糖尿病治療新趨勢

1. 糖尿病治療新趨勢 時間：2009-04-24 (09:00-10:30) 地點：花蓮高中 主講人：三軍總醫院 石光中主任(MD, PhD)

2. MANAGEMENT OF TYPE 2 DIABETES • ORAL ANTIDIABETIC AGENTS (OAD) • INSULIN

3. MANAGEMENT OF TYPE 2 DIABETES • ORAL ANTIDIABETIC AGENTS (OAD) • INSULIN

4. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

5. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

6. 治療糖尿病的藥物（1）

7. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

8. 治療糖尿病的藥物（2）

9. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

10. 治療糖尿病的藥物（3）

11. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

12. 治療糖尿病的藥物（4）

13. Thiazolidinediones Increase glucose uptake in skeletal muscle and decrease lipolysis in adipose tissue Meglitinides Increase insulin secretion from pancreatic -cells Biguanide (metformin) Decreases hepatic glucose production and increases uptake Sulfonylureas Increase insulin secretion from pancreatic -cells -Glucosidase inhibitors Delay intestinal carbohydrate absorption Pharmacologic targets of current drugs used in the treatment of T2DM Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.

14. Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach” Published Conceptual Approach OAD plus multiple daily insulininjections Diet andexercise OAD monotherapy OAD up-titration OAD combination OAD plus basal insulin Mean HbA1cof patients 10 9 HbA1c, % 8 7 6 Time Duration of Diabetes OAD=oral anti-hyperglycaemic drug. Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. 12

15. Major Side Effects of oral anti-diabetes drugs

16. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

17. PRAMLINTIDE • Pramlintide, a synthetic analog of amylin, is an injectable antihyperglycemic that modulates postprandial glucose levels and is approved for preprandial use in individuals with type 1 and type 2 diabetes. • Pramlintidesuppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects. • It is rapidly absorbed after subcutaneous administration; levels peakwithin 20 minutes, and the durationof action is not more than 150 minutes. • Pramlintide should be injected immediately before eating; doses range from 15 mcg to 120 mcg subcutaneously.

18. PRAMLINTIDE • Therapy with this agent should be initiated with the lowest dose andtitrated upward. • Because of the risk of hypoglycemia, concurrent rapid- or short-acting mealtime insulin doses should be decreasedby 50% or more. • Pramlintide should always be injected by itself with a separate syringe; it cannot be mixed with insulin. • The major side effects of pramlintide are hypoglycemiaandgastrointestinal symptoms including nausea, vomiting, and anorexia.

19. ORAL ANTIDIABETIC AGENTS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide(Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

20. The Incretin Approach

21. Glucagon-like peptide-1 (GLP-1): a new approach for type 2 diabetes therapy

22. GLP-1 and GIP Are the Two Major Incretins GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ DiabetesCare 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.

23. 200 400 50 g glucose 150 300 Glucose (mg/dL) Insulin (pmol/L) 100 200 50 100 0 0 -30 0 30 60 90 120 150 180 210 -30 0 30 60 90 120 150 180 210 Time (min) Time (min) Insulin Secretion Increases Dramatically in Response to Oral Glucose Ingestion Oral Glucose Tolerance Test Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.

24. 200 150 100 50 0 -30 0 30 60 90 120 150 180 210 Time (min) Oral IV Proof of a Gastrointestinal ‘Incretin Effect’: Different Responses to Oral vs. IV Glucose OGTT and Matched IV Infusion 400 300 Glucose (mg/dL) Insulin(pmol/L) 200 100 0 -30 0 30 60 90 120 150 180 210 Time (min) Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.

25. Type 2 diabetes patients haveimpaired GLP-1 secretion n =33 n=54 Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3717–3723

26. Glucose (mg/dL) C-peptide (nmol/L) Glucagon (pmol/L) 300 30 3.0 GLP-1 infusion GLP-1 infusion GLP-1 infusion 250 25 2.5 * * 200 * 20 2.0 * * * 150 * 15 1.5 * * * 100 * 10 1.0 * * * * * GLP-1 50 5 0.5 Saline 0 0 0.0 –30 0 30 60 90 120 150 180 210 240 –30 –30 0 0 30 30 60 60 90 90 120 120 150 150 180 180 210 210 240 240 Time (min) Time (min) Time (min) GLP-1 Restores Islet Cell Glucose Sensing in T2DM *P < .05 GLP-1 = glucagon-like peptide–1; T2DM= type 2 diabetes mellitus Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

27. GLP-1 has multiple desirableeffects • Stimulates insulin secretion • Preserves or increases β-cell mass in animal models • Decreases glucagon secretion • Delays gastric emptying • Induces satiety and decreases food intake • Beneficial effects on memory and learning in animal models

28. GLP-1 is Rapidly Degraded by DPP-4 DPP-4  A G F S S V L G A H E T T D Y E S Q A 7 9 K A K F L R I V E W G G 37 T½ = 1–2 minutes *Amino acids shown in gold are homologous with the structure of glucagon.

