Diabetes pharmacotherapy(1)

2nd Pharm D - Pharmacotherapeutics I

1. Diabetes- Pharmacotherapy 1 Diabetes

2. Dibetes Mellitus Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia ; is associated with abnormalities in carbohydrate, fat and protein metabolism; and results in chronic complications including microvascular , macrovascular , and neuropathic disorders. DM is the leading cause of blindness in adults aged 20 to 74 years , and the leading contributor to development of end-stage renal disease . Finally, a cardiovascular event is responsible for 75% of deaths in individuals with type 2 DM. 2 Diabetes

3. CLASSIFICATION OF DIABETES TYPE 1 DIABETES TYPE 2 DIABETES GESTATIONAL DIABETES MELLITUS Maturity onset diabetes of youth (MODY) 3 Diabetes

4. TYPE 1 DIABETES This form of diabetes results from autoimmune destruction of the β cells of the pancreas. Markers of immune destruction of the β cell are present at the time of diagnosis in 90% of individuals and include islet cell antibodies , antibodies to glutamic acid decarboxylase , and antibodies to insulin . While this form of diabetes usually occurs in children and adolescents , it can occur at any age. Younger individuals typically have a rapid rate of β-cell destruction and present with ketoacidosis , while adults often maintain sufficient insulin secretion to prevent ketoacidosis for many years, which is often referred to as latent autoimmune diabetes in adults (LADA). 4 Diabetes

5. TYPE 2 DIABETES This form of diabetes is characterized by insulin resistance and at least initially, a relative lack of insulin secretion . Most individuals with type 2 diabetes exhibit abdominal obesity which itself causes insulin resistance . In addition, hypertension , dyslipidemia (high triglyceride levels and low HDL-cholesterol levels), and elevated inhibitor plasminogen activator-1 (PAI-1) levels are often present in these individuals. This clustering of abnormalities is referred to as the “insulin resistance syndrome” or the “ metabolic syndrome .” 5 Diabetes

6. GESTATIONAL DIABETES MELLITUS Gestational diabetes mellitus (GDM) is defined as glucose intolerance which is first recognized during pregnancy. Gestational diabetes complicates about 7% of all pregnancies . Clinical detection is important, as therapy will reduce perinatal morbidity and mortality. 6 Diabetes

7. Maturity onset diabetes of youth (MODY) Maturity onset diabetes of youth (MODY) is characterized by impaired insulin secretion with minimal or no insulin resistance . Patients typically exhibit mild hyperglycemia at an early age . The disease is inherited in an autosomal dominant pattern with at least three different loci identified to date. Genetic inability to convert proinsulin to insulin results in mild hyperglycemia and is inherited in an autosomal dominant pattern. Similarly, the production of mutant insulin molecules has been identified in a few families and results in mild glucose intolerance. 7 Diabetes

8. PATHOGENESIS 8 Diabetes

9. PATHOGENESIS OF TYPE 1 DM Viral infection Molecular mimicry And/or Damage to beta cells Immune response against normal beta cells And/or Immune response against altered beta cells Genetic predisposition Beta cell destruction T T ype 1 DM

10. Environmental factors Insufficient insulin production or insulin resistance Genetic predisposition Persistently high levels of blood glucose T T ype 2 DM Increase in glucose synthesis PATHOGENESIS OF TYPE 2 DM

11. TYPE 1 DIABETES MELLITUS Type 1 DM is characterized by an absolute deficiency of insulin . Most often this is the result of an immune-mediated destruction of pancreatic β cells , but rare unknown or idiopathic processes may contribute. What is evident are four main features : (1) A long preclinical period marked by the presence of immune markers when β-cell destruction is thought to occur; (2) Hyperglycemia when 80% to 90% of β cells are destroyed ; (3) Transient remission (the so-called, “honeymoon” phase); and (4) Established disease with associated risks for complications and death . 11 Diabetes

