Update in Diabetes Management Oral Therapies

1. Update in Diabetes Management � Oral Therapies Amy M. Lugo, PharmD, BCPS, CDM Clinical Coordinator Department of Pharmacy National Naval Medical Center Bethesda, Maryland

2. Objectives Review the epidemiology of diabetes Define IFG and IGT Discuss screening for DM Identify the goals of therapy for diabetes Describe the major metabolic defects in Type 2 Diabetes Review the MOA, pertinent kinetics, SE, and CI of each class Discuss new oral therapies available and in the pipeline

3. Epidemiology 21 million people with diabetes in the US 5.2 million people don�t even know they have the disease 41 million people in the US have pre-diabetes

4. �Pre-Diabetes� Patients with IFG and/or IGT are now referred to as having "pre-diabetes" Impaired Fasting Glucose (IFG) = 100 mg/dL to < 126 mg/dL Impaired Glucose Tolerance (IGT) 2-hr PG = 140 and < 200 mg/dL This glucose load is 75gmThis glucose load is 75gm

5. Screening for DM Should be considered by health care providers at 3-year intervals beginning at age 45 Particularly in those with BMI > 25 kg/m2 Testing should be considered at a younger age or be carried out more frequently in individuals who are overweight and have one or more other risk factors

6. Risk Factors for Type 2 DM Age > 45 years Overweight (BMI > 25 kg/m2) Family history of diabetes (i.e., parents or siblings with diabetes) Habitual physical inactivity Race/ethnicity (e.g., African-Americans, Hispanic-Americans, Native Americans, Asian-Americans, and Pacific Islanders) Previously identified IFG or IGT History of GDM or delivery of a baby weighing >9 lbs Hypertension (140/90 mmHg in adults) HDL cholesterol < 35 mg/dl and/or a triglyceride level > 250 mg/dl Polycystic ovary syndrome History of cardiovascular disease

7. Treatment Goals for the �Whole� Patient FPG 70-110 mg/dL HbA1c < 7% AACE < 6.5% BP < 130/80 mmHg LDL < 100 mg/dL HDL > 40 mg/dL (men) HDL > 50 mg/dL (women) TG < 150 mg/dL

8. Therapies for Diabetes Approximately 90% of persons with diabetes require oral medications, insulin injections, or both Monotherapy with any of these agents is associated with a 0.5-2.0% reduction in HbA1C 10% of patients are able to control their DM with dietary modification10% of patients are able to control their DM with dietary modification

9. Major Metabolic Defectsin Type 2 Diabetes Peripheral insulin resistance in muscle and fat Decreased pancreatic insulin secretion Increased hepatic glucose output The endocrine characteristics of type 2 diabetes include peripheral insulin resistance in muscle and fat tissue, decreased pancreatic insulin secretion, and increased hepatic glucose output.The endocrine characteristics of type 2 diabetes include peripheral insulin resistance in muscle and fat tissue, decreased pancreatic insulin secretion, and increased hepatic glucose output.

10. Oral Agents Sulfonylureas Meglitinides Biguanides Thiazolidinediones Alpha-glucosidase inhibitors 5 classes of agents - broken down into insulin sensitizers and insulin secretagogues; alpha-glucosidase inhibitors are the odd ball out5 classes of agents - broken down into insulin sensitizers and insulin secretagogues; alpha-glucosidase inhibitors are the odd ball out

11. Sulfonylureas First Generation Tolbutamide (Orinase�) Acetohexamide (Dymelor�) Tolazamide (Tolinase�) Chlorpropamide (Diabinese�) Second Generation Glyburide (Diabeta�, Micronase�) Micronized glyburide (Glynase�) Glipizide (Glucotrol�, Glucotrol XL�) Glimepiride (Amaryl�) Disadvantages of First Generation: not used much now because of side effects, specifically hypoglycemia and drug interactions **Although, you may see some used because of their inexpensive costDisadvantages of First Generation: not used much now because of side effects, specifically hypoglycemia and drug interactions **Although, you may see some used because of their inexpensive cost

