Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control. Conducted during the 41 st ASHP Midyear Clinical Meeting Anaheim, California

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1 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control Conducted during the 41 st ASHP Midyear Clinical Meeting Anaheim, California

2 CONTINUING EDUCATION ACCREDITATION The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1 hour (.1 CEU) of continuing education credit (program number H1). After successful completion of the CE post test, participants can print the CE statement online at

3 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control PROGRAM AGENDA Introductory Remarks Philip T. Rodgers, Pharm.D., BCPS, CDE, CPP, Program Moderator Overview of New Options for Glycemic Control: Focus on the Incretin Concept Douglas F. Covey, Pharm.D., FCCP, MHA Clinical Experiences and Potential of New Agents for Improving Outcomes in Type 2 Diabetes Philip T. Rodgers, Pharm.D., BCPS, CDE, CPP PROGRAM FACULTY Philip T. Rodgers, Pharm.D., BCPS, CDE, CPP Clinical Pharmacist Duke University Hospital Clinical Associate Professor University of North Carolina School of Pharmacy Chapel Hill, North Carolina Douglas F. Covey, Pharm.D., FCCP, MHA Clinical Pharmacy Specialist and Associate Professor James A. Haley Veterans Hospital and Clinics University of Florida Tampa, Florida

4 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control PROGRAM DESCRIPTION Until recently, oral antidiabetic therapy for type 2 diabetes primarily has involved the use of sulfonylureas, metformin, thiazolidinediones, insulin, or a combination of these agents. Avoiding postprandial hyperglycemia and achieving and maintaining glycemic control using these agents remain elusive goals for many patients. Clinical research has led to the development of new drug therapies with the potential to improve the clinical management of type 2 diabetes. The endogenous gastrointestinal hormone glucagon-like peptide 1 (an incretin known as GLP-1) has been a focus for drug development research because it enhances glucose-dependent insulin secretion by pancreatic beta cells, which helps correct the diminished postprandial insulin secretion associated with the disease. GLP-1 is highly susceptible to degradation by dipeptidyl peptidase IV (DPP IV), so incretin mimetics that are resistant to degradation and DPP IV inhibitors have been developed. Exenatide, the first incretin mimetic approved by the Food and Drug Administration (in 25), improves glycemic control and may provide other benefits in patients with type 2 diabetes. Liraglutide is another incretin mimetic in development. Exenatide and liraglutide are resistant to degradation by DPP IV, but they must be given by injection. Sitagliptin and vildagliptin are oral DPP-IV inhibitors with effects on blood glucose similar to those of exenatide. This program will describe the physiologic effects of GLP-1 as they relate to the pathophysiologic defects in patients with type 2 diabetes mellitus. The mechanisms of action, routes of administration, efficacy, and safety of new drug therapies for patients with type 2 diabetes will be discussed in the context of other antidiabetic therapies. Clinical experiences will be presented to educate participants on emerging therapeutic options for patients with uncontrolled type 2 diabetes. LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: Identify the roles and limitations of sulfonylureas, metformin, thiazolidinediones, and insulin in the management of type 2 diabetes. Describe the physiologic effects of GLP-1 as they relate to the pathophysiologic defects in patients with type 2 diabetes mellitus. Discuss the mechanisms of action, routes of administration, efficacy, and safety of new drug therapies for type 2 diabetes, including incretin mimetics and DPP IV inhibitors. Describe the potential impact of incretin agents in the management of uncontrolled type 2 diabetes.

5 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control 41st ASHP Midyear Clinical Meeting Anaheim ~ Orange County, California Learning Objectives Identify the roles and limitations of sulfonylureas, metformin, thiazolidinediones, and insulin in the management of type 2 diabetes. Describe the physiologic effects of GLP-1 as they relate to the pathophysiologic defects in patients with type 2 diabetes mellitus. Discuss the mechanisms of action, routes of administration, efficacy, and safety of new drug therapies for type 2 diabetes, including incretin mimetics and DPP- 4 inhibitors. Describe the potential impact of incretin agents in the management of uncontrolled type 2 diabetes. Diabetes Mellitus Affects 2.8 million people in the U.S. Disproportionately greater numbers of Black, Latino, and Native Americans 6 th leading cause of death 65% of deaths due to heart disease and stroke Leading cause of blindness, renal failure, and nontraumatic lower-extremity amputations Cost: $132,,, annually 13% due directly to drug costs accessed 9/18/6

