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Part 10

Part 10. Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF Rats. *. *. †. *. *. †. †. Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg (n=6) 10 mg/kg (n=6). 400. 300. FPG (mg/dL). 200. 100. 0. Baseline. Day 8. Day 15.

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Part 10

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  1. Part 10

  2. Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF Rats * * † * * † † Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg (n=6) 10 mg/kg (n=6) 400 300 FPG (mg/dL) 200 100 0 Baseline Day 8 Day 15 *P<0.05; †P<0.0001 vs vehicle. ZDF=Zucker diabetic fatty. Han S, et al. Diabetes. 2008;57:1723-1729; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P.

  3. Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Production in ZDF Rats 4.0 8.0 P<0.01 3.0 6.0 Hepatic Glucose Production(mg/kg • min) Glucose Infusion Rate(mg/kg • min) 2.0 4.0 P<0.01 1.0 2.0 0 0 CON DAPA CON DAPA CON=controls; DAPA=dapagliflozin. Han S, et al. Diabetes. 2008;57:1723-1729.

  4. Dapagliflozin-Induced GlucosuriaReduces HbA1c: A Dose-Ranging Trial List JF, et al. Diabetes Care. 2009;32:650-657.

  5. Effect of Dapagliflozin on HbA1c Baseline HbA1c (%) 7.7 8.0 8.0 7.8 7.9 7.7 0 DAPA 2.5 DAPA 5 DAPA 10 DAPA 50 PBO MET XR1500 -0.2 -0.4 Δ HbA1c (%) -0.6 -0.8 P<0.01 P<0.01 P<0.01 P<0.01 -1 All comparisons vs placebo; no statistical comparisons with metformin were made. List JF, et al. Diabetes Care. 2008;2009;32:650-657.

  6. Dapagliflozin: Glucosuric and Metabolic Effects List JF, et al. Diabetes Care. 2009;32:650-657.

  7. Adverse Events With Dapagliflozin UTI=urinary tract infection. List JF, et al. Diabetes Care. 2009;32:650-657.

  8. Investigational SGLT2 Inhibitors

  9. Highly specific for the kidney and SGLT2 transporter ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1 Marked reduction in FPG, PPG, and HbA1c in all three species No changes in plasma or urine electrolytes ISIS 388626 – A Specific SGLT2Antisense Oligonucleotide Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR.

  10. Unanswered Questions About SGLT2 Inhibition

  11. SGLT2 Inhibition: Meeting UnmetNeeds in Diabetes Care Corrects a NovelPathophysiologicDefect Multiple Defects in Type 2 Diabetes No Hypoglycemia Adverse Effectsof Therapy ComplementsAction of OtherAntidiabeticAgents PromotesWeight Loss Weight Management Hyperglycemia Type 2Diabetes Improvements inGlucose and WeightSupport OtherCVD Interventions CVD Risk (Lipid andHypertensionControl) Improves GlycemicControl

  12. Conclusions • SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes • Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity • Restores normoglycemia • Improves -cell function and insulin sensitivity

  13. Conclusions • Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans • Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes

  14. Overall Conclusions • Understanding of the pathophysiology of type 2 diabetes is an evolving process • As new concepts emerge, there is potential for new treatment modalities • Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis

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