12. TYPE 1 DIABETES MELLITUS Unknown is whether there is one or more inciting factors (e.g., cow’s milk, or viral, dietary, or other environmental exposure) that initiate the autoimmune process. The autoimmune process is mediated by macrophages and T lymphocytes with circulating auto antibodies to various β-cell antigens . The most commonly detected antibody associated with type 1 DM is the islet cell antibody . 12 Diabetes

13. TYPE 2 DIABETES MELLITUS Normal Insulin Action In the fasting state 75% of total body glucose disposal takes place in non–insulin dependent tissues : the brain and splanchnic tissues (liver and gastrointestinal tissues). In fact, brain glucose uptake occurs at the same rate during fed and fasting periods and is not altered in type 2 diabetes. The remaining 25% of glucose metabolism takes place in muscle, which is dependent on insulin. 13 Diabetes

14. Normal Insulin Action In the fasting state approximately 85% of glucose production is derived from the liver, and the remaining amount is produced by the kidney . In the fed state, carbohydrate ingestion increases the plasma glucose concentration and stimulates insulin release from the pancreatic β cells. The resultant hyperinsulinemia (1) Suppresses hepatic glucose production and (2) Stimulates glucose uptake by peripheral tissues. Diabetes 14

15. Normal Insulin Action Small increments in the plasma insulin concentration exert a potent anti lipolytic effect, leading to a marked reduction in the plasma free fatty acid (FFA) level. The decline in plasma FFA concentration results in increased glucose uptake in muscle and reduces hepatic glucose production. Thus a decrease in the plasma FFA concentration lowers plasma glucose by both decreasing its production and enhancing the uptake in muscle. Type 2 diabetic individuals are characterized by: (1) Defects in insulin secretion; and (2) Insulin resistance involving muscle, liver, and the adipocyte . Insulin resistance is present even in lean type 2 diabetic individuals. Diabetes 15

16. CELLULAR MECHANISMS OF INSULIN RESISTANCE Obesity and Insulin Resistance Visceral adipose tissue represents 20% of fat in men and 6% of fat in women . This fat tissue has been shown to have a higher rate of lipolysis than subcutaneous fat, resulting in an increase in free fatty acid production. These fatty acids are released into the portal circulation and drain into the liver, where they stimulate the production of very-low-density lipoproteins and decrease insulin sensitivity in peripheral tissues . 16 Diabetes

17. ETIOLOGY GENETIC FACTORS ENVIRONMENTAL FACTORS FACTORS WITHIN INDIVIDUAL Genetic mutation of β -c ells Mutation in mitochondrial DNA Genetic defects in insulin action Obesity Lifestyle changes Lack of physical activity TYPE 1 DM Production of autoantibodies to destroy β - cells Deficiency in insulin secretion TYPE 2 DM Insulin resistance

18. SIGNS AND SYMPTOMS Ketoacidosis Ketonuria Glycosuria (presence of glucose in urine) Polydypsia (increased thirst) Polyuria (increased frequency of urination) Polyphagia (extreme hunger) Weight loss Fatigue and headache Blurred vision Frequent infections Ketones are by-products of muscle and fat breakdown when there is no enough insulin

19. The Metabolic Syndrome 19 Diabetes

20. CLINICAL PRESENTATIONS AND DIAGNOSIS 20 Diabetes

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25. The major components of the treatment of diabetes are: Management of DM 25 Diabetes

26. DIET Medical nutrition therapy is recommended for all persons with DM. For individuals with type 1 DM, the focus is on regulating insulin administration with a balanced diet to achieve and maintain a healthy body weight. Patients with type 2 DM often require caloric restriction to promote weight loss. 26 Diabetes

