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Yunona Khomitskaya, Nadezhda Tikhonova, Konstantin Gudkov, Svetlana Erofeeva, Victoria Holmes, Brian Dayton, Nigel Davies, David W Boulton, Weifeng Tang
PURPOSE: Fixed-combination drug products (FCDPs) combining dapagliflozin and metformin extended release (XR) may provide patients with type 2 diabetes mellitus with an alternative antihyperglycemic treatment, which could improve adherence by reducing tablet burden. This study evaluated the bioequivalence of dapagliflozin/metformin XR FCDP versus the co-administration of the individual monotherapy tablets currently available for use in the Russian Federation. METHODS: Healthy subjects aged 18 to 45 years were enrolled in this randomized, open-label, 2-period crossover study, conducted in a single Russian center...
March 13, 2018: Clinical Therapeutics
Lisa Menegazzo, Valentina Scattolini, Roberta Cappellari, Benedetta Maria Bonora, Mattia Albiero, Mario Bortolozzi, Filippo Romanato, Giulio Ceolotto, Saula Vigili de Kreutzeberg, Angelo Avogaro, Gian Paolo Fadini
AIMS: Diabetes is associated with an excess release of neutrophil extracellular traps (NETs) and an enhanced NETosis, a neutrophil cell death programme instrumental to anti-microbial defences, but also involved in tissue damage. We herein investigated whether the antidiabetic drug metformin protects against NETosis. METHODS: We measured NET components in the plasma of patients with pre-diabetes who were randomized to receive metformin or placebo for 2 months. To control for the effect on glucose, we also measured NET components in the plasma of patients with type 2 diabetes before and after treatment with insulin or dapagliflozin...
March 15, 2018: Acta Diabetologica
Mikhail Kosiborod, Carolyn S P Lam, Shun Kohsaka, Dae Jung Kim, Avraham Karasik, Jonathan Shaw, Navdeep Tangri, Su-Yen Goh, Marcus Thuresson, Hungta Chen, Filip Surmont, Niklas Hammar, Peter Fenici
BACKGROUND: Randomized trials demonstrated lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with broader risk profile, but focused on heart failure and death, and were limited to US and Europe. OBJECTIVES: To examine a broad range of CV outcomes in patients initiated on SGLT-2i vs. other glucose lowering drugs (oGLD) across six countries in Asia Pacific, Middle East and North America (NCT02993614)...
March 7, 2018: Journal of the American College of Cardiology
Laura Van den Mooter, Simon Caerels, Chantal Mathieu
There is a clear unmet clinical need in people with Type 1 diabetes (T1DM) considering present day insulin therapy. New insulin analogues and novel technologies allowing more tailored insulin administration have improved the quality of life of people with T1DM, but issues like hypoglycemia, weight gain and variability in glucose profiles remain problematic. Areas covered: In this review, the clinical efficacy, safety and tolerability of dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor, in type 1 diabetes (T1DM) is described based on a review of phase 2 and 3 studies to date...
March 14, 2018: Expert Opinion on Pharmacotherapy
Annas Al-Sharea, Andrew J Murphy, L A Huggins, Y Hu, Ira J Goldberg, Prabhakara R Nagareddy
BACKGROUND AND AIMS: Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia...
March 2, 2018: Atherosclerosis
Gian Paolo Fadini, Giancarlo Zatti, Ileana Baldi, Daniele Bottigliengo, Agostino Consoli, Andrea Giaccari, Giorgio Sesti, Angelo Avogaro
In randomized controlled trials (RCTs), SGLT-2 inhibitors (SGLT2i) showed glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) was a multicenter retrospective study designed to evaluate baseline characteristics of patients receiving dapagliflozin versus selected comparators (DPP-4 inhibitors, gliclazide, or GLP-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281,217 patients, the analysis included 17,285 initiating dapagliflozin or comparator glucose lowering medications (GLM), 6751 of whom had a follow-up examination...
March 8, 2018: Diabetes, Obesity & Metabolism
Liping Meng, Hiroyasu Uzui, Hangyuan Guo, Hiroshi Tada
Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy (DCM), which leads to cardiac remodeling, dilated cardiomyopathy and congestive heart failure. Human cardiac fibroblasts (HCF) constitute the predominant cell type in the heart and matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are also involved in cardiac fibrosis. However, it is unclear whether high glucose levels affect the expression of MMPs and TIMPs in HCF. Sodium‑glucose cotransporter (SGLT) inhibitors have been developed as therapeutic agents and the anti‑DCM effect of SGLT inhibitors has been demonstrated by previous studies...
March 6, 2018: Molecular Medicine Reports
Rhona Johnston, Olalekan Uthman, Ewen Cummins, Christine Clar, Pamela Royle, Jill Colquitt, Bee Kang Tan, Andrew Clegg, Saran Shantikumar, Rachel Court, J Paul O'Hare, David McGrane, Tim Holt, Norman Waugh
No abstract text is available yet for this article.
February 2018: Health Technology Assessment: HTA
Yochai Birnbaum, Mandeep Bajaj, Hsiu-Chiung Yang, Yumei Ye
BACGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied...
March 5, 2018: Cardiovascular Drugs and Therapy
Hiroki Nakajima, Sadanori Okada, Takako Mohri, Eiichiro Kanda, Naoyuki Inaba, Yoko Hirasawa, Hiroaki Seino, Hisamoto Kuroda, Toru Hiyoshi, Tetsuji Niiya, Hitoshi Ishii
Background: The benefits of sodium glucose cotransporters 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus include plasma glucose control, reduction in body weight and blood pressure, and low risk of hypoglycemia, although they may also cause genitourinary infections, polyuria, or volume depletion. It is not clear whether dapagliflozin, an SGLT2 inhibitor, improves treatment satisfaction among patients in a comprehensive way despite the negative side effects. This study assessed the effect of dapagliflozin on glycosylated hemoglobin (HbA1c), body weight, and treatment satisfaction in overweight patients with type 2 diabetes mellitus treated with oral hypoglycemic agents...