12. Sulfonylureas Insulin secretagogues MOA: Increases insulin release from the pancreas Maximum hypoglycemic effect between agents is similar Initial dosage may need to be adjusted for patients with hepatic or renal dysfunction Kinetics: absorption is rapid, fairly complete, and unaffected by food, except for glipizide, which is most effective when taken on an empty stomach Sulfonylureas decrease HbA1c by ~ 1-2% Glipizide is the only 2nd generation with an active metabolite, important to remember in pts with renal impairmentSulfonylureas decrease HbA1c by ~ 1-2% Glipizide is the only 2nd generation with an active metabolite, important to remember in pts with renal impairment

13. Antihyperglycemic Agents Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting

14. Sulfonylureas Side Effects Hypoglycemia Weight gain GI (nausea, vomiting, heartburn) Skin reactions Hematologic reactions %%%% %%%%

15. Sulfonylureas Contraindications Not recommended during pregnancy, breastfeeding or for children Sulfonylurea hypersensitivity Diabetic ketoacidosis Severe infection Surgery, trauma, or other severe metabolic stressor For pregnancy, breastfeeding, or children - studied but not shown to achieve the tight control necessary in these dz states For DKA, severe infxn, surgery, trauma, severe metabolic stressor - these dz states probably will require insulin to achieve normal sugar Elderly, debilitated, or malnourished patients and patients with adrenal, pituitary, or hepatic insufficiency who are particularly susceptible to the hypoglycemic effects of glucose-lowering agents Treatment failure Primary failure: no response to the initial sulfonylurea therapy (20% of patients) Secondary failure: no or diminished response to therapy following an initial therapeutic response (5-10% of patients) For pregnancy, breastfeeding, or children - studied but not shown to achieve the tight control necessary in these dz states For DKA, severe infxn, surgery, trauma, severe metabolic stressor - these dz states probably will require insulin to achieve normal sugar Elderly, debilitated, or malnourished patients and patients with adrenal, pituitary, or hepatic insufficiency who are particularly susceptible to the hypoglycemic effects of glucose-lowering agents Treatment failure Primary failure: no response to the initial sulfonylurea therapy (20% of patients) Secondary failure: no or diminished response to therapy following an initial therapeutic response (5-10% of patients)

16. Meglitinides Repaglinide (Prandin�) Benzoic acid derivative 0.5mg, 1mg, 2mg tablets Nateglinide (Starlix�) D-Phenylalanine derivative 60mg and 120mg tablets Different based on structure, different side effect profilesDifferent based on structure, different side effect profiles

17. Meglitinides Insulin secretagogues MOA: Increases insulin release from the pancreas Kinetics: Absorption is rapid and complete from the GI tract; slightly decreased by food Rapid hepatic metabolism Meglitinides decrease HbA1c ~ same amount as sulf�s (1-2%) �Add a meal, add a dose, skip a meal, skip a dose�Meglitinides decrease HbA1c ~ same amount as sulf�s (1-2%) �Add a meal, add a dose, skip a meal, skip a dose�

18. Antihyperglycemic Agents Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting

19. Meglitinides Side Effects Repaglinide (Prandin�) GI disturbances URI Arthralgias Headache Hypoglycemia Nateglinide (Starlix�) Mild hypoglycemia Dizziness Weight gain Nateglinide - mild hypoglycemia (2.4%) - dizziness (3.6%) - weight gain <1kg from baseline Repaglinide - GI disturbances in approx 4% of users - URI infection or problems - arthralgia or back pain - headache - hypoglycemia (16-31%) Nateglinide - mild hypoglycemia (2.4%) - dizziness (3.6%) - weight gain <1kg from baseline Repaglinide - GI disturbances in approx 4% of users - URI infection or problems - arthralgia or back pain - headache - hypoglycemia (16-31%)