27. Diet Multiple Insulin Injection I N S U L I N I N J E C T I O N 25 years male IBW 60 kgm Carbohydrate (65%) 390 Protein (10%) 60 Fat (25%) 150 Carbohydrate 100 gm Protein (10%) 15 gm Fat (25%) 17 gm Diet Carbohy. Protein Fat _ Arabian bread 30 gm --- --- Cheese 5 gm 10 gm 10 gm Honey 50 gm 2 gm 3 gm Glass of milk 10 gm 5 gm 5 gm_ Total 95 gm 17 gm 18 gm Carbohydrate (65%) 520 Protein (10%) 80 Fat (25%) 200 Carbohydrate 130 gm Protein (10%) 20 gm Fat (25%) 22 gm Diet Carbohy . Protein Fat _ Rice 80 gm --- 6 gm chicken 5 gm 15 gm 12 gm Salad 30 gm 4 gm 4 gm Orange 10 gm --- ---___ Total 125 gm 19 gm 22 gm Carbohydrate (65%) 260 Protein (10%) 40 Fat (25%) 100 Carbohydrate 65 gm Protein (10%) 10 gm Fat (25%) 11 gm Diet Carbohy. Protein Fat _ Tuna sandwich 45 gm 12 gm 10 gm Apple 15 gm --- --- Tea --- --- --- _ Total 95 gm 17 gm 18 gm 60 Kg X 30 kcal = 1800 kcal Breakfast 600 kcal Lunch 800 kcal Dinner 400 kcal The total calories intake depends on patients age and activity but have to related to the desirable body weight. Total daily calories = IBW X Estimated daily energy Add 300 kcal/day during pregnancy. Add 500 kcal/day during lactation. Fibers, sweeteners, vitamins, and minerals. 27 Diabetes

28. Exercise In general, most patients with DM can benefit from increased activity . Aerobic exercise improves insulin resistance and glycemic control in the majority of individuals, and reduces cardiovascular risk factors, contributes to weight loss or maintenance, and improves wellbeing. Start exercise slowly in previously sedentary patients. 28 Diabetes

29. Insulin Insulin is an anabolic and anti catabolic hormone . It plays major roles in protein, carbohydrate, and fat metabolism. Endogenously produced insulin is cleaved from the larger proinsulin peptide in the β cell to the active peptide of insulin and C-peptide , which can be used as a marker for endogenous insulin production. All commercially available insulin preparations contain only the active insulin peptide . 29 Diabetes

30. Structure of Insulin 30 Diabetes

31. Sources of Insulin Beta islet cells of pancreas 30 to 40 units per day Bovine – differs three amino acids from human Porcine - differs one amino acid from human Three forms of insulin EMP – Enzyme modified porcine PRB – Proinsulin recombinant in bacteria PYR – Precursor insulin yeast recombinant 31 Diabetes

32. Endogenous insulin is secreted from cells in the pancreas Islet of Langerhans Alpha cell: 20%, glucagon Beta cell: 75%, insulin Delta cell: 5%, somatostatin (Inhibits the release of GH and TSH) 32 Diabetes

33. 33 -60 60 120 180 240 20.0 18.3 16.6 15.0 13.3 6.1 4.4 140 130 120 110 100 90 120 90 60 30 Glucose (mmol/l) Insulin (mU/l) Glucagon (ng/l) Meal Time (min) Type 2 diabetes Normal subjects Source : M ü ller et al. N Engl J Med. 1970 INSULIN AND GLUCAGON DYNAMICS IN RESPONSE TO MEALS IN NORMAL SUBJECTS AND TYPE 2 DIABETES Diabetes

34. Action of Insulin on Various Tissues Liver Muscle Adipose ↓ glucose production ↑ Glucose transport ↑ glucose transport ↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis ↑ Protein synthesis ↑ protein synthesis 34 Diabetes

35. TYPES OF INSULIN PREPARATIONS Ultra-short-acting Short-acting (Regular) Intermediate-acting Long-acting 35 Diabetes

36. Short-acting (regular) insulins e.g. Humulin R, Novolin R Ultra-Short acting insulins e.g. Lispro , aspart , glulisine Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis Similar to regular insulin but designed to overcome the limitations of regular insulin Physical characteristics Clear solution at neutral pH Clear solution at neutral pH Chemical structure Hexameric analogue Monomeric analogue Route & time of administration S.C. 30 – 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis) S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis) Onset of action 30 – 45 min ( S.C ) 0 – 15 min ( S.C ) Peak serum levels 2 – 4 hr 30 – 90 min Duration of action 6 – 8 hr 3 – 4 hr Usual administration 2 – 3 times/day or more 2 – 3 times / day or more 36 Diabetes

