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Dapagliflozin and moderate renal impairment

Paola Fioretto, Stefano Del Prato, John B Buse, Ronald Goldenberg, Francesco Giorgino, Daniel Reyner, Anna Maria Langkilde, C David Sjӧstrӧm, Peter Sartipy
AIMS: Dapagliflozin is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2). This study assessed the efficacy and safety of dapagliflozin 10 mg versus placebo in patients with type 2 diabetes (T2D) and moderate renal impairment (estimated glomerular filtration rate [eGFR] 45-59 mL/min/1.73m2 ; chronic kidney disease [CKD] stage 3A). MATERIALS AND METHODS: In this double-blind, parallel group, Phase 3 study (NCT02413398, patients with inadequately controlled T2D (HbA1c 7...
June 11, 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...
2018: Cellular Physiology and Biochemistry
Christian W Mende
Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys...
March 2017: Current Medical Research and Opinion
(no author information available yet)
* In early 2016, metformin monotherapy remains the treatment of choice for most patients with type 2 diabetes. There are several alternatives for patients in whom metformin is poorly tolerated or ineffective. However, dapagliflozin and canagiflozin have an unfavourable harm-benefit balance and should not be used to enhance the action of metformin. Empagliflozin is the third glifozin to be authorised in the European Union for the treatment of type 2 diabetes. A randomised, double-blind, placebo-controlled trial of empaglifloznin, in combination with other glucose-lowering drugs, involved 7020 patients with type 2 diabetes, an average glycated haemoglobin (HbA1c) concentration of about 8%, and a history of at least one cardiovascular event...
June 2016: Prescrire International
Donald Elliott Kohan, Paola Fioretto, Kristina Johnsson, Shamik Parikh, Agata Ptaszynska, Lisa Ying
BACKGROUND: Dapagliflozin's antihyperglycemic effects are mediated by inhibition of renal sodium-glucose cotransporter-2; therefore, renal safety of dapagliflozin was assessed. METHODS: Twelve double-blind, placebo-controlled, randomized clinical trials were analyzed up to 24 weeks (N = 4545). Six of the 12 studies included long-term data for up to 102 weeks (N = 3036). Patients with type 2 diabetes with normal or mildly impaired renal function [estimated glomerular filtration rate (eGFR) 60 to <90 mL/min/1...
June 2016: Journal of Nephrology
Yshai Yavin, Traci A Mansfield, Agata Ptaszynska, Kristina Johnsson, Shamik Parikh, Eva Johnsson
INTRODUCTION: Hyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM)...
March 2016: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
André J Scheen
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin)...
July 2015: Clinical Pharmacokinetics
Theodosios D Filippatos, Evangelos N Liberopoulos, Moses S Elisaf
Dapagliflozin is a selective and reversible inhibitor of sodium-glucose linked transporter type 2 (SGLT2), which mediates approximately 90% of active renal glucose reabsorption in the early proximal tubule of the kidney. Dapagliflozin significantly reduces glucose reabsorption and decreases serum glucose concentration in an insulin-independent manner. The decrease of glucose reabsorption by dapagliflozin has also been associated with a reduction in body weight. Furthermore, the drug modestly reduces blood pressure levels through weight loss and its action as osmotic diuretic...
February 2015: Therapeutic Advances in Endocrinology and Metabolism
S Halimi, B Vergès
In type 2 diabetes (T2DM), glycaemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM...
December 2014: Diabetes & Metabolism
André J Scheen
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug...
January 2015: Drugs
Greg L Plosker
Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs...
December 2014: Drugs
Robert G Moses, Stephen Colagiuri, Carol Pollock
The prevalence of type 2 diabetes mellitus (T2DM) is rising in Australia. Sodium glucose co-transporter 2 (SGLT2) inhibitors are an emerging treatment for T2DM. SGLT2 inhibitors offer a novel approach to lowering hyperglycaemia by suppressing renal glucose reabsorption and increasing urinary glucose excretion. The increased urinary glucose excretion has also been associated with caloric loss and osmotic diuresis. Dapagliflozin and canagliflozin are the SGLT2 inhibitors that are approved for clinical use in the US, the European Union (EU), and Australia...
