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      Dapagliflozin: a sodium glucose cotransporter 2 inhibitor in development for type 2 diabetes

      review-article
      1 , 2 , , 1 , 2
      Diabetes Therapy
      Springer Healthcare Communications
      dapagliflozin, diabetes, SGLT2, inhibitor

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          Abstract

          Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic. Patients face lifelong therapy to control hyperglycemia and prevent the associated complications. There are many medications, with varying mechanisms, available for the treatment of T2DM, but almost all target the declining insulin sensitivity and secretion that are associated with disease progression. Medications with such insulin-dependent mechanisms of action often lose efficacy over time, and there is increasing interest in the development of new antidiabetes medications that are not dependent upon insulin. One such approach is through the inhibition of renal glucose reuptake. Dapagliflozin, the first of a class of selective sodium glucose cotransporter 2 inhibitors, reduces renal glucose reabsorption and is currently under development for the treatment of T2DM. Here, we review the literature relating to the preclinical and clinical development of dapagliflozin.

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          Most cited references31

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          Metformin.

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            Pathogenesis of type 2 diabetes mellitus.

            This article provides an overview of the pathogenesis of type 2 diabetes mellitus. Discussion begins by describing normal glucose homeostasis and ingestion of a typical meal and then discusses glucose homeostasis in diabetes. Topics covered include insulin secretion in type 2 diabetes mellitus and insulin resistance, the site of insulin resistance, the interaction between insulin sensitivity and secretion, the role of adipocytes in the pathogenesis of type 2 diabetes, cellular mechanisms of insulin resistance including glucose transport and phosphorylation, glycogen and synthesis,glucose and oxidation, glycolysis, and insulin signaling.
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              Is Open Access

              Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes

              OBJECTIVE Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements. RESULTS After 12 weeks, dapagliflozin induced moderate glucosuria (52–85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (ΔA1C −0.55 to −0.90% and ΔFPG −16 to −31 mg/dl). Weight loss change versus placebo was −1.3 to −2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups. CONCLUSIONS Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of ∼200–300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.
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                Author and article information

                Contributors
                a.a.tahrani@bham.ac.uk
                Journal
                Diabetes Ther
                Diabetes Therapy
                Springer Healthcare Communications (Heidelberg )
                1869-6953
                1869-6961
                19 January 2011
                19 January 2011
                December 2010
                : 1
                : 2
                : 45-56
                Affiliations
                [1 ]Heart of England NHS Foundation Trust, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS UK
                [2 ]University of Birmingham, Birmingham, UK
                Article
                7
                10.1007/s13300-010-0007-3
                3138480
                22127745
                9d5cd7be-6e74-4b10-8d30-424864ec5f9f
                © Springer Healthcare 2010
                History
                : 4 August 2010
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2010

                Endocrinology & Diabetes
                inhibitor,diabetes,sglt2,dapagliflozin
                Endocrinology & Diabetes
                inhibitor, diabetes, sglt2, dapagliflozin

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