20. Meglitinides Contraindications Not recommended during pregnancy, breastfeeding, or for children Diabetic ketoacidosis Severe infection Surgery, trauma, or other metabolic stressor Impaired hepatic function For pregnancy, breastfeeding, or children - studied but not shown to achieve the tight control necessary in these dz states For DKA, severe infxn, surgery, trauma, severe metabolic stressor - these dz states probably will require insulin to achieve normal sugarFor pregnancy, breastfeeding, or children - studied but not shown to achieve the tight control necessary in these dz states For DKA, severe infxn, surgery, trauma, severe metabolic stressor - these dz states probably will require insulin to achieve normal sugar

21. Biguanides Agents Metformin (Glucophage�) 500mg, 850mg, and 1000mg tablets Metformin (Glucophage XR�) 500mg extended-release tablets Glyburide/Metformin (Glucovance�) 1.25/250mg, 2.5/500mg, 5/500mg tablets Glipizide/Metformin (MetaglipTM) 2.5/250mg, 2.5/500mg, 5/500mg

22. Metformin (Glucophage�) MOA Primary effect Reduces hepatic glucose production by inhibiting glycogenolysis Increases insulin sensitivity in adipose tissue and skeletal muscle Secondary effect (minor) Decreases intestinal absorption of glucose Kinetics Food decreases the extent of bioavailability and slightly delays the absorption of metformin Major excretion via kidneys Metformin decrease HbA1c ~ 1-2% but less than sulfonylurea therapy Maximum dose: 2550 mg/day or 850mg tid Sometimes Glucophage XR is given in divided doses - bid divided doses for tolerability Metformin decrease HbA1c ~ 1-2% but less than sulfonylurea therapy Maximum dose: 2550 mg/day or 850mg tid Sometimes Glucophage XR is given in divided doses - bid divided doses for tolerability

23. Antihyperglycemic Agents Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting

24. Metformin (Glucophage�) Side Effects Gastrointestinal effects (30% of patients) Diarrhea Abdominal bloating Nausea Cramping Feeling of fullness Miscellaneous: agitation, sweating, headache, and metallic taste

25. Metformin (Glucophage�) Contraindications and Precautions Generally not indicated during pregnancy, breastfeeding, or for children Renal dysfunction: SrCr > 1.5 in males or > 1.4 in females Hepatic dysfunction Acute or chronic lactic acidosis Contraindicated in any situation which would predispose the individual to acute renal dysfunction or tissue hypoperfusion - cardiovascular collapse - AMI - Acute exacerbation of CHF - use of iodinated contrast media - major surgical procedureContraindicated in any situation which would predispose the individual to acute renal dysfunction or tissue hypoperfusion - cardiovascular collapse - AMI - Acute exacerbation of CHF - use of iodinated contrast media - major surgical procedure

26. Alpha-Glucosidase Inhibitors Agents Acarbose (Precose�) 25mg, 50mg, 100mg tablets Miglitol (Glyset�) 25mg, 50mg, 100mg tablets

27. Alpha-Glucosidase Inhibitors Not hypoglycemic agents MOA Inhibit intestinal absorption of starches and sucrose, thereby decreasing CHO-mediated postprandial blood glucose elevation Kinetics Miglitol is almost completely absorbed Acarbose is negligibly absorbed Alpha-glucosidase inhibitors decrease HbA1c ~ 1/2%Alpha-glucosidase inhibitors decrease HbA1c ~ 1/2%

28. Alpha-Glucosidase Inhibitors Side Effects Monotherapy is not associated with hypoglycemia GI effects Diarrhea Abdominal pain Flatulence Increased LFTs Pts taking an alpha gluc inhibitor and a sulfonylurea experiencing hypoglycemia, USE fat-free MILK or GLUCOSE tablets NO SUCROSE or FRUCTOSE, these sugar sources are unsuitable for rapid correction of hypoglycemia GI effects - usually self limiting, transient, and can be minimized by starting with a low dose and slow titration of dosage Increased LFTs - seen in clinical trials where pts were taking acarbose at a dose of 200-300mg tidPts taking an alpha gluc inhibitor and a sulfonylurea experiencing hypoglycemia, USE fat-free MILK or GLUCOSE tablets NO SUCROSE or FRUCTOSE, these sugar sources are unsuitable for rapid correction of hypoglycemia GI effects - usually self limiting, transient, and can be minimized by starting with a low dose and slow titration of dosage Increased LFTs - seen in clinical trials where pts were taking acarbose at a dose of 200-300mg tid