6 Diabetes Control ADA 26 individual goal A 1c as close to 6% as possible without significant hypoglycemia Pre-1995 Diabetes Pharmacotherapy 1 oral drug class (7 sulfonylureas) 4 insulins and 2 premixed insulin products (human, beef, pork) 26 Diabetes Pharmacotherapy 6 oral drug classes 15 drugs and 6 combination products 2 non-insulin injectables 8 insulins and 5 premixed insulin products (human only) Have we improved control in the diabetes population?? Diabetes Care 26;29 (Suppl 1): S4-42. Diabetes Control: 1988 to s 2 s Mean A 1C 7.8%±.1 7.7%±.1 Percentage of diabetic patients with A 1C <7% 41% 59% 42% 58% Controlled Uncontrolled Percentage of diabetic patients with A 1C <8% 58% 42% 63% 37% ADA/EASD Management of Hyperglycemia in Type 2 Diabetes Diagnosis Lifestyle Intervention + Metformin No HbA1C 7% Yes Add Basal Insulin - Most effective Add Sulfonylurea - Least expensive Add Glitazone - No hypoglycemia No HbA1C 7% Yes No HbA1C 7% Yes No HbA1C 7% Yes Intensify insulin Add glitazone Add basal insulin Add sulfonylurea No HbA1C 7% Yes No HbA1C 7% Yes Diabetes Care 26;29: Intensive insulin + metformin +/- glitazone Add basal or intensify insulin

7 Traditional Drugs Class Biguanide Sulfonylureas Thiazolidinediones Nonsulfonylurea Secretagogues (aka, Meglitinides) Agents Metformin Glyburide, glipizide, glimeperide; 1 st generation drugs Pioglitazone Rosiglitazone Repaglinide Nateglinide Main Advantages A 1C 1.5-2%, weight neutral, evidencebased A 1C 1.5-2%, inexpensive, experience, QD A 1C 1-1.5%, increased sensitivity, HDL, ± TG, CV events Less hypoglycemia vs SU, minimal weight, targeted PPPG effect Main Disadvantages GI side effects, Renal/CHF precaution Hypoglycemia, weight gain, drug interactions Weight gain, edema, CHF precautions, LDL effect, cost A 1C <1%, QAC dosing, cost, no outcomes evidence Alpha-glucosidase inhibitors Acarbose Miglitol No hypoglycemia, no weight gain, targeted PPPG effect A 1C <1%, GI side effects, QAC dosing, hypoglycemia mgt, hepatic effects, cost

8 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control DOUGLAS F. COVEY, PHARM.D., FCCP, MHA Clinical Pharmacy Specialist and Associate Professor James A. Haley Veterans Hospital and Clinics University of Florida Tampa, Florida Douglas F. Covey is Clinical Pharmacy Specialist for Ambulatory Care at the James A. Haley Veterans Hospital in Tampa, Florida. In addition, Dr. Covey is Associate Professor of Pharmacy Practice for the University of Florida s College of Pharmacy and Regional Director of the Working Professional Doctor of Pharmacy Program. Dr. Covey received his Pharm.D. from the University of Florida and a Masters in Healthcare Administration from the University of South Florida. He serves as director of a primary-care residency and participates routinely on accreditation site surveys for the American Society of Health-System Pharmacists (ASHP). Dr. Covey s areas of interest are diabetes and cardiovascular pharmacotherapy, patient education, and professional training. For over 15 years Dr. Covey has had direct patient care responsibilities in diabetes and anticoagulation clinics, and previous responsibilities for a hypertension and lipid clinic. He is a member of the Patient Health Education and Wellness Committee at the James A. Haley Veterans Hospital. Dr. Covey has served as Chair of the American College of Clinical Pharmacy (ACCP) Ambulatory Care Practice and Research Network, Chair of the ACCP Leadership Task Force, and was recently a board member for the Florida Society of Health-System Pharmacists. He has written numerous scientific articles and several book chapters. Most recently Dr. Covey has assisted with the development of ASHP s lipid traineeship program, and authored ASHP residency standards for ambulatory care.

9 Overview of New Options for Glycemic Control with a Focus on the Incretin Concept Douglas F. Covey, Pharm.D., FCCP, MHA Clinical Pharmacy Specialist and Associate Professor Tampa Veterans Hospital and Clinics University of Florida Overview Pathophysiology Core defects Beta-cell workload and beta-cell response The paracrine effect: Amylin and Insulin Pramlintide FDA-approved synthetic amylin analog The incretin concept and GLP-1 Incretin mimetics: GLP-1 Agonists/Analogues Exenatide FDA-approved (agonist) Liraglutide phase 3 trials (analogue) Incretin Enhancers: DPP- 4 Inhibitors Sitagliptin FDA-approved 1/17/6 Vildagliptin awaiting FDA approval decision Saxagliptin phase 3 trials Role of Selected Organs in Normal Glucose Homeostasis Plasma Glucose glucose production Liver Insulin-independent glucose uptake Brain Glucagon α Insulin β Pancreas Insulin Muscle Insulin-dependent glucose uptake Adapted with permission from Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25: Fat

10 Insulin and Glucagon Regulate Normal Glucose Homeostasis Fasting state Glucagon (α-cell) Fed state Pancreas Insulin (β-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. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25: Beta-Cell Workload and Response Are Balanced in Healthy Subjects Insulin (µu/ml) Glucagon (pg/ml) Carbohydrate Meal 36 3 Glucose (mg/dl) Time (min) n = 14; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 197;283: Meal Healthy Subjects Beta-Cell Workload Outpaces Response in Type 2 Diabetes Insulin (µu/ml) Glucagon (pg/ml) Carbohydrate Meal Healthy Subjects Type 2 Diabetes Glucose (mg/dl) N = 26; Mean (SE) Data from Mϋller WA, et al. N Engl J Med. 197;283: Meal Time (min)