37. 3. Intermediate - acting insulin e.g. isophane (NPH) Turbid suspension Injected S.C.(Only) Onset of action 1 - 2 hr Peak serum level 5 - 7 hr Duration of action 13 - 18 hr Insulin mixtures 75/25 70/30 50/50 ( NPH / Regular ) 37 Diabetes

38. 3. Intermediate - acting insulin (contd.) Lente insulin Turbid suspension Mixture of 30% semilente insulin 70% ultralente insulin Injected S.C. (only) Onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr 38 Diabetes

39. 3. Intermediate - acting insulins (contd.) Lente and NPH insulins Are roughly equivalent in biological effects. They are usually given once or twice a day. N.B: They are not used during emergencies ( e.g. diabetic ketoacidosis ). 39 Diabetes

40. 4. Long acting insulin e.g.Insulin glargine Onset of action 2 hr Absorbed less rapidly than NPH & Lente insulins . Duration of action upto 24 hr Designed to overcome the deficiencies of intermediate acting insulins Advantages over intermediate-acting insulins : Constant circulating insulin over 24hr with no pronounced peak. More safe than NPH & Lente insulins due to reduced risk of hypoglycemia( esp.nocturnal hypoglycemia). Clear solution that does not require resuspention before administration. 40 Diabetes

41. First calculate total daily dose of insulin Body weight in kgs / 2 For example in an 80-kg diabetic requiring 40 units per day, start with: 08:00 a.m. --- 10 units regular insulin s/c ½ hr before breakfast . 02:00 p.m. --- 10 units regular insulin s/c ½ hr before lunch . 08:00 p.m. --- 10 units regular insulin s/c ½ hr before dinner . 11:00 p.m. --- 10 units NPH/ lantus insulin s/c 41 Diabetes

42. Dose adjustment For adjustment of dosage, check fasting blood sugar the next day and adjust the dose of night time NPH Insulin accordingly i.e. keep on increasing the dose of NPH by approximately 2 units daily until you achieve a normal fasting blood glucose level of 80-110 mg/dl. Once the fasting blood glucose has been controlled, check 6-Point blood sugar as follows: Fasting. 2 hours after breakfast. Before lunch (and noon insulin) 2 hours after lunch. Before dinner (AND EVENING INSULIN) 2 hours after dinner 42 Diabetes

43. COMPLICATIONS OF INSULIN THERAPY Severe Hypoglycemia (< 50 mg/dl ) – Life threatening Overdose of insulin Excessive (unusual) physical exercise A meal is missed Weight gain Local or systemic allergic reactions (rare) Lipodystrophy at injection sites Insulin resistance Hypokalemia 43 Diabetes

44. Severe insulin reaction (Hypoglycemic Shock) Diabetic coma (Diabetic Ketoacidosis) Onset Rapid Slow- Over several days Insulin Excess Too little Acidosis & dehydration No Ketoacidosis Signs and symptoms B.P. Normal or elevated Subnormal or in shock Respiration Normal or shallow Deep & air hunger Skin Pale & Sweating Hot & dry CNS Tremors, mental confusion, sometimes convulsions General depression Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc Ketones Normal Elevated 44 Diabetes

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46. Insulin Injection Devices Insulin pens Faster and easier than syringes Improve patient attitude and adherence Have accurate dosing mechanisms Appropriate technique is critical! (air shot and 6 second hold time) 46 Diabetes

