SGLT2 inhibitors moa and dka relation in detail

sglt2i inhibitor and dka

1. SGLT2 inhibitors and DKA

2. The Kidneys Play an Important Role in Glucose Control Normal Renal Glucose Physiology 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs about 90% of the glucose SGLT1 reabsorbs about 10% of the glucose Virtually no glucose excreted in urine

3. Renal Glucose Transport

4. Effects of SGLT2 Inhibitors Inhibition of renal tubular Na + - glucose cotransporter reversal of hyperglycemia reversal of “ glucotoxicity Insulin sensitivity in muscle GLUT4 translocation Insulin signaling Insulin sensitivity in liver Glucose-6-phosphatase Gluconeogenesis inhibition Improved beta cell function

5. clinical effects of SGLT 2 inhibitor

6. Perspectives on SGLT2 Inhibition Potential advantages Insulin Independence Weight loss Low risk of hypoglycemia Blood pressure lowering Concerns Polyuria Risk of dehydration and Electrolyte disturbances Bacterial urinary tract infections Fungal genital infections Ketoacidosis

7. DRUGS Canagliflozin Dapagliflozin Empagliflozin Sergliflozin

8. Euglycemic DKA Euglycemic or normoglycemic DKA, was originally defined as DKA with a BG level of <300 mg/ dL , but it is now recognized as that in the presence of a BG concentration of <200 mg/ dL . May be missed as it presents with mild to moderate hyperglycemia.

9. A Janssen article  ( Eroundu et. Al.) demonstrating a low (but not zero) risk for DKA in a clinical-trial program of canagliflozin . 15 cases in > 40,000 type 2 DM patients  A case series report  of 13 episodes of euglycemic DKA in nine patients, seven with type 1 diabetes and two with type 2 diabetes, who developed the condition postoperatively. European Medicines Agency  initiated a review and identified 101 cases worldwide associated with type 2 diabetes. Incidence is less than 0.1 % Slightly higher with Canagliflozin

10. Full-dose SGLT2 inhibition induces a rapid increase in urinary glucose excretion, ranging 50–100 g/day. As glucose is the chief stimulus for insulin release under all circumstances, plasma insulin levels also fall. Plasma glucagon concentrations increased Diminished paracrine inhibition by insulin Decreased SGLT2-mediated glucose transport into a-cells

11. This hormonal shift favors gluconeogenesis in the liver leading to augmented endogenous glucose production both in the fasting state and during the meal.

12. Precipitating factors Withdrawal of insulin or insulin secretagogues Low-carbohydrate diet Decreased fluid intake Starvation Intercurrent illness History of alcohol intake.

13. This potential complication related to SGLT2 inhibition is predictable, detectable, and preventable. Initial symptoms – malaise, mild nausea with or without vomiting. Patients should temporarily stop the SGLT2 inhibitor . Take supplemental boluses of rapid insulin along with liquids and carbohydrates.

14. Thank you