11 β-cell Function Declines After Diagnosis, Insulin Sensitivity Remains Relatively Stable 8 β-cell Function 6 Insulin Sensitivity HOMA % B HOMA % S Years From Diagnosis Years From Diagnosis HOMA=Homeostasis Model Assessment; HOMA % B=β-cell function; HOMA % S=Insulin sensitivity. N= year follow-up of the Belfast Diet Study. Data from Group 2 shown: newly diagnosed T2DM subjects who required additional treatment (due to secondary failure to diet therapy) at 5 7 years. Reproduced with permission from Levy J et al. Diabet Med. 1998;15: Blackwell Publishing. Development and Progression of Type 2 Diabetes* NGT Insulin IGT/ IFG Type 2 Diabetes Resistance Glucose Postprandial glucose Fasting glucose Relative Activity Insulin level Insulin resistance hepatic and peripheral Beta-cell function Years from Diabetes Diagnosis *Conceptual representation. NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 26.; and Ramlo-Halsted et al. Prim Care. 1999;26: Islet Cell Dysfunction and Insulin Resistance 1,2 Glucagon (α-cell) Pancreas * Reduced effect of insulin indicating insulin resistance Insulin (β-cell) * Glucose output Glucose uptake Hyperglycemia Liver Muscle Adipose tissue 1. Del Prato S, Marchetti P. Horm Metab Res. 24;36: Porte D Jr, Kahn SE. Clin Invest Med. 1995;18: Adapted with permission from Kahn CR, Saltiel AR. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25:

12 Outline Pathophysiology Core defects Beta-cell workload and beta-cell response The paracrine effect: Amylin and Insulin Pramlintide FDA-approved synthetic amylin analog The incretin concept and GLP-1 Incretin mimetics: GLP-1 Agonists/Analogues Exenatide FDA-approved (agonist) Liraglutide phase 3 trials (analogue) Incretin Enhancers: DPP-4 Inhibitors Sitagliptin FDA-approved 1/17/6 Vildagliptin awaiting FDA approval decision Saxagliptin phase 3 trials The Paracrine Effect: Amylin and Insulin APPEARANCE AND DISAPPEARANCE Liver Brain Food Intake Gastric Emptying Stomach Insulin helps regulate glucose disappearance Amylin Rate of Postprandial glucose Glucagon appearance Plasma Glucose Insulin Rate of glucose disappearance Glucose Disposal Amylin helps regulate glucose appearance Pancreas Tissues Model derived from animal studies Adapted from Edelman S, et al. Diabetes Technol Ther 22; 4: Amylin Is Co-Secreted With Insulin Meal Meal Meal Insulin Amylin 3 Plasma Amylin (pm) Plasma Insulin (pm) 5 7 am 12 noon 5 pm Midnight Time (24 h) Healthy adults; n = 6 Data from Kruger D, et al. Diabetes Educ 1999; 25:

13 Amylin Is Deficient in Diabetes 2 Meal Plasma Amylin (pm) Without Diabetes Late Stage Type 2 Type Time After Sustacal Meal (min) Without diabetes; n = 27 Late-stage type 2; n = 12 Type 1; n = 19 Data from Kruger D, et al. Diabetes Educ 1999; 25: Pramlintide Information Symlin by Amylin Pharmaceuticals Indications Type 1 or Type 2 (insulin requiring) SQ injection with every meal Use insulin syringe Do not mix with insulin Dosing: micrograms 3 mcg = 5 units Type 2 DM: 6 mcg QAC, may increase to 12 mcg QAC after 7 days Type 1 DM: 15 mcg QAC, may increase by 15 mcg every 7 days to 6 mcg QAC Decrease prandial insulin dose by 5% at initiation SYMLIN Prescribing Information, 25. Pramlintide Summary Description Synthetic analog of human amylin Naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells Helps regulate the rate of glucose appearance Antihyperglycemic drug Improves glucose control in postprandial period Over 53 subjects in clinical studies leading to approval Safety Pramlintide acetate is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia (Boxed Warning) > Particularly in patients with type 1 Appropriate patient selection, careful patient instruction, and insulin dose adjustments help reduce this risk Nausea is mostly mild to moderate and decreases over time > Less frequent in patients with type 2 Clinical Effect Reduces postprandial hyperglycemia and glucose fluctuations Improves glycemic control with mean reduction of weight Pramlintide Acetate Prescribing Information, 25.

