Dale Clayton MHSc, MD, FRCPC Dalhousie University/Capital Health April 28, 2011 New and Emerging Therapies for Type 2 DM
The science of today, is the technology of tomorrow. Edward Teller American Physicist (1908 2003)
Objectives review insulin glucagon physiology understand incretin based therapies update on research pipeline 3
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
Outline Incretins DPP IV inhibitors GLP 1 analogues Glucokinase activators Glucagon receptor antagonists SGLT 2 inhibitors
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
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;18:247 254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145 168.
Beta Cell Workload and Response Are Balanced in Healthy Subjects Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) 120 60 0 140 120 100 360 300 240 140 80 Meal 60 0 60 120 180 240 Time (min) Healthy Subjects n = 14; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:109 115
Beta Cell Workload Outpaces Response in Type 2 Diabetes Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) 120 60 0 140 120 100 360 300 240 140 80 Meal 60 0 60 120 180 240 Time (min) Healthy Subjects Type 2 Diabetes N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:109 115
Beta Cell Workload Outpaces Response in Type 2 Diabetes Carbohydrate Meal Insulin (µu/ml) Glucagon (pg/ml) Glucose (mg/dl) 120 60 0 140 120 100 360 300 240 140 80 Meal 60 0 60 120 180 240 Time (min) Healthy Subjects Type 2 Diabetes N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 1970;283:109 115
The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose 200 2.0 Plasma Glucose (mg/dl) 100 C peptide (nmol/l) 1.5 1.0 0.5 0 0.0 0 60 120 180 Time (min) 0 60 120 180 Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492 498
The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose 200 2.0 Plasma Glucose (mg/dl) 100 C peptide (nmol/l) 1.5 1.0 0.5 0 0.0 0 60 120 180 Time (min) 0 60 120 180 Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492 498
The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose 200 2.0 Plasma Glucose (mg/dl) 100 C peptide (nmol/l) 1.5 1.0 0.5 0 0.0 0 60 120 180 Time (min) 0 60 120 180 Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492 498
The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) 200 100 C peptide (nmol/l) 2.0 1.5 1.0 0.5 * * * * Incretin Effect * * * 0 0.0 0 60 120 180 Time (min) 0 60 120 180 Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492 498
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
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Mechanism of Action of Incretins Beta cells Alpha cells
Mechanism of Action of Incretins Beta cells Alpha cells
Mechanism of Action of Incretins Beta cells Alpha cells
Mechanism of Action of Incretins Release of active incretins GLP 1 and GIP Beta cells Alpha cells
Mechanism of Action of Incretins Release of active incretins GLP 1 and GIP Beta cells Alpha cells
Mechanism of Action of Incretins Glucose dependent Insulin (GLP 1and GIP) Release of active incretins GLP 1 and GIP Beta cells Alpha cells
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)
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)
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
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
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
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
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
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
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
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
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
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
GLP 1 Modulates Numerous Functions in Humans Data from Flint A, et al. J Clin Invest. 1998;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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;101:515 520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413 422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546 1553; Data from Drucker DJ. Diabetes. 1998;47:159 169
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 0.8-1.5% 0.5-0.8% 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
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...
What to do with extra sugar?
What to do with extra sugar? Leave it on the plate!
What to do with extra sugar? Leave it on the plate! DIET & EXERCISE
What to do with extra sugar? Leave it on the plate!
What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect
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
Maechler & Wollheim, Nature 2001
Maechler & Wollheim, Nature 2001
Glucokinase activators Phase 1 & 2 trials 100+ patents for various GK activators 18 pharmaceutical companies pursuing
What to do with extra sugar? Leave it on the plate!
What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon
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
What to do with extra sugar? Leave it on the plate!
What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon
What to do with extra sugar? Leave it on the plate! Move it from blood into cells potentiate insulin effect turn off glucagon
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!
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)
SGLT 2 Inhibitors Lowers the renal threshold for glucose excretion Blunts hyperglycemia ( A1c by 0.5 0.9%) Reduces glucose toxicity (ac & pc)... Improved insulin sensitivity Calorie loss = weight loss (2 3kg over 3 months)
SGLT 2 Inhibitors Dapagliflozin (FDA submission Mar 2011) Canagliflozin (phase 2 trials) ISIS SGLT2Rx (antisense technology)
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!!
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