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      Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives

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          Abstract

          Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium–glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

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          Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs

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            Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition

            OBJECTIVE Sodium–glucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication. RESEARCH DESIGN AND METHODS Cases identified incidentally are described. RESULTS We identified 13 episodes of SGLT-2 inhibitor–associated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers. CONCLUSIONS SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.
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              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
                cefalo.chiara@gmail.com
                cinti_francesca@hotmail.com
                simona.moffa@gmail.com
                flavia.impronta@gmail.com
                sorice.gianpio@gmail.com
                teresa.mezza@gmail.com
                alfredo.pontecorvi@unicatt.it
                andrea.giaccari@unicatt.it
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                28 February 2019
                28 February 2019
                2019
                : 18
                : 20
                Affiliations
                [1 ]ISNI 0000 0004 1760 4193, GRID grid.411075.6, Center for Endocrine and Metabolic Diseases, , Fondazione Policlinico Universitario Agostino Gemelli IRCCS, ; Rome, Italy
                [2 ]ISNI 0000 0001 0941 3192, GRID grid.8142.f, Istituto di Patologia Speciale Medica e Semeiotica Clinica, , Università Cattolica del Sacro Cuore, ; Rome, Italy
                Article
                828
                10.1186/s12933-019-0828-y
                6393994
                30819210
                3350deb1-04a9-4797-9cb3-8225e8f4e72a
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 December 2018
                : 19 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001648, European Foundation for the Study of Diabetes;
                Award ID: Lilly fellowship
                Award ID: Novonordisk Rising Star fellowship
                Award Recipient :
                Funded by: Italian Ministry of education, research and university
                Award ID: Prin
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005743, Università Cattolica del Sacro Cuore;
                Award ID: Fondi Ateneo Linea D3.2
                Award Recipient :
                Funded by: FONDAZIONE ASSOCIAZIONE MEDICI DIABETOLOGI
                Award ID: BORSE DI STUDIO IN MEMORIA DI ADOLFO ARCANGELI
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Endocrinology & Diabetes
                sglt2 inhibitors,diabetes,hypoglycemic therapy
                Endocrinology & Diabetes
                sglt2 inhibitors, diabetes, hypoglycemic therapy

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