47. Oral hypoglycemic drugs OHA 47 Diabetes

48. Sulfonylureas - Pharmacology The primary mechanism of action of sulfonylureas is enhancement of insulin secretion. Sulfonylureas bind to a specific sulfonylurea receptor (SUR) on pancreatic β cells. Binding closes an adenosine triphosphate–dependent K+ channel, leading to decreased potassium influx and subsequent depolarization of the membrane. Voltage-dependent Ca+2 channels open and allow an inward flux of Ca+2. Increases in intracellular Ca+2 cause translocation of secretory granules of insulin to the cell surface and resultant exocytosis of the granule of insulin. Elevated secretion of insulin from the pancreas travels via the portal vein and subsequently suppresses hepatic glucose production. 48 Diabetes

49. Sulfonylureas - Pharmacology 49 Diabetes

50. 50 Sulfonylureas (Oral Hypoglycemic drugs) Tolbutamide Acetohexamide Tolazamide Chlorpropamide Glipizide Glyburide (Glibenclamide) Glimepiride Short acting First generation Intermediate acting Long acting Long acting Short acting Second generation Diabetes

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52. 52 SIDE EFFECTS OF SULPHONYLUREAS 1) Nausea, vomiting, abdominal pain, diarrhea 2) Hypoglycaemia 3) Dilutional hyponatraemia & water intoxication ( Chlorpropamide ) 4) Disulfiram -like reaction with alcohol ( Chlorpropamide ) 5) Weight gain 6) Blood dyscrasias (not common; less than 1% of patients) - Agranulocytosis - Haemolytic anaemia - Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9) Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ?? Diabetes

53. CONTRAINDICATIONS OF SULPHONYLUREAS 1) Type 1 DM ( insulin dependent) 2) Parenchymal disease of the liver or kidney 3) Pregnancy, lactation 4) Major stress 53 Diabetes

54. DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONE PROPRANOLOL ALCOHOL CHLORAMPHENICOL FLUCONAZOLE 54 Diabetes

55. DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL ( chronic pts ) 55 Diabetes

56. Pharmacology Metformin is the only biguanide available. Metformin has been used clinically for 45 years. Metformin enhances insulin sensitivity of both hepatic and peripheral (muscle) tissues. This allows for an increased uptake of glucose into these insulin- sensitive tissues. Metformin has no direct effect on the β cells, though insulin levels are reduced , reflecting increases in insulin sensitivity. 56 Diabetes

57. Actions of Metformin 57 Diabetes

58. METFORMIN Initiate: After meals 250 to 500mg twice or thrice a day Increase gradually if required in 1 or 2 weeks Mild loose stools in 10% initially, which reduces gradually Persistent loose stools in 5% Sustained released forms: more effective- vehicle excreted in stool Advantages: Perpetuates weight loss Can be combined with insulin to reduce insulin requirements 58 Diabetes

59. Diabetes Bio- avalability (% of dose) 50% to 60% C max ( g/ml) 1.0 to 1.5 t max (in hours) 1.9 to 3.0 Plasma ½ life (t ½) 2.0 to 5.4 Renal clearance (ml/min) 400 to 600 Total clearance (ml/min) 1,300 Metformin - Pharmacokinetics 59

60. METFORMIN Side effects: Occurs in 20-25 % of patients. Include.. Diarrhea, abdominal discomfort, nausea, metallic taste and decreased absorption of vitamin B 12 . Contraindications Patients with renal or hepatic impairment. Past history of lactic acidosis. Malabsorption or GI disturbances Low BMI---?less than 21kg/m2…….marked weight loss Organ Failure: Creatinine : >1.4mg/dl Liver failure: Acute/Chronic Cardiac Failure Hypotension/Sepsis Active Vitamin B12 Deficiency GI intolerance 60 Diabetes

61. α - Glucosidase Inhibitors Pharmacology Currently, there are two α- glucosidase inhibitors available in the United States ( acarbose and miglitol ). α- Glucosidase inhibitors competitively inhibit enzymes (maltase, isomaltase , sucrase , and glucoamylase ) in the small intestine, delaying the breakdown of sucrose and complex carbohydrates . They do not cause any malabsorption of these nutrients. The net effect from this action is to reduce the postprandial blood glucose rise . 61 Diabetes

