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Program Editors

Program Editors . Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA. Jaime A. Davidson, MD President, Worldwide Initiative

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Program Editors

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  1. Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA Jaime A. Davidson, MD President, Worldwide Initiative for Diabetes Education Clinical Professor of Internal Medicine Division of Endocrinology University of Texas Southwestern Medical School Dallas, Texas, USA

  2. Faculty Professor Rury Holman Professor of Diabetic Medicine Honorary Consultant Physician Diabetes Trials Unit University of Oxford Oxford, United Kingdom Professor Stefano Del Prato Professor of Endocrinology and Metabolism School of Medicine University of Pisa Pisa, Italy Professor Allan Vaag Chief Physician Steno Diabetes Center Gentofte, Denmark

  3. SGLT2 Inhibition A Novel Treatment Strategy for Type 2 Diabetes

  4. The Ominous Octet Impaired Insulin Secretion Islet a-cell Increased Glucagon Secretion Islet b-cell Neurotransmitter Dysfunction DecreasedIncretin Effect Increased Lipolysis Increased Glucose Reabsorption Increased HGP Decreased Glucose Uptake

  5. Renal Glucose Reabsorption in Type 2 Diabetes • Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule • Renal glucose reabsorption is increased in type 2 diabetes • Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43.

  6. Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% 10% No Glucose

  7. Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes SGLT2 GLUT2 AMG Uptake P<0.05 2000 8 P<0.05 1500 6 Normalized Glucose Transporter Levels CPM 1000 4 P<0.05 500 2 0 0 NGT T2DM NGT T2DM NGT T2DM AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

  8. Normal Glucose Homeostasis Pancreas  Fat Liver 5 mmol/L Muscle FastingPlasma Glucose

  9. Pathophysiology of Type 2 Diabetes Impaired Insulin Secretion Insulin Resistance Increased HGP Islet b-cell 10 mmol/L 5 mmol/L FastingPlasma Glucose

  10. Rationale for SGLT2 Inhibitors • Inhibit glucose reabsorption in the renal proximal tubule • Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity • This therapy is simple and nonspecific • Even patients with refractory type 2 diabetes are likely to respond

  11. Pathophysiology of Type 2 Diabetes Impaired Insulin Secretion Insulin Resistance Increased HGP Islet b-cell Glucosuria 10 mmol/L FastingPlasma Glucose

  12. Pathophysiology of Type 2 Diabetes Impaired Insulin Secretion Insulin Resistance Increased HGP 10 mmol/L 5 mmol/L Islet b-cell Glucosuria FastingPlasma Glucose

  13. Renal Handling of Glucose (180 L/day) (900 mg/L)=162 g/day Glucose SGLT2 S1 SGLT1 S3 90% 10% No Glucose

  14. Sodium-Glucose Cotransporters

  15. SGLT2 Mediates GlucoseReabsorption in the Kidney K+ ATPase Na+ SGLT2 GLUT2 Glucose Glucose Lumen Blood S1 Proximal Tubule Na+ Major transporter of glucose in the kidney • Low affinity, high capacity for glucose • Nearly exclusively expressed in the kidney • Responsible for ~90% of renal glucose reabsorption in the proximal tubule Hediger MA, Rhoads DB. Physiol. Rev. 1994;74:993-1026.

  16. Renal Glucose Handling TmG Splay Glucose Reabsorptionand Excretion Reabsorption Excretion Theoretical threshold Actual Threshold 5 10 15 Plasma Glucose Concentration (mmol/L)

  17. Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Design • Phlorizin treatment period: 4-5 weeks • Diet was same for all groups; body weight was similar across groups at end of study Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

  18. Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic Rats † 8 20 * † 15 6 Fasting Glucose (mmol/L) 4 10 Fed Glucose (mmol/L) 2 5 0 0 Control Diabetes Control Diabetes + Phlorizin Diabetes Diabetes + Phlorizin Diabetes +/- Phlorizin Diabetes +/- Phlorizin *P<0.05 vs control and phlorizin. †P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

  19. Insulin-Mediated Glucose Uptake in DiabeticRats Following Phlorizin Treatment 40 35 30 * * 25 20 Diabetes+/- Phlorizin Control Diabetes Diabetes+ Phlorizin Glucose Uptake(mg/kg ∙ min) *P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

  20. Mechanism of Action of SGLT2 Inhibitors Inhibition of SGLT2 Reversal of glucotoxicity Insulin sensitivity in muscle • ↑ GLUT4 translocation • ↑Insulin signaling • Other Insulin sensitivity in liver • ↓ Glucose- 6-phosphatase Gluconeogenesis • Decreased Cori cycle • ↓ PEP carboxykinase -Cell function

  21. Effect of Phlorizin on -Cell Functionin Diabetic Rats: Study Design • Sprague-Dawley male rats weighing 80-100 g • Phlorizin treatment period: 3 weeks • Arginine clamp (2 mM); hyperglycemic clamp (≥5.5 mmol/L) Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

  22. Plasma Insulin Response to Glucose First Phase Second Phase 6 4 Plasma Insulin (ng/mL ∙ min / g Pancreas) * 2 * 0 Control Diabetes Diabetes+ Phlorizin Control Diabetes Diabetes+ Phlorizin *P<0.001 vs control. Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

  23. Plasma Glucagon Concentration in DiabeticDogs Before and After Phlorizin Glucose Infusion Rate (mg/kg • min) 2 6 8 12 16 24 0 Diabetic  Glucagon (pg/mL) -200 Diabetic +Phlorizin -400 Starke A, et al. Proc Natl Acad Sci. 1985;82:1544-1546.

  24. Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition

  25. Familial Renal Glucosuria Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882; Wright EM, et al. J Intern Med. 2007;261:32-43.

  26. Familial Renal Glucosuria Theoretical Normal Observed Type B Glucose Reabsorption Type A 5 10 15 Plasma Glucose Concentration (mmol/L) Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.

  27. Analysis of SGLT2 Gene in Patients With Renal Glucosuria • 23 families analyzed for mutations • In 23 families, 21 different mutations were detected in SGLT2 • Cause of glucosuria in other 2 families remains unknown Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.

  28. Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes SGLT2 GLUT2 AMG Uptake P<0.05 2000 8 P<0.05 1500 6 Normalized Glucose Transporter Levels CPM 1000 4 P<0.05 500 2 0 0 NGT T2DM NGT T2DM NGT T2DM Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

  29. Implications • An adaptive response to conserve glucose (ie, for energy needs) becomes maladaptive in diabetes • Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal reabsorption of glucose

  30. SGLT2 Inhibitors for the Treatment of Type 2 Diabetes

  31. Effect of SGLT2 Inhibition on Renal Glucose Handling TmG Splay Glucose Reabsorptionand Excretion Reabsorption Excretion Theoretical threshold Actual Threshold 5 10 15 Plasma Glucose Concentration (mmol/L)

  32. Effects of SGLT2 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.

  33. Effect SGLT2-I 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.

  34. SGLT-2 Inhibitor GlucosuriaReduces HbA1c: A Dose-Ranging Trial List JF, et al. Diabetes Care. 2009;32:650-657.

  35. 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.

  36. SGLT2-I: Glucosuric and Metabolic Effects List JF, et al. Diabetes Care. 2009;32:650-657.

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

  38. 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.

  39. Unanswered Questions About SGLT2 Inhibition

  40. 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

  41. 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

  42. 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

  43. 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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