29. Thiazolidinediones Agents Pioglitazone (Actos�) 15mg, 30mg, 45mg tablets Rosiglitazone (Avandia�) 2mg, 4mg, 8mg tablets Rosiglitazone/Glimepiride (Avandaryl�) tablets Troglitazone (Rezulin�) Recalled by FDA Rosiglitazone/Metformin (Avandamet�) 2mg/500mg, 4mg/500mg Avandia max dose: 8mg qd Actos: 45mg qdAvandia max dose: 8mg qd Actos: 45mg qd

30. Thiazolidinediones Not hypoglycemic agents MOA Insulin sensitizers Act at the peroxisome-proliferator-activated receptor-gamma (PPAR-?) to reduce insulin resistance and improve blood glucose levels Kinetics Both well absorbed without regard to meals Extensively bound to albumin (>99%) Both extensively metabolized in the liver Glitazones decrease HbA1c by ~ 1 - 1 1/2 % Therapy initiated at a low dose, and slowly titrated Usual initial dose: rosiglitazone 2mg bid or 4mg qd; pioglitazone 15-30mg qd Response to therapy should not be evaluated for at least 4 weeks after dose increases Glitazones decrease HbA1c by ~ 1 - 1 1/2 % Therapy initiated at a low dose, and slowly titrated Usual initial dose: rosiglitazone 2mg bid or 4mg qd; pioglitazone 15-30mg qd Response to therapy should not be evaluated for at least 4 weeks after dose increases

31. Antihyperglycemic Agents Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting

32. Thiazolidinediones Side Effects Increased LFTs Plasma volume expansion, causing a decrease in Hgb, Hct, and neutrophil counts Weight gain Mild to moderate edema GI discomfort, headache, pharyngitis Glitazones have been shown to decrease BP as well Weight gain - >10% edema ~5% CNS ~6% URI ~ 10% Inc. LFT�s ~ <1%Glitazones have been shown to decrease BP as well Weight gain - >10% edema ~5% CNS ~6% URI ~ 10% Inc. LFT�s ~ <1%

33. Thiazolidinediones Contraindications and Precautions Not indicated during pregnancy, breastfeeding, or for children Use with caution in hepatic dysfunction Use in premenopausal anovulatory women may cause resumption of ovulation Contraindicated in NYHA class III and IV failure Edema may worsen heart failure Combo of glitazone plus insulin may worsen heart failure, not sure why, possibly an insulin osmotic mechanismEdema may worsen heart failure Combo of glitazone plus insulin may worsen heart failure, not sure why, possibly an insulin osmotic mechanism

34. Thiazolidinediones Drug interactions Rosiglitazone is metabolized by CYP2C9 and CYP2C8; usually not clinically significant Pioglitazone is partially metabolized by CYP3A4

35. Oral Agents and Effects on Lipids Sulfonylureas can indirectly affect lipid profile by getting blood sugars under control; indirectly they decrease Trigs and increase HDL; these are indirectly proportional Sulfonylureas can indirectly affect lipid profile by getting blood sugars under control; indirectly they decrease Trigs and increase HDL; these are indirectly proportional

36. New Oral Generics/Combinations Glimepiride 1mg, 2mg, 4mg Rosiglitazone 2mg, 4mg, 8mg Glimepiride/Rosiglitazone (Avandaryl�) 1mg/4mg, 2mg/4mg, 4mg/4mg Pioglitazone 15mg, 30mg, 45mg Pioglitazone/Metformin (Actoplus MetTM) 15mg/500mg, 15mg/850mg

