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      Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology

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          Abstract

          Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a newly developed class of oral anti-diabetic drugs (OADs) with a unique mechanism of action. This review describes the biochemistry and physiology underlying the use of SGLT2 inhibitors, and their clinical pharmacology, including mechanism of action and posology. The pragmatic placement of these molecules in the existing OAD arena is also discussed.

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          The online version of this article (doi:10.1007/s13300-014-0089-4) contains supplementary material, which is available to authorized users.

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          Most cited references21

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          Phlorizin: a review.

          Joel Ehrenkranz, Norman Lewis, C Kahn … (2004)
          The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia. Copyright (c) 2004 John Wiley & Sons, Ltd.
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            Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.

            J. Bolinder, O Ljunggren, B. Johansson … (2014)
            Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.
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              Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes

              Piero Ruggenenti, Esteban L. Porrini, Flavio Gaspari … (2012)
              OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: −0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.
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                Author and article information

                Contributors
                Sanjay Kalra: brideknl@gmail.com
                Journal
                Journal ID (nlm-ta): Diabetes Ther
                Journal ID (iso-abbrev): Diabetes Ther
                Title: Diabetes Therapy
                Publisher: Springer Healthcare (Heidelberg )
                ISSN (Print): 1869-6953
                ISSN (Electronic): 1869-6961
                Publication date (Electronic): 26 November 2014
                Publication date PMC-release: 26 November 2014
                Publication date (Print): December 2014
                Volume: 5
                Issue: 2
                Pages: 355-366
                Affiliations
                Bharti Hospital and B.R.I.D.E., Karnal, India
                Article
                Publisher ID: 89
                DOI: 10.1007/s13300-014-0089-4
                PMC ID: 4269649
                PubMed ID: 25424969
                SO-VID: 4e4b65ed-3a74-4293-b86d-1a97d8a36e94
                Copyright © © The Author(s) 2014
                History
                Date received : 21 August 2014
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer Healthcare 2014

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: anti-diabetic drugs,cardiovascular safety,canagliflozin,dapagliflozin,empagliflozin,perineal hygiene,sodium-glucose co-transporter-2 inhibitors
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: anti-diabetic drugs, cardiovascular safety, canagliflozin, dapagliflozin, empagliflozin, perineal hygiene, sodium-glucose co-transporter-2 inhibitors

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