14 Outline Pathophysiology Core defects Beta-cell workload and beta-cell response The paracrine effect: Amylin and Insulin Pramlintide FDA-approved synthetic amylin analog The incretin concept and GLP-1 Incretin mimetics: GLP-1 Agonists/Analogues Exenatide FDA-approved (agonist) Liraglutide phase 3 trials (analogue) Incretin Enhancers: DPP-4 Inhibitors Sitagliptin FDA-approved 1/17/6 Vildagliptin awaiting FDA approval decision Saxagliptin phase 3 trials The Incretin Effect in Healthy Subjects Oral Glucose Intravenous (IV) Glucose Plasma Glucose (mg/dl) 2 1 C-peptide (nmol/l) * * * * Incretin Effect * * * Time (min) N = 6; Mean (SE); *P.5 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63: Time (min) Modulation of Insulin and Glucagon Levels: The Enteroinsular Axis Hormonal signals Glucagon (GLP-1) Neural signals alpha cells beta cells Pancreas Gut Nutrient signals Insulin (GLP-1,GIP) Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16: Copyright 1979 Springer-Verlag. Drucker DJ. Diabetes Care. 23;26: Kieffer T et al. Endocr Rev. 1999;2: Nauck MA et al. Diabetologia. 1993;36:

15 Selected Peptide Hormones of the Gastrointestinal (GI) Tract Non-Incretin Hormones Gastrin Cholecystokinin Secretin Ghrelin Motilin Somatostatin Neurotensin PYY (peptide YY) GLP-2 (glucagon-like peptide 2) Incretin Hormones* GIP (glucose-dependent insulinotropic polypeptide) GLP-1 (glucagon-like peptide 1) * Gut hormones that enhance insulin secretion in response to food Boushey RP et al. In: Larsen PR et al. Williams Textbook of Endocrinology. 1th ed. WB Saunders Co. 23. GLP-1 and GIP Are Incretin Hormones GLP-1 Is released from L cells in ileum and colon 1,2 Stimulates insulin response from beta cells in a glucose-dependent manner 1 Inhibits gastric emptying 1,2 Reduces food intake and body weight 2 Inhibits glucagon secretion from alpha cells in a glucose-dependent manner 1 GIP Is released from K cells in duodenum 1,2 Stimulates insulin response from beta cells in a glucose-dependent manner 1 Has minimal effects on gastric emptying 2 Has no significant effects on satiety or body weight 2 Does not appear to inhibit glucagon secretion from alpha cells 1,2 1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 24;18: Drucker DJ. Diabetes Care. 23;26: Multihormonal Regulation of Glucose APPEARANCE AND DISAPPEARANCE Liver Brain Food Intake Gastric Emptying Stomach Insulin helps regulate glucose disappearance Amylin Postprandial Glucagon Insulin Rate of glucose appearance Plasma Glucose Rate of glucose disappearance Glucose Disposal Gut Amylin helps regulate glucose appearance Pancreas Tissues Model derived from animal studies Adapted from Edelman S, et al. Diabetes Technol Ther 22; 4: GLP-1 GLP-1 increases insulin and amylin secretion when glucose concentrations rise

16 GLP-1 and GIP Modulation of Insulin and Glucagon Glucagon (α-cell) Pancreas GLP-1 Glucose output Liver Insulin (β-cell) GIP 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. Joslin s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 25: GLP-1 Effects Are Glucose Dependent in Type 2 Diabetes Placebo GLP-1 Glucose (mg/dl) PBO GLP-1 * * * * * * * Time (min) Insulin (pmol/l) PBO GLP-1 * * * * * * * * Time (min) Glucagon (pmol/l) 2 1 PBO GLP-1 * * * * Time (min) N = 1; Mean (SE); *P<.5 Data from Nauck MA, et al. Diabetologia. 1993;36: IR Insulin, mu/l The Incretin Effect in Subjects Without and With Type 2 Diabetes Control Subjects (n=8) Incretin Effect nmol / L IR Insulin, mu/l Patients With Type 2 Diabetes (n=14).6 The incretin effect is diminished.5 in type 2 diabetes nmol/l 6 12 Time, min Time, min 18 Oral glucose load Intravenous (IV) glucose infusion Adapted from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag. Permission pending.

17 Decreased Postprandial Levels of GLP-1 in Type 2 Diabetes GLP-1, pmol/l * * * * * * * Type 2 diabetes, n=54 IGT, n=15 NGT, n=33 (1-15) Meal Started Meal Finished Time after start of meal, minutes *P<.5, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab. 21;86: Copyright 21, The Endocrine Society. Incretin Flow and DPP- 4 Degradation Pancreas 2,3 Ingestion of food GI tract Release of gut hormones Incretins 1,2 Active GLP-1 & GIP DPP- 4 Enzyme β-cells α-cells Glucose-dependent insulin from beta cells (GLP-1 and GIP) Glucagon from alpha cells (GLP-1) 2,4 Glucose uptake by muscles Glucose production by liver Blood glucose Inactive GLP-1 and GIP Glucose dependent 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;2: Ahrén B. Curr Diab Rep. 23;2: Drucker DJ. Diabetes Care. 23;26: Holst JJ. Diabetes Metab Res Rev. 22;18: GLP-1 and GIP Are Degraded by the DPP- 4 Enzyme Meal Intestinal GIP and GLP-1 release DPP-4 Enzyme GIP (1 42) GLP-1 (7 36) Intact GIP and GLP-1 Actions Rapid Inactivation Half-life* GLP 1 ~ 2 minutes GIP ~ 5 minutes GIP (3 42) GLP-1 (9 36) Metabolites Deacon CF et al. Diabetes. 1995;44: *Meier JJ et al. Diabetes. 24;53:

18 DPP- 4 Inhibitors Retards the degradation of endogenous GLP-1 Increased elimination half-life of endogenous GLP-1 Shown to result in >8% inhibition of DPP-4 for as long as 24 hours (sitagliptin), and 2- to 3-fold increases in GLP-1 plasma levels (sitagliptin and vildaglipitin) 1 Clinical effects Similar to GLP-1 agonist on glucose and A1c (-.6% to - 1.4%) Combination effective with metformin, TZDs Lack weight loss effect compared to GLP-1 agonists Animal studies (neonatal rats) showed significant reduction in beta-cell apoptosis, and increased beta cell mass 2 1 Diabetes 25;54(suppl):A Clin Pharmacol Ther. 25;78; 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;11:515-52; Data from Larsson H, et al. Acta Physiol Scand. 1997;16: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47: Outline Pathophysiology Core defects Beta-cell workload and beta-cell response The paracrine effect: Amylin and Insulin Pramlintide FDA-approved synthetic amylin analog The incretin concept and GLP-1 Incretin mimetics: GLP-1 Agonists/Analogues Exenatide FDA-approved (agonist) Liraglutide phase 3 trials (analogue) Incretin Enhancers: DPP- 4 Inhibitors Sitagliptin FDA-approved 1/17/6 Vildagliptin awaiting FDA approval decision Saxagliptin phase 3 trials

19 Exenatide Indication Byetta by Amylin Pharmaceuticals and Eli Lilly Company Indication adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking MET SFU A combination of MET and SFU But have not achieved adequate glycemic control Supplied in fixed-dose prefilled pens: 5 µg or 1 µg per dose 6 doses per pen (3-day supply) Exenatide Prescribing Information, 25. Exenatide Administration and Storage SC injection Administer BID within 6 minutes before morning and evening meals (do not give after meal) Abdomen, thighs, and arms Missed dose Wait until the next scheduled dose Storage Refrigerate (36-46 F) between injections Do not freeze Discard 3 days after first use Exenatide Prescribing Information, 25 Exenatide Safety Information Adverse Reactions Patients receiving exenatide in combination with a sulfonylurea had an increased risk of hypoglycemia (14% at 5 µg and 36% at 1 µg vs 3% placebo). Patients receiving exenatide in combination with metformin plus a sulfonylurea had an increased risk of hypoglycemia (19% at 5 µg and 28% at 1 µg vs 13% placebo). To reduce the risk of hypoglycemia, clinicians may consider reducing the sulfonylurea dose. The most common treatment-emergent adverse event associated with exenatide (vs placebo) in three 3-week placebo-controlled clinical trials (excluding hypoglycemia) was nausea (44% vs 18%). Other common events were: vomiting (13% vs 4%), diarrhea (13% vs 6%), feeling jittery (9% vs 4%), dizziness (9% vs 6%), headache (9% vs 6%), and dyspepsia (6% vs 3%). Exenatide Prescribing Information, 25

20 Outline Pathophysiology Core defects Beta-cell workload and beta-cell response The paracrine effect: Amylin and Insulin Pramlintide FDA-approved synthetic amylin analog The incretin concept and GLP-1 Incretin mimetics: GLP-1 Agonists/Analogues Exenatide FDA-approved (agonist) Liraglutide phase 3 trials (analogue) Incretin Enhancers: DPP- 4 Inhibitors Sitagliptin FDA-approved 1/17/6 Vildagliptin awaiting FDA approval decision Saxagliptin phase 3 trials Sitagliptin Januvia by Merck & Co., Inc. Indication Adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus as: monotherapy combination therapy with MET or TZD Not for patients with type 1 diabetes mellitus, or for DKA Dosage and Administration Take 1mg once daily with or without food Adjustment in moderate, severe and end stage renal disease Supplied as 1mg, 5mg, 25mg tablets JANUVIA Prescribing Information, 26. Sitagliptin Pharmacodynamics Inhibition of DPP-4 activity for a 24-hour period in patients with type 2 diabetes, resulting in: 2- to 3-fold in circulating levels of active GLP-1 and GIP glucagon concentrations responsiveness of insulin release to glucose plasma levels of insulin and C-peptide fasting glucose and glucose excursion after an oral glucose load or a meal In healthy subjects, did not lower blood glucose or cause hypoglycemia