37. Peroxisome Proliferator-Activated Receptors (PPARs) PPAR Receptors Located in the cell nucleus PPAR? (fat) ? FFA, ? insulin sensitivity, ? glucose uptake ? plasma glucose PPAR? (liver, muscle) ? FA oxidation, ? apo CIII, ? apo A1 ? plasma TG, ? HDL-C

38. Muraglitazar (PargluvaTM) Glitazars Dual alpha/gamma PPAR activators PPAR gamma activation Lowers plasma glucose and free fatty acid concentrations PPAR alpha activation Lowers plasma triglyceride concentrations and increases HDL cholesterol

39. Muraglitazar (PargluvaTM) NDA submitted to the FDA in Dec 2004 Concerns FDA requested additional cardiovascular safety information from ongoing trials Considering conducting additional studies or terminating further development Additional studies could take approximately five years to complete 

40. The Incretin System Incretin hormones Glucose-dependent insulinotropic polypeptide (GIP) Glucagon-like peptide-1 (GLP-1) Eating causes secretion of hormones from the GI tract Enzyme Dipeptidyl peptidase-4 (DPP-4) inactivates GLP-1 G-protein-coupled receptors (GPCR�s)

41. The Incretin System Actions of GLP-1 Inhibits glucagon secretion Inhibits gastric emptying Inhibits food ingestion Promotes glucose disposal GLP-1 receptors (GLP-1R) are expressed in islet ? and ? cells and in peripheral tissues

42. Exenatide (ByettaTM) Class Incretin mimetics GLP-1R agonists Indication Adjunctive therapy in patients with Type 2 diabetes uncontrolled on metformin, a sulfonylurea, or their combination Do not need to be on insulin therapy

43. Exenatide (ByettaTM) MOA Mimics the effects of the incretin glucagon-like peptide 1 (GLP-1) Enhances glucose-dependent insulin secretion by pancreatic beta-cells Suppresses inappropriately elevated glucagon secretion Slows gastric emptying Administration SQ injections in pre-filled pens Major adverse effect: nausea GLP-1 is an incretinGLP-1 is an incretin

44. Sitagliptin (Januvia�) Class Dipeptidyl peptidase-4 inhibitor (DPP-4) Indication Treatment of DM2 Monotherapy and as add-on therapy to metformin or thiazolidinediones (TZDs) NOT approved with insulin or sulfonylureas Dose: 100 mg once daily

45. Sitagliptin (Januvia�) MOA Enhances the incretin system by inhibiting DPP-4, which breaks down GLP-1 Helps to regulate glucose by affecting beta cells and alpha cells Adverse effects (= 5%) stuffy or runny nose, sore throat, URI, and headache

46. Advantages Does not cause weight gain Less GI side effects Safety concerns May effect other endogenous hormones No long-term studies published 52 week ongoing study of patients inadequately controlled on metformin monotherapy Pts randomized to either sitagliptin 100mg qd plus metformin or glipizide plus metformin Abstract suggested only HbA1c %0.67 decrease Sitagliptin (Januvia�)

47. Cost Comparison

48. On the Horizon GLP-1R Agonists Liraglutide � Novo Nordisk DPP-4 inhibitors Vildagliptin (Galvus�) � Novartis Saxagliptin Denagliptin

49. Summary of Changesin 2007 Guidelines Revisions Components of the comprehensive diabetes evaluation revised Lowering A1C has been associated with a reduction of microvascular and neuropathic complications of diabetes and possibly macrovascular Medical nutrition therapy extensively revised Nephropathy Reduction of protein intake to 0.8-1.0 g/kg/day may improve measures of renal function

50. Summary of Changesin 2007 Guidelines Revisions Celiac disease Children with positive antibodies should be referred to a gastroenterologist for evaluation Children with confirmed celiac dz should have consultation with a dietitian and placed on a gluten-free diet

51. Summary of Changesin 2007 Guidelines Diabetes care in the hospital Using correction dose or �supplemental� insulin to correct premeal hyperglycemia in addition to scheduled prandial and basal insulin is recommended Preconception care Based on recent research, ACE inhibitors should also be D/C�d before conception

52. Questions