polygenic disease. Due to genetic variation, variations in lifestyle and other environmental exposures, there are certain variations in the phenotype of T2DM patients. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel hypoglycaemic agents that increase urinary glucose excretion by inhibiting glucose reabsorption in the proximal tubules of the kidney. For glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, studies have confirmed a variety of gene variants that may modify their effects...

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a kidney protective effect in patients with diabetic kidney disease. Several mechanisms have been proposed but why precisely SGLT2 inhibition has a kidney protective effect is incompletely understood. Clinical trials using SGLT2 inhibitors have found them to induce a rapid weight loss likely due to loss of sodium and subsequently fluid. While SGLT2 inhibitors are reported to increase hematocrit, it remains unknown whether the natriuretic and aquaretic effect reduces patient's blood volume and whether this could partly explain its kidney protective effects...

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells...

BACKGROUND: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM). It has been proposed that modifications in the function of proximal tubule epithelial cells (PTECs) precede glomerular damage during the onset of DKD. This study aimed to identify modifications in renal sodium handling in the early stage of DM and its molecular mechanism. METHODS: Streptozotocin (STZ)-induced diabetic BALB/c mice (STZ group) and LLC-PK1 cells, a model of PTECs, were used...

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents...

Arterial stiffness is a hallmark of vascular ageing and results in increased blood flow pulsatility to the periphery, damaging end-organs such as the heart, kidneys and brain. Treating or "reversing" arterial stiffness has therefore become a central target in the field of vascular ageing. SGLT2 inhibitors, initially developed in the context of type 2 diabetes mellitus, have become a cornerstone of heart failure treatment. Additionally, effects on the vasculature have been reported. Here, we demonstrate that treatment with the SGLT2 inhibitor empagliflozin (7 weeks, 15 mg/kg/day) decreased ageing-induced arterial stiffness of the aorta in old mice with normal blood glucose levels...

OBJECTIVE: To develop a risk assessment tool to identify patients with type 2 diabetes (T2D) at higher risk for kidney disease progression and who might benefit more from sodium-glucose cotransporter 2 (SGLT2) inhibition. RESEARCH DESIGN AND METHODS: A total of 41,204 patients with T2D from four Thrombolysis In Myocardial Infarction (TIMI) clinical trials were divided into derivation (70%) and validation cohorts (30%). Candidate predictors of kidney disease progression (composite of sustained ≥40% decline in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney death) were selected with multivariable Cox regression...

Underlying molecular mechanisms of the kidney protective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors are not fully elucidated. Therefore, we studied the association between urinary epidermal growth factor (uEGF), a mitogenic factor involved in kidney repair, and kidney outcomes in patients with type 2 diabetes (T2D). The underlying molecular mechanisms of the SGLT2 inhibitor canagliflozin on EGF using single-cell RNA sequencing from kidney tissue were examined. Urinary EGF-to-creatinine ratio (uEGF/Cr) was measured in 3521 CANagliflozin cardioVascular Assessment Study (CANVAS) participants at baseline and week 52...

In the EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial, empagliflozin reduced cardiorenal outcomes by 28% (hazard ratio 0.72; 95% confidence interval 0.64-0.82; P  < .0001) in a diverse population of over 6000 chronic kidney disease (CKD) patients, of whom >50% were not diabetic. It expanded the spectrum of CKD that may benefit from sodium-glucose cotransporter 2 (SGLT2) inhibition to participants with urinary albumin: creatinine ratio <30 mg/g and estimated glomerular filtration rate (eGFR) >20 mL/min/1...

AIMS: Vascular calcification (VC) is prevalent in pathological processes such as diabetes, chronic kidney disease (CKD), and atherosclerosis, but effective therapies are still lacking by far. Canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor, has been approved for the treatment of type 2 diabetes mellitus and exhibits beneficial effects against cardiovascular disease. However, the effect of CANA on VC remains unknown. In this study, we hypothesize that CANA protects against VC...

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear...

BACKGROUND: The insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes. METHODS: Samples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events...

The primary pharmacological action of sodium-glucose co-transporter 2 (SGLT2) inhibitors is to inhibit the reabsorption of glucose and sodium ions from the proximal tubules of the kidney and to promote urinary glucose excretion. Notably, several clinical trials have recently demonstrated potent protective effects of SGLT2 inhibitors in patients with heart failure (HF) or chronic kidney disease (CKD), regardless of the presence or absence of diabetes. However, the impact of SGLT2 inhibitors on sudden cardiac death (SCD) or fatal ventricular arrhythmias (VAs), the pathophysiology of which is partly similar to that of HF and CKD, remains undetermined...