Treatment Options for Diabetes

1.  Treatment Options for Diabetes Presented By: Daphne E. Smith, Pharm.D., CDE Clinical Assistant Professor UIC College of Pharmacy

2. Overview Review pathophysiology of diabetes Evaluate current diabetes treatment options, including Exenatide (Byetta) Discuss considerations for medication selection for diabetes management

3. Major Pathophysiologic Defects in Type 2 Diabetes1,2 Major Pathophysiologic Defects in Type 2 Diabetes Speaker notes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis. In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1 Most patients with type 2 diabetes have insulin resistance. Normally, pancreatic beta cells increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1 By the time diabetes is diagnosed, beta-cell function has already decreased substantially and continues to decline over time.1 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production, which leads to an increase in blood glucose.1 Likewise, with decreased secretion of insulin, less glucose is taken up by muscle and adipose tissue.2Major Pathophysiologic Defects in Type 2 Diabetes Speaker notes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis. In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.1 Most patients with type 2 diabetes have insulin resistance. Normally, pancreatic beta cells increase insulin secretion to compensate for insulin resistance. However, when beta-cell function is impaired, hyperglycemia develops.1 By the time diabetes is diagnosed, beta-cell function has already decreased substantially and continues to decline over time.1 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production, which leads to an increase in blood glucose.1 Likewise, with decreased secretion of insulin, less glucose is taken up by muscle and adipose tissue.2

4. Current therapies Sulfonylureas Metformin Thiazolidinediones Alpha-Glucosidase Inhibitors Meglitinides DPP-4 Inhibitor Insulin Injectable Inhaled Pramlintide Exenatide (Byetta)

5. Sulfonylureas Stimulates insulin release from pancreatic beta cells Reduces glucose output from liver Improves insulin sensitivity in periphery Available products: Glyburide, Glipizide, Glimepiride (Amaryl)

6. Sulfonylureas Advantages: Rapid, pronounced decrease in glucose Once or twice daily dosing Inexpensive Available in combination with other oral agents Disadvantages: Hypoglycemia Drug Interactions Concern for effectiveness after several years of treatment

7. Metformin Decreases hepatic glucose production Improves insulin sensitivity in periphery Decreases intestinal absorption of glucose

8. Metformin Advantages Considerable A1c reduction Used in combination with orals and insulin Available as extended release tablet and liquid formulation Inexpensive Disadvantages Gastrointestinal adverse effects Avoid in heart failure, renal and hepatic insufficiency Risk for lactic acidosis

9. Thiazolidinediones (TZDs) Insulin sensitizer (improves target cell response to insulin) Does not increase pancreatic insulin secretion Available products: Avandia (rosiglitazone), Actos (pioglitazone)

10. Thiazolidinediones (TZDs) Advantages Use as monotherapy or in combination with other medications No hypoglycemia (monotherapy or with metformin) Once or twice daily dosing Increase in HDL Decrease in Triglycerides Disadvantages Several weeks of therapy before optimal glucose reduction Peripheral edema Weight gain Macular edema Monitoring of liver function Increase in LDL (Avandia) Expensive

11. Alpha-Glucosidase Inhibitors Starch blockers (delay glucose absorption and decrease postprandial glucose) Glyset (Miglitol) and Precose (Acarbose)

12. Alpha-Glucosidase Inhibitors Advantages Reduces postprandial glucose Disadvantages Gastrointestinal adverse effects Dosed with first bite of each meal Pure glucose must be used to treat hypoglycemia Drug Interactions Expensive

13. Meglitinides Stimulates insulin release of pancreatic beta cells Different chemical structure than sulfonylureas Available products: Prandin (repaglinide), Starlix (nateglinide)

14. Meglitinides Advantages Short half life/duration of action Meal time glucose coverage Less hypoglycemia compared to sulfonylureas Disadvantages Short duration of action Dosed with each meal Drug Interactions Expensive

15. DPP-4 Inhibitor Inhibits the dipeptidyl-peptidase 4 enzyme Enhances the incretin hormones GLP-1 (Glucagon-like peptide 1) GIP (glucose-dependent insulinotropic polypeptide)

16. Incretin Hormones

17. DPP-4 Inhibitor Available product: Januvia (Sitagliptin) Once daily dosing Indicated for use with metformin or thiazolidinedione Dosing adjustment for renal impairment Adverse effects: HA, Diarrhea, upper respiratory infection Expensive

18. Insulin Regulates metabolism of carbohydrates, protein and fats Facilitates entry of glucose into cells Increases protein and glycogen synthesis First and Second phases of release

19. Insulin Rapid acting Lispro, Aspart, Glulisine, Inhaled* Short acting Regular Intermediate acting NPH Long acting Glargine Detemir

20. Insulin Advantages Mimics normal pancreatic response to glucose Can achieve normal blood glucose levels Newer delivery options Disadvantages Hypoglycemia Weight gain Patient resistance to injections Frequent blood glucose monitoring Expensive cost of inhaled insulin Spirometry needed for inhaled insulin

21. Pramlintide Amylin analog (co-secreted with insulin from beta cells) Prolongs gastric emptying time Reduces postprandial glucagon secretion Reduces food intake (centrally-mediated appetite suppression Available product: Symlin

22. Pramlintide Advantages: Use in Type 1 and Type 2 diabetes Improves postprandial glucose Disadvantages: Multiple injections Small dosing in insulin syringe Gastrointestinal adverse effects Hypoglycemia Drug Interactions Expensive Cannot be mixed with insulin in same syringe

23. Exenatide (Byetta) Incretin mimetic Increases insulin secretion Increase beta cell growth/replication Slows gastric emptying May decrease food intake

24. Role of Incretins in Glucose Homeostasis Role of Incretins in Glucose Homeostasis Speaker notes After food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).1–3 Under normal circumstances, DPP-4 (dipeptidyl-peptidase 4) rapidly degrades these incretins to their inactive forms after their release into the circulation.1,2 Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.2,3 The subsequent increase in glucose uptake in muscles3,4 and reduced glucose output from the liver2 help maintain glucose homeostasis. Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.2,3 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.2,5Role of Incretins in Glucose Homeostasis Speaker notes After food is ingested, GIP is released from K cells in the proximal gut (duodenum), and GLP-1 is released from L cells in the distal gut (ileum and colon).1–3 Under normal circumstances, DPP-4 (dipeptidyl-peptidase 4) rapidly degrades these incretins to their inactive forms after their release into the circulation.1,2 Actions of GLP-1 and GIP include stimulating insulin response in pancreatic beta cells (GLP-1 and GIP) and suppressing glucagon production (GLP-1) in pancreatic alpha cells when the glucose level is elevated.2,3 The subsequent increase in glucose uptake in muscles3,4 and reduced glucose output from the liver2 help maintain glucose homeostasis. Thus, the incretins GLP-1 and GIP are important glucoregulatory hormones that positively affect glucose homeostasis by physiologically helping to regulate insulin in a glucose-dependent manner.2,3 GLP-1 also helps to regulate glucagon secretion in a glucose-dependent manner.2,5

25. Exenatide (Byetta) Advantages Indicated for use with sulfonylureas, metformin, thiazolidinediones Prefilled, disposable pen (5 mcg, 10 mcg) Additional A1c reduction: 0.5-1% Weight loss Disadvantages Twice daily injection given within 60 minutes of food Short half-life Gastrointestinal adverse effects Expensive Not for use in Type 1 patients

26. Considerations for medication selection Efficacy and Safety Dosing regimen Use with other agents Cost (patient and institution) Primary v.s. Secondary treatment Monitoring Barriers to adherence