62. α - Glucosidase Inhibitors 62 Diabetes

63. Efficacy Postprandial glucose concentrations are reduced ( 40 to 50 mg/ dL ), while fasting glucose levels are relatively unchanged (∼10% reduction). Efficacy on glycemic control is modest (average reductions in HbA1c of 0.3% to 1%), affecting primarily postprandial glycemic excursions . Thus patients near target HbA1c levels with near normal fasting plasma glucose levels, but high postprandial levels, may be candidates for therapy . α - Glucosidase Inhibitors 63 Diabetes

64. Dosing and Administration. Dosing for both miglitol and acarbose are similar. Initiate with a very low dose ( 25 mg with one meal a day ); increase very gradually (over several months) to a maximum of 50 mg three times a day for patients ≤60 kg or 100 mg three times a day for patients >60 kg . Both α- glucosidase inhibitors should be taken with the first bite of the meal so that drug may be present to inhibit enzyme activity . Only patients consuming a diet high in complex carbohydrates will have significant reductions in glucose levels. α- Glucosidase inhibitors are contraindicated in patients with short-bowel syndrome or inflammatory bowel disease , and neither should be administered in patients with serum creatinine >2 mg/ dL , as this population has not been studied. α - Glucosidase Inhibitors 64 Diabetes

65. α - Glucosidase Inhibitors 65 Diabetes

66. Adverse Effects The gastrointestinal side effects, such as flatulence, bloating, abdominal discomfort, and diarrhea , are very common and greatly limit the use of α- glucosidase inhibitors. Mechanistically, these side effects are caused by distal intestinal degradation of undigested carbohydrate by the microflora , which results in gas (CO2 and methane) production . α- Glucosidase inhibitors should be initiated at a low dose and titrated slowly to reduce gastrointestinal intolerance. α - Glucosidase Inhibitors 66 Diabetes

67. ALPHA-GLUCOSIDASE INHIBITORS Postprandial hyperglycemia Inhibits glycoside hydrolases glucosidase Taken at beginning of a meal Gastrointestinal side effects Common Higher efficacy than Voglibose Postprandial hyperglycemia Inhibit glycoside hydrolases Taken at beginning of a meal Miglitol is systemically absorbed Excreted by the kidneys Voglibose is newest: less side effects economical Acarbose Miglitol & Voglibose Acarbose Miglitol Voglibose 67 Diabetes

68. Pharmacology Though the binding site is adjacent to the binding site of sulfonylureas , nateglinide and repaglinide stimulate insulin secretion from the β cells of the pancreas, similarly to sulfonylureas . Repaglinide , a benzoic acid derivative, and nateglinide , a phenylalanine amino acid derivative, both require the presence of glucose to stimulate insulin secretion. As glucose levels diminish to normal, stimulated insulin secretion diminishes. Short-Acting Insulin Secretagogues 68 Diabetes

69. Efficacy In monotherapy, both significantly reduce postprandial glucose excursions and reduce HbA1c levels . Repaglinide , dosed 4 mg three times a day Nateglinide , dosed 120 mg three times a day The lower efficacy of these agents vs. sulphonylureas should be considered when patients are >1% above their HbA1c goal . These agents can be used to provide increased insulin secretion during meals , when it is needed, in patients close to glycemic goals. Short-Acting Insulin Secretagogues 69 Diabetes

70. Short-Acting Insulin Secretagogues 70 Diabetes

71. Adverse Effects Hypoglycemia is the main side effect noted with both agents. Hypoglycemic risk appears to be less vs. sulfonylurea. In part, this is due to the glucose-sensitive release of insulin . If the glucose concentration is normal, less glucose-stimulated release of insulin will occur. Short-Acting Insulin Secretagogues 71 Diabetes

72. Current Medications for Treatment of Diabetes Sulfonylureas Meglitinides Metformin Thiazolidinediones α - Glucosidase inhibitors Insulin Hypoglycemia, weight gain Hypoglycemia, weight gain GI intolerance Edema, weight gain GI intolerance Hypoglycemia, weight gain Drug Class Side Effects 72 Diabetes