2018: Diabetology & Metabolic Syndrome
Wathik Alsalim, Margaretha Persson, Bo Ahrén
AIMS: Previous studies have shown that dipeptidyl peptidase (DPP)-4 inhibition lowers whereas sodium-glucose co-transporter 2 (SGLT-2) inhibition increases glucagon levels. This study evaluated the extent of these opposite effects in a direct comparative head-to-head study. METHODS: In a single-centre, randomized study with a cross-over design, 28 metformin-treated patients with type 2 diabetes (T2D; mean age 63 years, baseline HbA1c 6.8%) were treated with vildagliptin (50 mg twice daily) or dapagliflozin (10 mg once daily) for two weeks with a four week wash out period in between...
March 2, 2018: Diabetes, Obesity & Metabolism
Yingli Jia, Jinzhao He, Liang Wang, Limin Su, Lei Lei, Wei Huang, Xiaoqiang Geng, Shun Zhang, Xiaolu Meng, Hong Zhou, Baoxue Yang
BACKGROUND/AIMS: A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. METHODS: Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks...
February 23, 2018: Cellular Physiology and Biochemistry
Mahakpreet Singh, Anoop Kumar
Sodium glucose co-transport 2 inhibitors (SGLT2-i) are the new class of anti-diabetic medications which are the recently approved (2013) by FDA for the treatment of diabetes. These inhibitors block the SGLT2 protein which involved in glucose reabsorption from proximal renal tubule which results in increased glucose excretion and lower blood glucose levels. These inhibitors exert favourable effects beyond glucose control such as consistent body weight, blood pressure, and serum uric acid reductions. Canagliflozin, Dapagliflozin, and Empagliflozin belong to the class of SGLT2 inhibitors...
February 25, 2018: Current Drug Safety
Robert Puckrin, Marie-Philippe Saltiel, Pauline Reynier, Laurent Azoulay, Oriana H Y Yu, Kristian B Filion
AIMS: There is concern about the infection-related safety profile of sodium-glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator...
February 27, 2018: Acta Diabetologica
Stefano Del Prato, Julio Rosenstock, Ricardo Garcia-Sanchez, Nayyar Iqbal, Lars Hansen, Eva Johnsson, Hungta Chen, Chantal Mathieu
The safety of triple oral therapy with dapagliflozin plus saxagliptin plus metformin, versus dual therapy with dapagliflozin or saxagliptin plus metformin, was compared in a post hoc analysis of three randomized trials of sequential or concomitant add-on of dapagliflozin and saxagliptin to metformin. In the concomitant add-on trial, patients with type 2 diabetes on stable metformin received dapagliflozin 10 mg/day plus saxagliptin 5 mg/day. In sequential add-on trials, patients on metformin plus either saxagliptin 5 mg/day or dapagliflozin 10 mg/day received add-on dapagliflozin 10 mg/day or saxagliptin 5 mg/day, respectively...
February 15, 2018: Diabetes, Obesity & Metabolism
Philipp F Secker, Sascha Beneke, Nadja Schlichenmaier, Johannes Delp, Simon Gutbier, Marcel Leist, Daniel R Dietrich
Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin...
February 14, 2018: Cell Death & Disease
Christopher S Wilcox, Wen Shen, David W Boulton, Bruce R Leslie, Steven C Griffen
BACKGROUND: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. METHODS AND RESULTS: Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d-1 of Na+ were randomized to bumetanide (1 mg·d-1 ), dapagliflozin (10 mg·d-1 ), or both for 7 days, followed by 7 days of both...
February 10, 2018: Journal of the American Heart Association
Charles Khouri, Jean-Luc Cracowski, Matthieu Roustit
OBJECTIVE: Inhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose lowering agents showing promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear. METHODS: We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase®) to address this issue. RESULTS: Among the 8,293,886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputations associated with SGLT-2 inhibitors...
February 12, 2018: Diabetes, Obesity & Metabolism
Konstantinos Avranas, Konstantinos Imprialos, Konstantinos Stavropoulos, Georgios Lales, Alexandos Manafis, Anastasia Skalkou, Lars Kihm
BACKGROUND: The treatment of diabetes remains over the decades challenging, even after the introduction of numerous novel drugs of different classes. Most patients with type 2 diabetes necessitate the combination of multiple agents and eventually use of insulin. The newest, and possibly with the most pleiotropic actions after metformin are the sodium-glucose cotransporter 2 inhibitors (SGLT-2i). This class has a unique mechanism inhibiting the glucose reabsorption in the proximal tubule of the kidney...
February 6, 2018: Cardiovascular & Hematological Disorders Drug Targets
Cheryl Neslusan, Anna Teschemaker, Michael Willis, Pierre Johansen, Lien Vo
INTRODUCTION: Agents that inhibit sodium glucose co-transporter 2 (SGLT2), including canagliflozin and dapagliflozin, are approved in the United States for the treatment of adults with type 2 diabetes mellitus (T2DM). SGLT2 inhibition lowers blood glucose by increasing urinary glucose excretion, which leads to a mild osmotic diuresis and a net loss of calories that are associated with reductions in body weight and blood pressure. This analysis evaluated the cost-effectiveness of canagliflozin 300 mg versus dapagliflozin 10 mg in patients with T2DM inadequately controlled with metformin in the United States...
February 6, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
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