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SGLT2 inhibition diabetic kidney disease

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https://www.readbyqxmd.com/read/28431667/the-potential-and-pitfalls-of-glp-1-receptor-agonists-for-renal-protection-in-type-2-diabetes
#1
Merlin C Thomas
Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) offer substantial benefits for the management of glucose levels in type 2 diabetes. In addition, recent data from clinical trials have demonstrated that treatment with Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) are also able to reduce new onset macroalbuminuria. These benefits may be consistent with the known effects of GLP-1 RA on traditional risk factors for progressive kidney disease including glucose lowering, blood pressure lowering, reduced insulin levels and weight reduction...
April 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28364032/sodium-glucose-transporter-2-inhibition-has-no-renoprotective-effects-on-non-diabetic-chronic-kidney-disease
#2
Qiuyue Ma, Stefanie Steiger, Hans-Joachim Anders
Sodium glucose transporter (SGLT)-2 inhibition has renoprotective effects in diabetic kidney disease. Whether similar effects can be achieved also in non-diabetic kidney disease is speculative. Chronic kidney disease was induced in C57BL/6N mice by feeding an oxalate-rich diet for 14 days, known to induce nephrocalcinosis-related tubular atrophy and interstitial fibrosis without directly affecting the glomerular compartment. Empagliflozin treatment started from day 0 of oxalate feeding had no effect on the decline of glomerular filtration rate, crystal deposition, blood urea nitrogen or serum creatinine levels on day 7 and 14...
April 2017: Physiological Reports
https://www.readbyqxmd.com/read/28254770/sglt2-inhibition-in-the-diabetic-kidney-from-mechanisms-to-clinical-outcome
#3
Erik J M van Bommel, Marcel H A Muskiet, Lennart Tonneijck, Mark H H Kramer, Max Nieuwdorp, Daniel H van Raalte
Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously...
April 3, 2017: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/28196866/sglt2-protein-expression-is-increased-in-human-diabetic-nephropathy-sglt2-protein-inhibition-decreases-renal-lipid-accumulation-inflammation-and-the-development-of-nephropathy-in-diabetic-mice
#4
Xiaoxin X Wang, Jonathan Levi, Yuhuan Luo, Komuraiah Myakala, Michal Herman-Edelstein, Liru Qiu, Dong Wang, Yingqiong Peng, Almut Grenz, Scott Lucia, Evgenia Dobrinskikh, Vivette D D'Agati, Hermann Koepsell, Jeffrey B Kopp, Avi Z Rosenberg, Moshe Levi
There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known...
March 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28120497/rationale-design-and-baseline-characteristics-of-the-canagliflozin-cardiovascular-assessment-study-renal-canvas-r-a-randomized-placebo-controlled-trial
#5
Bruce Neal, Vlado Perkovic, David R Matthews, Kenneth W Mahaffey, Greg Fulcher, Gary Meininger, Ngozi Erondu, Mehul Desai, Wayne Shaw, Frank Vercruysse, Jacqueline Yee, Hsiaowei Deng, Dick de Zeeuw
AIMS: The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes. MATERIALS AND METHODS: CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events...
March 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27977934/longer-term-safety-and-tolerability-of-canagliflozin-in-patients-with-type-2-diabetes-a-pooled-analysis
#6
Rong Qiu, Dainius Balis, John Xie, Michael J Davies, Mehul Desai, Gary Meininger
OBJECTIVE: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: The safety/tolerability of canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52-104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-canagliflozin treatments (i...
March 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/27941935/renal-metabolic-and-cardiovascular-considerations-of-sglt2-inhibition
#7
REVIEW
Ralph A DeFronzo, Luke Norton, Muhammad Abdul-Ghani
The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity...
January 2017: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27878313/targeting-renal-glucose-reabsorption-to-treat-hyperglycaemia-the-pleiotropic-effects-of-sglt2-inhibition
#8
REVIEW
Volker Vallon, Scott C Thomson
Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule...
February 2017: Diabetologia
https://www.readbyqxmd.com/read/27754289/br-08-1-high-sodium-intake-reduction-in-diabetes-with-hypertension
#9
Zhiming Zhu
Management of hypertension in diabetes is critical for reducing cardiovascular mortality and morbidity. Dietary approaches for controlling high blood pressure have historically focused on sodium. Thus, many guidelines recommend that patients with type 2 diabetes reduce high sodium intake. Nonetheless, the potential benefits of sodium reduction are debatable. The kidney has a crucial role in glucose filtration and reabsorption in addition to its regulation of fluid and electrolyte homeostasis. A key factor linking sodium uptake and glucose transport is the sodium-glucose cotransporter 2 (SGLT2) in renal proximal tubular cells...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27748201/renoprotective-effects-of-sglt2-inhibitors-beyond-glucose-reabsorption-inhibition
#10
Vasilios Tsimihodimos, Theodosios D Filippatos, Sebastian Fillippas-Ntekouan, Moses S Elisaf
Sodium-glucose co-transporter 2 inhibitors (SGLT-2) inhibitors) represent a new class of antidiabetic drugs that act through the inhibition of glucose and sodium reabsorption at proximal tubules. It has been shown that tThese substances may exhibit renonephroprotective properties, since they expressed clinically as a prevention of the deterioration of the glomerular filtration rate and a reductionreduce in the degree of albuminuria in patients with established diabetes-associated kidney disease. In this review we present in detail the pathophysiologic mechanisms that have been recently implicated in the rennephroprotective properties of SGLT-2 inhibitors...