73. Role of Active GLP-1 and GIP in Glucose Homeostasis Glucagon-Like-Peptide ( GLP-1 ) and Glucose - Dependent- Insulotropic -Polypeptide ( GIP ) -are secreted in response to food intake (glucose-dependent mechanism) GLP-1 and GIP - ( ↑ ) stimulate insulin biosynthesis & secretion GLP-1 inhibits - ( ↓) glucagon secretion GLP-1 and GIP - (↓)lower blood sugar level 73 Diabetes

74. 74 ROLE OF INCRETINS IN GLUCOSE HOMEOSTASIS Ingestion of food Beta cells Alpha cells Release of gut hormones : Incretins Pancreas Glucose-dependent  Insulin from beta cells (GLP-1 and GIP) Glucose uptake by muscles Glucose production by liver Blood glucose Glucose dependent  Glucagon from alpha cells (GLP-1) Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Diabetes

75. 75 NEW DRUG TARGET Incretins : Gut hormones that enhance insulin secretion in reponse to food Glucose - dependant insulin secretion Medication affecting the incretin system : GLP1 analogues : Exenatide DPP4 Inhibitors : Sitagliptin Diabetes

76. Incretin mimetics Exenatide The first incretin-related therapy available for patients with type 2 diabetes. Naturally occurring peptide from the saliva of the Gila Monster . Has an approximate 50% amino acid homology with GLP-1. Binds to GLP-1 receptors and behaves as GLP-1. 76 Diabetes

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78. Dipeptidyl peptidase-4 (DPP-4) inhibitor 78 Diabetes

79. During a meal the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent gastric inhibitory polypeptide (GIP) are released from the small intestine into the vasculature. The hormones regulate insulin secretion in a glucose-dependent manner. GLP-1 has many roles in the human body; it stimulates insulin biosynthesis , inhibits glucagon secretion , slows gastric emptying, reduces appetite and stimulates regeneration of islet β-cells. GIP and GLP-1 have extremely short plasma half-lives due to a very rapid inactivation . The enzyme responsible for the metabolism is DPP-4. Inhibition of DPP-4 leads to potentiation of endogenous GIP and GLP-1 and hence improves treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitor 79 Diabetes

80. Dipeptidyl peptidase-4 (DPP-4) inhibitor Drugs belonging to this class are : Sitagliptin (FDA approved 2006, marketed by Merck & Co) Vildagliptin (EU approved 2007, marketed in the EU by Novartis) Saxagliptin (FDA approved in 2009) linagliptin (FDA approved in 2011, marketed by Eli Lilly Co) Dutogliptin (being developed by Phenomix Corporation), Phase III gemigliptin (being developed by LG Life Sciences, Korea) alogliptin ( FDA approved 2013, marketed by Takeda Pharmaceutical Company) 80 Diabetes

81. Adverse effects Nasopharyngitis Headache Nausea Hypersensitivity Hypersensitivity reactions and Pancreatitis 81 Diabetes

82. Thiazolidinediones Pharmacology Thiazolidinediones are also referred to as TZDs or glitazones. Pioglitazone and rosiglitazone are the two recently banned thiazolidinediones for the treatment of type 2 DM. Thiazolidinediones work by binding to the peroxisome proliferator activator receptor-γ (PPAR-γ), which are primarily located on fat cells and vascular cells. 82 Diabetes

83. Thiazolidinediones Efficacy Pioglitazone and rosiglitazone, given for about 6 months, reduce HbA1c values∼1.5% and reduce FPG levels by approximately 60 to 70 mg/ dL at maximal doses. Glycemic -lowering onset is slow, and maximal glycemic -lowering effects may not be seen until 3 to 4 months of therapy . It is important to inform patients of this fact and that they should not stop therapy even if minimal glucose lowering is initially encountered . The efficacy of both drugs is dependent on sufficient insulinemia . If there is insufficient endogenous insulin production (β-cell function) or exogenous insulin delivery via injections, neither will lower glucose concentrations efficiently. 83 Diabetes