21 Sitagliptin Drug Interactions and Pharmacokinetics No known clinically meaningful drug interactions. Did not have clinically meaningful effects on the pharmacokinetics of metformin, simvastatin, rosiglitazone, warfarin, glyburide, and oral contraceptives. Based on in vitro data, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6 or induce CYP3A4. Based on in vivo assessment, sitagliptin has a low propensity for causing drug interactions with substrates of CYP3A4, 2C8, and 2C9. Digoxin: No dosage adjustment of digoxin or of sitagliptin is recommended. Sitagliptin Adverse Reactions Adverse Reactions Reported in 5% of Patients and More Commonly Than in Patients Given Placebo, Regardless of Investigator Assessment of Causality* Monotherapy Nasopharyngitis Combination with pioglitazone Upper respiratory tract infection Headache Number of Patients (%) Placebo (N=363) 12 (3.3) sitagliptin 1 mg (N=443) 23 (5.2) sitagliptin 1 mg + pioglitazone (N=175) 11 (6.3) 9 (5.1) Placebo + pioglitazone (N=178) 6 (3.4) 7 (3.9) Combination with metformin None *Intent-to-treat population. sitagliptin 1 mg + metformin NA Placebo + metformin NA Summary Amylin, a neuroendocrine hormone that is co-secreted with insulin at mealtimes, appears to play an important role in postprandial glucose regulation. Its actions are centrally mediated. Incretin release positively affects glucose homeostasis by physiologically helping to regulate insulin from beta cells in a glucose-dependent manner. GLP-1 also helps to regulate glucagon in a glucose-dependent manner. Type 2 diabetes manifests with suppressed amylin levels and abnormal incretin axis. Increasing levels of active incretins in type 2 diabetes improves multiple aspects of beta-cell function and glucose homeostasis. This can be accomplished through incretin mimetics or DPP-4 inhibitors.

22 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control PHILIP T. RODGERS, PHARM.D., BCPS, CDE, CPP Clinical Pharmacist Duke University Hospital Clinical Associate Professor University of North Carolina School of Pharmacy Chapel Hill, North Carolina Dr. Philip Rodgers is Clinical Associate Professor at the University of North Carolina at Chapel Hill School of Pharmacy, where his teaching and research focus on diabetes, hypertension, and dyslipidemia. In addition, Dr. Rogers is a clinical pharmacist in the primary care clinics at Duke University Hospital (DUH). At DUH, Dr. Rodgers also serves as Director for the Primary Care Pharmacy Residency Program and is Director of Pharmacy Education for the Duke Area Health Education Center (AHEC). Dr. Rodgers earned his Bachelor of Science in pharmacy degree and Doctor of Pharmacy degree from the University of North Carolina at Chapel Hill. He also completed an ASHPaccredited pharmacy residency in ambulatory care at the Medical College of Virginia Hospitals in Richmond, Virginia, where he served on the faculty for three years. His certifications include the Board of Pharmaceutical Specialties in Pharmacotherapy (BCPS), Certified Diabetes Educator (CDE), and Clinical Pharmacist Practitioner (CPP) in the state of North Carolina in the area of diabetes and associated diseases. He has spoken to pharmacy and medical groups at state and national meetings on the topics of diabetes, dyslipidemia, hypertension, and clinical practice management. Dr. Rodgers is active with state and national professional organizations to promote pharmacy and the care of people with diabetes.

23 Clinical Experiences and Potential of New Agents for Improving Glycemic Control in Type 2 Diabetes Philip T Rodgers, PharmD, BCPS, CDE, CPP, FCCP Clinical Pharmacist Duke University Hospital University of North Carolina Chapel Hill, North Carolina Patient Cases Successes and Failures Mrs. G 47 year old white female Type 2 diabetes x 5 years, obesity, dyslipidemia, adenocarcinoma of colon, HTN, proteinuria 2 o to immune glomerulopathy, cervical dysplasia History of gestational diabetes, used insulin injections. History of chronic edema due to glomerulopathy Metformin 15mg BID, glipizide 5mg BID, lisinopril/hctz, atorvastatin, metoprolol, aspirin, estradiol patch, fluticasone nasal spray. PCP advised increase in glipizide to 1mg BID last month but did not due to unclear instructions. Metformin increased by covering MD to 3g/day due to hyperglycemia at bedtime several weeks earlier (no GI side effects) 268 lbs Will be starting formal weight loss program in next 1-2 weeks. No formal exercise at this time. A 1C =8.6%, FBG=13-18 s, bedtime=15-3 s Referred to pharmacy for insulin vs TZD

24 Mrs. G Assessment Uncontrolled diabetes, A1C goal about 6% Supertherapeutic dose of metformin Suboptimal dose of glipizide Increased glipizide not likely to achieve goal Concerned about gaining weight from meds as she starts the weight loss program Plan Decrease metformin to 1mg QAM, 15mg QPM Maintain glipizide at 5mg BID Options Do nothing with drugs. Eat better and lose weight. Add TZD Add a different oral drug Add insulin (basal or 7/3 at dinner?) Add exenatide Clinical Inertia: Failure to advance therapy when required Percent of Patients Advancements in therapy when HbA 1C > 8% 66.6% At Insulin Initiation, the average patient had: 5 years with HbA 1C > 8% 1 years with HbA 1C > 7% 35.3% 44.6% 18.6% Diet Sulfonylurea Metformin Combination Diabetes Care 24;27: Fasting versus Postprandial: Contribution to A 1C 1 FPG (Fasting Plasma Glucose) PPG (Postprandial Plasma Glucose) 8 3% 5% 55% % Contribution % 5% 45% 6% 4% 7% 3% < >1.2 A 1C Quintiles (%) Adapted from Monnier L, et al. Diabetes Care 23; 26:

25 Diabetes Pharmacotherapy By Glucose Effect Primarily Fasting Glucose Effect Metformin Thiazolidinediones NPH insulin Glargine Detemir Mixed Effect Sulfonylureas Primarily Postprandial Glucose Effect Alpha glucosidase inhibitors Nonsulfonylurea secretagogues Regular insulin Lispro Aspart Glulisine Exenatide Pramlintide Inhaled insulin Sitagliptin Bold: Released Mrs. G Options: Do nothing? Stop the clinical inertia! Add TZD? chronic edema, weight gain Add a different oral drug? Prefer postprandial action NSS: Not effective in combination with SU α-glucosidase inh: TID, GI side effects Add insulin: Basal (per MD) or even 7/3 at dinner Postprandial plus basal effect, once daily Weight gain Add exenatide? Combined Pivotals: Effect on Postprandial Glucose Glucose (mg/dl) Results of 3-Week Exenatide Pivotal Studies Placebo (N = 44) Baseline Week 3 5 µg BID (N = 42) 1 µg BID (N = 52) 3 3 Placebo Study Medication Meal Meal Glucose (mg/dl) Time (min) Mean ± SE Evaluable Meal Tolerance Cohort Time (min) Buse J, et al. Diabetes Care 24; 27: Kendall DM, et al. Diabetes Care 25; 28: DeFronzo RA, et al. Diabetes Care 25; 27:192-11

26 No diet and exercise regimen was provided. Exenatide Weight Effects: 2-Year Completers Placebo-Controlled Open - Label Extensions 1 Δ Weight (kg) Baseline Weight 1 kg -4.7±.3 kg N = 283; Mean (± SE); P<.5. Henry R, et al. Diabetes 26; 55:A116. Time (wk) Exenatide vs Basal Insulin Emerging choice in therapy Patients on dual or triple therapy Traditional choice: Basal insulin Comparative trial Randomized, open-label, multicenter trial Patients inadequately controlled (A 1C 7-1%) despite metformin + sulfonylurea (n=551) Interventions Exenatide 5 mcg BID titrated to 1 mcg BID Glargine 1 units QD, self-titrated to achieve FBG<1 mg/dl Oral drugs continued at fixed doses Ann Intern Med 25;143: Exenatide vs Glargine: A 1C Effect A 1C Exenatide Glargine Baseline 12 weeks 26 weeks p=ns Ann Intern Med 25;143:

27 Exenatide vs Glargine: Weight Effects Weight Change (kg) Exenatide -.5 Glargine Study Week Ann Intern Med 25;143: Exenatide vs. Glargine Equal effects A 1C Overall hypoglycemia Exenatide advantages Postprandial glucose control Weight reduction Less nocturnal hypoglycemia Glargine advantages FBG control consequently lower PPPG Less GI side effects Fewer withdrawals from study Ann Intern Med 25;143: Mrs. G Started exenatide 5 mcg SQ BID May self-increase to 1mcg SQ BID after 4 weeks if tolerated. First 24 hours of use (via ) 1 st dose: 1.5hr PP BG=72mg/dl Bedtime BG=112 mg/dl FBG next morning=11 mg/dl Haven t seen a reading in the low 1 s in a long time. No nausea 1 week later Continued with lower BG, no side effects 2 weeks later ( ) Reported late-night hypoglycemia x 2, continues exenatide Action: reduce metformin and glipizide

28 Exenatide Experience Patient A 1C (%) A 1C Δ Weight (lb) Weight Δ 65 WF WF BM WM WF WF Average Data courtesy of Scott Joy, MD, CDE, FCP. Now: Sitagliptin Januvia (Merck Co.): Approved October 26 First DPP-IV inhibitor Indications: Monotherapy or in combo with metformin or TZD Clinical Effects: A 1c.6% FBG 13 mg/dl, PPPG 5 mg/dl Dose: 1 mg QD Reduce dose for renal dysfunction: CrCl 3-5 ml/min: 5 mg QD CrCl <3 ml/min: 25 mg QD ADRs (>5%): URIs, nasopharyngitis, headache Drug Interactions: slight increase in digoxin Pregnancy Cat. B Cost: ~ $5 per tablet DPP- IV Inhibitors Increase basal and postprandial GLP-1, GIP Also affects about 4 other substrates T-cell inhibition effects? DPP-IV is T-Cell marker CD26 (helps stimulate activation) Clinical effects Similar to GLP-1 agonist on glucose Combination effective with metformin, TZDs Nausea Lack weight loss effect compared to GLP-1 agonists Clinical Advantages Orally available; QD - BID dosing Questions we will face: Long term effects? Immunological effects? Combination with GLP-1 agonists? Ann Pharmacother 26;4:

29 Mr. L 5-year-old white male Type 2 diabetes, HTN, tobacco (2ppd), h/o colitis, h/o pancreatitis, migraines Meds: Metformin 1mg BID, Glipizide 1mg BID, enalapril 2mg QD, simvastatin 4mg QD, ASA 325mg QD A 1C = 7.8% 27 lb Chronic trace edema Self-monitored BG: FBG 9-13 mg/dl PPPG 18 to >2 s Concerned about weight gain from therapy options discussed Mr. L Assessment Pattern suggests postprandial hyperglycemia as primary problem Options Add TZD: weight gain, edema Add insulin: prefers not to add Add exenatide: interested in weight effect Start exenatide 5mcg SQ BID Mr. L Moderate nausea noted with some 5 mcg doses but wishes to continue 2.5 months later: Increased to 1 mcg SQ BID Weight decreased 13 lb Max BG 16 mg/dl Reported nausea with every dose, especially if did not eat for >3 min after injection 1 week later: Presents to ED with pancreatitis Only other episode was 4 years earlier Current episode complicated by increased beer intake Emergency dept continued exenatide

30 Exenatide and Pancreatitis Case report 69-year-old male Metformin, pioglitazone, NPH, aspart A 1C =1.5% No history of pancreatitis Started exenatide 5mcg SQ BID, stopped metformin, pioglitazone After 1 day on exenatide developed with severe epigastric pain Presented to ED after 5 days of therapy and ongoing pain Diagnosed with acute pancreatitis No alcohol or other known causative agents Resolved with discontinuation of exenatide Diabetes Care 26;29:471. Mr. L Next Visit (2 months later) Out of exenatide A 1C =8.3%, weight increased 7 lb Due to pancreatitis, persistent nausea, and worsened BG control: Stop exenatide, start premixed insulin therapy Mr. N 54-year-old white male Type 2 diabetes, hypertension, dyslipidemia, CAD (s/p PTCA with 3 stents 2 years ago), GERD, Right ACL injury. Metformin 1mg BID, glipizide XL 5mg QD, rosiglitazone 8mg QD, NPH insulin 45 units QHS, carvediolol 25 mg BID, ramipril 2mg QD, amlodipine 1mg QD,HCTZ 25 mg QD, simvastatin 8 mg QD, clopidogrel 75mg QD, aspirin 81 mg QD, omeprazole 2mg QD, sertraline 5mg QD 264 lb A 1C = 7.4% Self-monitored BG (not daily) FBG: mid-1 s Post-supper, HS: mid-2 s

31 Mr. N Assessment Poor evening BG control Indicative of poor postprandial control FBG not adequately controlled Options Increase glipizide Increase basal insulin Add rapid-acting insulin Add exenatide Mr. N Interested in exenatide Started 5 mcg SQ BID Follow-up, 2 months later Still on 5 mcg dose Admits to missing PM doses frequently Refrigeration issue (eats out before getting home) A 1C = 8.3% ( ), weight unchanged Solution: Provided 2 pens (home & work) Follow-up, 1.5 months later Continues to have difficulty with PM doses Refrigeration issue A 1C = 9.6%, weight 262 lb Discontinue exenatide, increase glipizide Later: Switched to premixed insulin Mr. N: Other Considerations Exenatide Not FDA indicated for use with insulin, no studies Storage issues BID dosing Basal-bolus injection therapy Inhaled insulin Pramlintide

32 Other New Options Pramlintide For use in patients on multiple insulin doses Type 2 or 1 Improves PPPG Hepatic gluconeogenesis Satiety GI motility Weight loss Reduced insulin doses Hypoglycemia, nausea Dosing: micrograms (units) Inhaled Insulin Substitutes for mealtime insulin Type 2 or 1 Onset=rapid acting analogs Duration=regular Less hypoglycemia vs regular Similar effect as regular or rapid acting analog insulins Pulmonary warnings Smokers, chronic disease PFT monitoring Dosing: milligrams Device maintenance Emerging Drugs Liraglitide Exenatide LAR Vildagliptin Rimonabant Other inhaled insulins Summary Traditional antihyperglycemic drugs continue to play a major role. Incretin mimetics offer appealing mechanisms and weight effects. DPP- IV inhibitors offer an oral dosing option with less nausea but will need to be monitored for adverse events. Other postprandial drug options, such as pramlintide or inhaled insulin, could be considered for patients with specific parameters.

33 Improving Outcomes in Type 2 Diabetes: New Options for Glycemic Control FACULTY DISCLOSURE STATEMENTS ASHP Advantage requires that faculty members disclose any relationships (e.g., shareholder, recipient of research grant, consultant or member of an advisory committee) that the faculty may have with commercial companies whose products or services may be mentioned in their presentations. The existence of these relationships is provided for the information of attendees and should not be assumed to have an adverse impact on faculty presentations. The faculty reports the following relationships: Philip T. Rodgers, Pharm.D., BCPS, CDE, CPP Dr. Rodgers states that he is a consultant for Amylin Pharmaceuticals and serves on the Speakers Bureau for Pfizer and sanofi-aventis. Douglas F. Covey, Pharm.D., FCCP, MHA Dr. Covey reports that he serves on the Speakers Bureau for Merck and Kos Pharmaceuticals.