October 7, 2016: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/27643287/br-08-1-high-sodium-intake-reduction-in-diabetes-with-hypertension
#11
Zhiming Zhu
Management of hypertension in diabetes is critical for reducing cardiovascular mortality and morbidity. Dietary approaches for controlling high blood pressure have historically focused on sodium. Thus, many guidelines recommend that patients with type 2 diabetes reduce high sodium intake. Nonetheless, the potential benefits of sodium reduction are debatable. The kidney has a crucial role in glucose filtration and reabsorption in addition to its regulation of fluid and electrolyte homeostasis. A key factor linking sodium uptake and glucose transport is the sodium-glucose cotransporter 2 (SGLT2) in renal proximal tubular cells...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27533948/sodium-glucose-cotransporter-2-inhibition-cardioprotection-by-treating-diabetes-a-translational-viewpoint-explaining-its-potential-salutary-effects
#12
REVIEW
Anne E de Leeuw, Rudolf A de Boer
Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general reduction of hyperglycaemia is considered a therapeutic goal, hypoglycaemic therapies do not necessarily reduce cardiovascular mortality and may even aggravate cardiovascular risk factors, such as body weight. A new class of antidiabetic drugs acts by inhibition of the sodium-glucose cotransporter 2 (SGLT2), which (partially) prevents reabsorption of glucose from the renal filtrate...
October 2016: European Heart Journal. Cardiovascular Pharmacotherapy
https://www.readbyqxmd.com/read/27531551/sodium-glucose-cotransporter-2-sglt2-inhibitors-current-status-and-future-perspective
#13
REVIEW
Tushar Madaan, Mohd Akhtar, Abul Kalam Najmi
Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes...
October 10, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27470878/sodium-glucose-cotransporter-2-inhibitors-in-the-treatment-of-diabetes-mellitus-cardiovascular-and-kidney-effects-potential-mechanisms-and-clinical-applications
#14
REVIEW
Hiddo J L Heerspink, Bruce A Perkins, David H Fitchett, Mansoor Husain, David Z I Cherney
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits...
September 6, 2016: Circulation
https://www.readbyqxmd.com/read/27423646/sodium-glucose-cotransporter-2-inhibition-and-the-glomerulus-a-review
#15
REVIEW
Sanjay Kalra, Vikram Singh, Dinesh Nagrale
UNLABELLED: Blood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2) genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening the hyperglycemic condition. The SGLT2 inhibitors (SGLT2i) are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion...
September 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27316632/the-effect-of-sodium-glucose-cotransporter-2-inhibition-with-empagliflozin-on-microalbuminuria-and-macroalbuminuria-in-patients-with-type-2-diabetes
#16
David Cherney, Søren S Lund, Bruce A Perkins, Per-Henrik Groop, Mark E Cooper, Stefan Kaspers, Egon Pfarr, Hans J Woerle, Maximilian von Eynatten
AIMS/HYPOTHESIS: Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent...
September 2016: Diabetologia
https://www.readbyqxmd.com/read/27226136/once-daily-administration-of-the-sglt2-inhibitor-empagliflozin-attenuates-markers-of-renal-fibrosis-without-improving-albuminuria-in-diabetic-db-db-mice
#17
Linda A Gallo, Micheal S Ward, Amelia K Fotheringham, Aowen Zhuang, Danielle J Borg, Nicole B Flemming, Ben M Harvie, Toni L Kinneally, Shang-Ming Yeh, Domenica A McCarthy, Hermann Koepsell, Volker Vallon, Carol Pollock, Usha Panchapakesan, Josephine M Forbes
Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27012770/intestinal-sglt1-in-metabolic-health-and-disease
#18
REVIEW
Anders Lehmann, Pamela J Hornby
The Na(+)-glucose cotransporter 1 (SGLT1/SLC5A1) is predominantly expressed in the small intestine. It transports glucose and galactose across the apical membrane in a process driven by a Na(+) gradient created by Na(+)-K(+)-ATPase. SGLT2 is the major form found in the kidney, and SGLT2-selective inhibitors are a new class of treatment for type 2 diabetes mellitus (T2DM). Recent data from patients treated with dual SGLT1/2 inhibitors or SGLT2-selective drugs such as canagliflozin (SGLT1 IC50 = 663 nM) warrant evaluation of SGLT1 inhibition for T2DM...
June 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/26998950/sodium-glucose-cotransporter-sglt1-as-a-therapeutic-target-in-diabetes-mellitus
#19
Panai Song, Akira Onishi, Hermann Koepsell, Volker Vallon
INTRODUCTION: Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium-glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. AREAS COVERED: This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes...
September 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/26513131/sglt2-inhibition-efficacy-and-safety-in-type-2-diabetes-treatment
#20
REVIEW
André J Scheen
INTRODUCTION: Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity. AREAS COVERED: This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 - 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin...
2015: Expert Opinion on Drug Safety
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