29. GLP-1 related agents • NN2211(Liraglutide) : long-acting GLP-1 derivative • Exenatide: synthetic exendin 4 compound • DPP-4 inhibitors

30. GLP-1 related agents • NN2211(Liraglutide) : long-acting GLP-1 derivative • Exenatide: synthetic exendin 4 compound • DPP-4 inhibitors

31. NN2211(Liraglutide) is a long-acting GLP-1 analogue 26 34 Knudsen et al. J Med Chem 2000;43:1664–1669

32. GLP-1 related agents • NN2211(Liraglutide) long-acting GLP-1 derivative • Exenatide synthetic exendin 4 compound • DPP-4 inhibitors

33. EXENATIDE • As a synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes. • In clinical studies, exenatide therapy is shown to have multiple actions such as potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emptying and a central loss of appetite. • Exenatide is absorbed equally from arm, abdomen, or thigh injection sites, reaching a peak concentration in approximately 2 hours with a duration of up to 10 hours.

34. EXENATIDE • Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 mcg twice daily, with a maximum dosage of 10 mcg twice daily. • When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. • The major side effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage.

35. GLP-1 related agents • NN2211(Liraglutide) long-acting GLP-1 derivative • Exenatide synthetic exendin 4 compound • DPP-4 inhibitors

36. Pancreatic Islet Cells are Targets for Incretin Hormones β-Cell α-Cell Foodintake Incretin Pancreatic Islet Incretin Response GLP-1=Glucagon-Like Peptide-1 Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940. Wang Q, et al. Diabetologia. 2004;47:478-487.

37. DPP-4 Inhibitors Mixed meal GLP-1 Inactive Intestinal GLP-1 release DPP-IV GLP-1 Active Rapid inactivation (>80% of pool) Plasma GLP-1 Actions Excreted by kidneys Improvement of glucose metabolic profile Mechanism of Action of DPP-4 Inhibitors Primary actions of GLP-1 - Promote insulin secretion (β- cell) - Reduce glucagon secretion/hepatic glucose production (α- cell)

38. ProGIP Capillary GIP [1-42] Synthesis, Secretion, and Metabolism of GLP-1 and GIP L-Cell K-Cell Proglucagon GLP-1 [7-37] Capillary GLP-1 [7-36NH2] GIP [1-42] ACTIVE GLP-1[7-36NH2] ACTIVE DPP-4 DPP-4 • Dipeptidyl peptidase-4 (DPP-4) • Ubiquitous, specific protease • Cleaves N-terminal dipeptide • Inactivates > 50% of GLP-1 in ~ 1 min • > 50% of GIP in ~ 7 min GIP [3-42] INACTIVE GLP-1 [9-36NH2] INACTIVE

39. Endocrine and neural pathways for GLP-1-mediated actions

40. The Need for a More Comprehensive Approach for Treating Type 2 Diabetes

41. ORAL ANTIDIABETIC DRUGS • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives) • Biguanides • Thiazolidinediones • α-glucosidase inhibitors • Pramlintide (Amylin) • Exenatide (GLP-1) • Sitagliptin (DPP-4 inhibitor)

42. ↑insulin and ↓glucagon reduce hepatic glucose output GI tract X DPP-4 Inhibitor DPP-4 Inhibitors Improve Glucose Control by Increasing Incretin Levels in Type 2 Diabetes Ingestion of food • Glucose dependent • Insulin from beta cells(GLP-1 and GIP) Insulinincreases peripheral glucose uptake Pancreas Release of incretins from the gut β-cells Hyperglycemia Improved Physiologic Glucose Control α-cells DPP-4 Enzyme • Glucagon from alpha cells (GLP-1)Glucose dependent Inactive incretins DPP-4 = dipeptidyl peptidase 4 Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

43. SITAGLIPTIN • Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules. • Control of hyperglycemia and reductions in HbA1c were documented at doses of 100 mg orally once daily. • Dosage should be reduced in patients with renal impairment. Hypoglycemic episodes were rare and the drug facilitated weight loss. • Sitagliptin therapy can be combined with metformin, TZDs, or sulfonylureas.

45. Characteristics of an Ideal Therapy • Characteristics of an ideal oral antidiabetic agent • Lowers HbA1cto normal levels • Decreases insulin resistance and hepatic glucose production and increasesor preserves β-cell mass while restoring first-phase insulin response • Does not cause weight gain • Does not increase risk of hypoglycemia • Does not cause edema or congestive heart failure

46. Combination Therapy Offers Advantages Over Monotherapy • Combination therapy may provide more glycemic control than the individual monotherapies • Combination therapy may provide more comprehensive coverage of the key pathophysiologies of type 2 diabetes than monotherapy • An appropriately chosen combination therapy may help more patients achieve their HbA1c goal without increasing side effects1 Adapted from Del Prato Int J Clin Pract 2005;59:1345-1355.

47. MANAGEMENT OF TYPE 2 DIABETES • ORAL ANTIDIABETIC AGENTS (OAD) • INSULIN

48. 胰島素種類（1）

49. 胰島素種類（2）

50. Introduction • Insulin replacement consists of 1. Prandial (bolus) insulin：mimic the response of endogenous insulin to food intake, but onlythe first phase of insulin secretion 2. The basal-insulin：mimics the relatively small but constant release of insulin 3.Correction-dose insulin supplement：addresses pre-meal or between-meal hyperglycemia, independentlyof the prandial insulin.