2014: Australasian Medical Journal
K Kaku, A Kiyosue, S Inoue, N Ueda, T Tokudome, J Yang, A M Langkilde
AIMS: To evaluate the efficacy and safety of the selective sodium glucose co-transporter 2 inhibitor dapagliflozin in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by diet and exercise. METHODS: Patients received placebo or dapagliflozin (5 or 10 mg) once daily for 24 weeks. The primary outcome measure was change from baseline in glycated haemoglobin (HbA1c). RESULTS: Patients (N = 261) had modestly elevated baseline HbA1c (mean ≈ 7...
November 2014: Diabetes, Obesity & Metabolism
Courtney S Davis, Joshua W Fleming, Laurie E Warrington
PURPOSE: The purpose of this article is to educate nurse practitioners about the newest class of oral medications developed to treat type 2 diabetes mellitus (T2DM). This article will review dapagliflozin and canagliflozin, the two Food and Drug Administration (FDA) approved sodium glucose co-transporter 2 (SGLT2) inhibitors, and discuss their place in therapy. DATA SOURCES: A comprehensive literature search was conducted using MEDLINE with the key terms: dapagliflozin, canagliflozin, SGLT2 inhibitors, and SGLT2 inhibitors...
July 2014: Journal of the American Association of Nurse Practitioners
André J Scheen
INTRODUCTION: Inhibitors of sodium-glucose cotransporters type 2 (SGLT2), which increase urinary glucose excretion independently of insulin, are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). AREAS COVERED: An extensive literature search was performed to analyze the pharmacokinetic characteristics, toxicological issues and safety concerns of SGLT2 inhibitors in humans. This review focuses on three compounds (dapagliflozin, canagliflozin, empagliflozin) with results obtained in healthy volunteers (including drug-drug interactions), patients with T2DM (single dose and multiple doses) and special populations (those with renal or hepatic impairment)...
May 2014: Expert Opinion on Drug Metabolism & Toxicology
Donald E Kohan, Paola Fioretto, Weihua Tang, James F List
In patients with diabetes, glycemic improvement by sodium-glucose cotransporter-2 inhibition depends on the kidney's ability to filter glucose. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces hyperglycemia in patients with diabetes and normal or mildly impaired renal function. In this randomized, double-blind, placebo-controlled study we assessed daily treatment with dapagliflozin in 252 patients with inadequately controlled type 2 diabetes and moderate renal impairment. The primary endpoint, the mean change in HbA1c, was not statistically different from placebo after 24 weeks (-0...
April 2014: Kidney International
J-S van der Walt, Y Hong, L Zhang, M Pfister, D W Boulton, M O Karlsson
Dapagliflozin is a sodium-glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40-55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min)...
May 8, 2013: CPT: Pharmacometrics & Systems Pharmacology
Sreeneeranj Kasichayanula, Xiaoni Liu, Melanie Pe Benito, Ming Yao, Marc Pfister, Frank P LaCreta, William Griffith Humphreys, David W Boulton
AIM(S): This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, a renal sodium glucose co-transporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus (T2DM). METHODS: A single 50 mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy non-diabetic subjects; patients with T2DM and normal kidney function and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance...
September 2013: British Journal of Clinical Pharmacology
Sreeneeranj Kasichayanula, Xiaoni Liu, Weijiang Zhang, Marc Pfister, Frank P LaCreta, David W Boulton
BACKGROUND: Dapagliflozin, a selective inhibitor of renal sodium glucose co-transporter 2, is under development for the treatment of type 2 diabetes mellitus. Dapagliflozin elimination is primarily via glucuronidation to an inactive metabolite, dapagliflozin 3-O-glucuronide. Pharmacokinetic studies are recommended in subjects with impaired hepatic function if hepatic metabolism accounts for a substantial portion of the absorbed drug. OBJECTIVE: The purpose of our study was to compare the pharmacokinetics of dapagliflozin in patients with mild, moderate, or severe hepatic impairment (HI) with healthy subjects...
November 2011: Clinical Therapeutics
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