84. Thiazolidinediones Adverse Effects Troglitazone, the first thiazolidinedione approved, caused idiosyncratic hepatotoxicity and had 28 deaths from liver failure, which prompted removal from the U.S. market in March 2000. Approximately 1.9% of patients placed on troglitazone had alanine aminotransferase (ALT) levels more than three times the upper limit of normal. The incidence, using these criteria for elevated liver enzymes, with pioglitazone (0.25%) and rosiglitazone (0.2%) has been low. Pioglitazone – Bladder cancer Rosiglitazone – Increased risk of cardiovascular events 84 Diabetes

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86. 86 GLUCOSE ABSORPTION GLUCOSE PRODUCTION Biguanides Thiazolidinediones MUSCLE PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Biguanides) PANCREAS INSULIN Secretion Sulfonylureas Meglitinides Insulin Amylin INTESTINAL HORMONES Incretin ADIPOSE TISSUE LIVER alpha-glucosidase inhibitors INTESTINE THERAPEUTIC OPTIONS : SITES OF ACTION Diabetes

87. ADA/EASD Consensus Algorithm for Management of Diabetes At diagnosis: Lifestyle + Metformin Lifestyle+Metformin + Pioglitazone (No hypoglycemia, edema, CHF, bone loss) Lifestyle+Metformin + Sulfonylurea Lifestyle+Metformin + Intensive insulin Lifestyle+Metformin + Basal Insulin Lifestyle+Metformin + GLP1 (No hypoglycemia, wt loss, Nausea/vomiting) Lifestyle+Metformin + Pioglitazone + Sulfonylurea Lifestyle+Metformin + Basal Insulin Tier 2: less well-validated therapies Tier 1: Well-validated core therapies Step 1 Step 2 Step 3 Amylin agonists, Glinides DPP-4 inhibitors may be appropriate in selected patients *Useful when hypoglycemia is to be avoided 87 Diabetes

88. If glycaemic control is not achieved (HbA1c > 6.5% and/or; FPG > 7.0 mmol /L or; RPG >11.0mmol/L) with lifestyle modification within 1 –3 months, ORAL ANTI-DIABETIC AGENT should be initiated. In the presence of marked hyperglycaemia in newly diagnosed symptomatic type 2 diabetes (HbA1c > 8%, FPG > 11.1 mmol /L, or RPG > 14 mmol /L), oral anti-diabetic agents can be considered at the outset together with lifestyle modification . B.1 Oral Agent Monotherapy 88 Diabetes

89. As first line therapy: Obese type 2 patients, consider use of metformin , acarbose or TZD . Non-obese type 2 patients, consider the use of insulin secretagogues Metformin is the drug of choice in overweight/obese patients . TZDs and acarbose are acceptable alternatives in those who are intolerant to metformin. If monotherapy fails, a combination of TZDs, acarbose and metformin is recommended. If targets are still not achieved, insulin secretagogues may be added B.1 Oral Agent Monotherapy (cont.) 89 Diabetes

90. Combination oral agents is indicated in: Newly diagnosed symptomatic patients with HbA1c >10 Patients who are not reaching targets after 3 months on monotherapy B.2 Combination Oral Agents 90 Diabetes

91. If targets have not been reached after optimal dose of combination therapy for 3 months, consider adding intermediate-acting/long-acting insulin (BIDS). Combination of insulin+ oral anti-diabetic agents (BIDS) has been shown to improve glycaemic control in those not achieving target despite maximal combination oral anti-diabetic agents. Combining insulin and the following oral anti-diabetic agents has been shown to be effective in people with type 2 diabetes: Biguanide (metformin) Insulin secretagogues (sulphonylureas) Insulin sensitizers (TZDs)(the combination of a TZD plus insulin is not an approved indication) α- glucosidase inhibitor (acarbose) Insulin dose can be increased until target FPG is achieved. B.3 Combination Oral Agents and Insulin 91 Diabetes

92. Diabetes Management Algorithm 92 Diabetes

93. 93 Diabetes