1. Canagliflozin: Background and Evidence Update Inass Shaltout Cairo University
2. Diabetes is a huge and growing problem, and the costs to society are high and escalating Diabetes is a neglected development issue, affecting all countries There are cost-effective solutions to reverse the global diabetes epidemic Diabetes is not only a health issue, its causes are multi-sectoral and it requires a multi-sectoral response
3. 2014 Diabetes is a huge and growing problem 2035
4. and the costs to society are high and escalating Diabetes is a human and economic burden 4.9 million deaths per year 50% of deaths under 60 years of age Intersects with all dimensions of development US$612 billion 11% of worldwide healthcare expenditure
5. For Egypt the IDF updates Egypt ranking to be the 9th in the the number of people with diabetes (20- 79 years), with 7.5 Millions 2014 (Vs. 4.78 Million in 2010) and to be at the 6th position with 13.1 Million in 2030
6. Is there a need for a new antidiabetic ?
7. Two thirds of individuals do not achieve target A1c despite dedicated efforts to achieve glycemic control 1. Liebl A, et al. Diabetologia. 2002;45(7):S23-S28. Europe CODE-2 study - HbA1c goal 6.5%
8. Pathophysiology of Diabetes: The Ominous Octet
9. The Triumvirate Liver hepatic glucose production Muscle and adipose tissue Insulin-dependent glucose uptake by adipose tissue and muscle Pancreas Impaired insulin secretion by pancreatic -cells Ralph DeFronzo: Banting Lecture ADA June 2008.
10. The Septet Liver hepatic glucose production Muscle and adipose tissue Insulin-dependent glucose uptake by adipose tissue and muscle Pancreas Impaired insulin secretion by pancreatic -cells Ralph DeFronzo: Banting Lecture ADA June 2008. Increased Lipolysis Decreased Incretin EffectPancreatic alpha cells Kidney Increased glucose reabsorption
11. The Role of the Kidney in Diabetes
12. The Kidney and Glucose The kidney Plays a significant role in glucose homeostasis under both physiological and pathological conditions Contributes to, and regulates blood glucose levels via three mechanisms: Glucose utilization Gluconeogenesis Glucose reabsorption following glomerular filtration Marsenic, O. (2009) Am J Kidney Dis. 53(5):875-83 Gerich, J.E. (2010) Diabet Med. 27(2):136-42
13. Glomerular Filtration and Glucose Reabsorption Marsenic, O. (2009) Am J Kidney Dis. 53(5):875-83 Gerich, J.E. (2010) Diabet Med. 27(2):136-42 SGLT2 Primarily expressed in kidney Responsible for majority of renal glucose reabsorption SGLT1 Responsible for small portion of renal glucose reabsorption Prominent role in intestinal glucose absorption
14. Major SGLT Glucose Transporters Modified from Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35. Characteristic SGLT1 SGLT2 Major sites of expression Intestine & kidney Kidney Sugar specificity Glucose or galactose Glucose Main role Dietary absorption of glucose and galactose Renal glucose reabsorption Renal glucose reabsorption Renal location Late proximal straight tubule (distal S2/3 segment) Early proximal convoluted tubule (S1/S2 segment) Affinity for glucose (Km) High (0.4 M) Low (2 M) Capacity for glucose transport Low High % Renal glucose reabsorption 10% 90%
15. Glucose Transport in Tubular Epithelial Cells G Glucose Na+ Sodium K Potassium BloodLumen S1 Proximal Tubule G Na+ K GLUT2 ATPase SGLT2 High Capacity Low Affinity BloodLumen S3 Proximal Tubule G 2Na + 2K GLUT1 ATPase SGLT1 Low Capacity High Affinity Adapted from Bakris GL et al. Kidney Int 2009;75:1272-7 Marsenic O. Am J Kidney Dis. 2009;53:875-83
16. Glucose Reabsorption in a Nondiabetic Person (Plasma Glucose 10 and