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. 2012:5:135-48.
doi: 10.2147/DMSO.S22503. Epub 2012 Jul 23.

Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Jean M Whaley  1 , Mark Tirmenstein, Timothy P Reilly, Simon M Poucher, Joanne Saye, Shamik Parikh, James F List
Affiliations

Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

Jean M Whaley et al. Diabetes Metab Syndr Obes. 2012.

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a positive benefit-risk ratio across the continuum of diabetes patients. To date, data on dapagliflozin, a selective SGLT2 inhibitor in development, demonstrate that the kidney is an efficacious and safe target for therapy, and that SGLT2 inhibition may have benefits for patients with type 2 diabetes mellitus beyond glycemic control.

Keywords: SGLT2; dapagliflozin; mechanism of action; type 2 diabetes mellitus.

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Figures

Figure 1
Figure 1
(A) In the normal range of blood glucose levels, the majority of glucose is reabsorbed in the kidney predominantly via the action of SGLT2 and GLUT2 in the S1 segment of the proximal tubule. (B) SGLT2 inhibitors block the reabsorption of glucose in the S1 proximal tubule under normal or hyperglycemic conditions, resulting in urinary glucose excretion. Abbreviations: SGLT, sodium-glucose cotransporter; GLUT, glucose transporter.
Figure 2
Figure 2
SGLT2 expression was determined in an array of 72 human tissues. Shown are representative tissues quantified using TaqMan quantitative PCR analysis with primer/probe sets designed to amplify and detect regions of (A) exon 6–7 and (B) exon 13 of SGLT2 and normalized to GAPDH. Note: Copyright © 2010. Reprinted with permission from Springer Science+Business Media B.V. Chen J, William S, Ho S, et al. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther. 2010;1(2):57–92. Abbreviations: SGLT, sodium-glucose cotransporter; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Figure 3
Figure 3
Single oral doses of dapagliflozin were demonstrated to stimulate an increase in urinary glucose excretion in Zucker diabetic fatty rats (A) over 6 hours, and (B) 24 hours post dose. Notes: *P < 0.0001; †P < 0.05, each versus vehicle. Copyright © 2008. Reprinted with permission from American Diabetes Association. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–1729. Abbreviation: BW, body weight.
Figure 4
Figure 4
Once-daily oral administration of dapagliflozin resulted in significant, dose-dependent reductions in the plasma glucose of fed and fasting Zucker diabetic fatty rats over 15 days. Notes: *P < 0.0001; †P < 0.05, each versus vehicle. Copyright © 2008. Reprinted with permission from American Diabetes Association. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57(6):1723–1729. Abbreviation: Ad lib, Ad libitum.
Figure 5
Figure 5
Dapagliflozin treatment of Zucker diabetic fatty rats at the initiation of a high-fat diet (A) did not have a significant effect on β-cell mass and (B) improved islet morphology. Box plots of the same data presented as insets. Representative 10× images of immunofluorescently stained β-cells (anti-insulin, green) and Hoescht-stained nuclei showed (C) poor islet morphology and scattered β-cells in obese, vehicle-treated Zucker diabetic fatty rats compared with (D) improved islet morphology and insulin-staining intensity in dapagliflozin-treated animals. Islet size was increased in these obese, dapagliflozin-treated rats compared with (E) lean Zucker diabetic fatty rats. Note: †P < 0.05 versus obese fat-fed group. Copyright © 2010. Reprinted with permission from John Wiley and Sons. Macdonald FR, Peel JE, Jones HB, et al. The novel SGLT2 inhibitor dapagliflozin sustains pancreatic function and preserves islet morphology in obese, diabetic rats. Diabetes Obes Metab. 2010;12(11): 1004–1012. Abbreviation: Dapa, dapagliflozin.
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