New and Emerging Therapies for Type 2 DM

Transcription

1 Dale Clayton MHSc, MD, FRCPC Dalhousie University/Capital Health April 28, 2011 New and Emerging Therapies for Type 2 DM

2 The science of today, is the technology of tomorrow. Edward Teller American Physicist ( )

3 Objectives review insulin glucagon physiology understand incretin based therapies update on research pipeline 3

4 Disclosure Grants/research support: sanofi aventis Speakers bureau/honoraria: Lilly, Novo Nordisk, sanofi, GSK, AstraZeneca, DCPNS, Canadian Agency for Drugs & Technologies in Health, Canadian Diabetes Association Consulting fees: sanofi aventis, Novo Nordisk, Pfizer

5 Outline Incretins DPP IV inhibitors GLP 1 analogues Glucokinase activators Glucagon receptor antagonists SGLT 2 inhibitors

6 Normal Glucose Homeostasis Glucagon (alpha cell) Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

7 Normal Glucose Homeostasis Fasting state Glucagon (alpha cell) Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

8 Normal Glucose Homeostasis Fasting state Glucagon (alpha cell) Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

9 Normal Glucose Homeostasis Fasting state Glucagon (alpha cell) Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

10 Normal Glucose Homeostasis Fasting state Glucagon (alpha cell) Fed state Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

11 Normal Glucose Homeostasis Fasting state Glucagon (alpha cell) Fed state Pancreas Insulin (beta cell) Glucose output Liver Blood glucose Glucose uptake Muscle Adipose tissue Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:

12 Beta Cell Workload and Response Are Balanced in Healthy Subjects Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) Meal Time (min) Healthy Subjects n = 14; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:

13 Beta Cell Workload Outpaces Response in Type 2 Diabetes Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) Meal Time (min) Healthy Subjects Type 2 Diabetes N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:

14 Beta Cell Workload Outpaces Response in Type 2 Diabetes Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) Meal Time (min) Healthy Subjects Type 2 Diabetes N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:

15 The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) 100 C peptide (nmol/l) Time (min) Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

16 The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) 100 C peptide (nmol/l) Time (min) Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

17 The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) 100 C peptide (nmol/l) Time (min) Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

18 The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) C peptide (nmol/l) * * * * Incretin Effect * * * Time (min) Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

19 Incretin Hormones Incretin hormones are produced in GI tract in response to nutrients which in turn stimulate insulin secretion Predominant hormones are GLP 1 and GIP

20 11

21 Mechanism of Action of Incretins Beta cells Alpha cells

22 Mechanism of Action of Incretins Beta cells Alpha cells

23 Mechanism of Action of Incretins Beta cells Alpha cells

24 Mechanism of Action of Incretins Release of active incretins GLP 1 and GIP Beta cells Alpha cells

25 Mechanism of Action of Incretins Release of active incretins GLP 1 and GIP Beta cells Alpha cells

26 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Release of active incretins GLP 1 and GIP Beta cells Alpha cells

27 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1)

28 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1)

29 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Hepatic glucose production

30 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Hepatic glucose production

31 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Hepatic glucose production

32 Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Hepatic glucose production

33 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Hepatic glucose production

34 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Hepatic glucose production

35 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP DPP IV enzyme Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Hepatic glucose production

36 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP DPP IV enzyme Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Inactive GLP 1 Inactive GIP Hepatic glucose production

37 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue Release of active incretins GLP 1 and GIP X DPP IV enzyme Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Inactive GLP 1 Inactive GIP Hepatic glucose production

38 Mechanism of Action of Incretins GLP 1 analogue Glucose dependent Insulin (GLP 1and GIP) Glucose uptake by peripheral tissue DPP IV inhibitor Release of active incretins GLP 1 and GIP X DPP IV enzyme Beta cells Alpha cells Glucosedependent Glucagon (GLP 1) Blood glucose in fasting and postprandial states Inactive GLP 1 Inactive GIP Hepatic glucose production

39 GLP 1 Modulates Numerous Functions in Humans Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

40 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

41 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Beta cells: Enhances glucose dependent insulin secretion Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

42 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose dependent insulin secretion Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

43 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

44 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

45 GLP 1 Modulates Numerous Functions in Humans GLP 1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

46 GLP 1 Agonists versus DPP 4 Inhibitors GLP-1 Agonists DPP-4 Inhibitors Administration Injection Orally available Frequency OD, BID, q-weekly OD GLP-1 concentrations Pharmacological Physiological Mechanisms of action GLP-1 GLP-1 + GIP Insulin secretion Glucagon secretion Gastric emptying Inhibited +/- A1C % % Weight loss Yes No Blood Pressure Yes No Expansion of β-cell mass in Yes Yes preclinical studies Nausea and vomiting Yes No Potential immunogenicity Yes No

47 Incretin therapies available GLP 1 analogues exenatide [Byetta] liraglutide [Victoza] albiglutide [Syncria] (ongoing phase 3 trials) many others coming... DPP IV inhibitors sitagliptin [Januvia] saxagliptin [Onglyza] many others coming...

48 What to do with extra sugar?

49 What to do with extra sugar? Leave it on the plate!

50 What to do with extra sugar? Leave it on the plate! DIET & EXERCISE

51 What to do with extra sugar? Leave it on the plate!

52 What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect

53 Glucokinase Activators Glucokinase the first enzyme to act on glucose once it enters a cell ( locks it in ) Commits the glucose to enter metabolic pathways In beta cell, stimulates insulin secretion

54 Maechler & Wollheim, Nature 2001

55 Maechler & Wollheim, Nature 2001

56 Glucokinase activators Phase 1 & 2 trials 100+ patents for various GK activators 18 pharmaceutical companies pursuing

57 What to do with extra sugar? Leave it on the plate!

58 What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon

59 Glucagon receptor antagonists Failure to suppress glucagon is hallmark of type 2 diabetes Several investigational compounds identified which block the receptor for glucagon reducing hepatic glucose output Phase 1 studies appear promising

60 What to do with extra sugar? Leave it on the plate!

61 What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon

62 What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon

63 What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon Pass it into the urine and flush it!

64 Renal glucose handling SGLT2 mediates 90% of filtered glucose reabsorption in the convoluted segment of the proximal renal tubule SGLT1 mediates 10% of reabsorption in the distal straight segment With euglycemia, all filtered glucose is reabsorbed Glycosuria results when maximal reabsorptive capacity is exceeded (>10mmol/L)

65 SGLT 2 Inhibitors Lowers the renal threshold for glucose excretion Blunts hyperglycemia ( A1c by %) Reduces glucose toxicity (ac & pc)... Improved insulin sensitivity Calorie loss = weight loss (2 3kg over 3 months)

66 SGLT 2 Inhibitors Dapagliflozin (FDA submission Mar 2011) Canagliflozin (phase 2 trials) ISIS SGLT2Rx (antisense technology)

67 Summary Many new drugs with new mechanisms of action: Recent DPP IV inhibitors Newest GLP 1 analogues Future SGLT 2 inhibitors, GK activators, glucagon antagonists Stay tuned!!

68 Questions?