Approaches to Addressing Incretin Deficiency. Non-Insulin Injectable Agents. Incretin Mimetics. Exendin-4 in the Gila Monster

Transcription

1 Non-Insulin Injectable Agents Approaches to Addressing Incretin Deficiency Longer-acting analogs? (Incretin mimetics) GLP-1 Analogs Inhibition of inactivation? (Incretin enhancers) DPP-4 Inhibitors Drucker DJ et al Lancet 26;368: Approaches to Addressing Incretin Deficiency Ingestion of food Incretin Mimetics Supraphysiologic 2,3 GLP-1 Pancreas Analogues Incretin Glucose-dependent Concentrations Insulin from beta cells Release of gut (GLP-1 and GIP) hormones Incretins GI tract 1,2 Beta cells Alpha cells Incretin Enhancers DPP-4 Inhibitors Active GLP-1 & GIP Inactive GLP-1 Inactive GIP DPP-4 = dipeptidyl-peptidase 4 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;18:43 41 Glucose dependent Glucagon from alpha cells (GLP-1) Glucose uptake by muscles 2,4 Glucose production by liver Blood glucose Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging their action GLP-1 vs DPP-4 Inhibitors: Understanding the Actions of Incretin-Based Therapies GLP-1: Secreted upon the ingestion of food β-cell Function Beta cells: Enhances glucose-dependent insulin secretion GLP-1 & DPP-4 Inhibitors Food Intake CNS GLP-1 Promotes satiety and reduces appetite Alpha cells: Glucose-dependent post-prandial glucagon secretion Liver: Glucagon reduces hepatic glucose output Stomach: GLP-1 Delays gastric emptying Data from Flint A, et al J Clin Invest 1998;11: 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: Glucose Production GLP-1 & DPP-4 Inhibitors Glucose Absorption Incretin Mimetics Exendin-4 in the Gila Monster Develop Drugs that Bind to the Incretin Receptor (mimetics that are resistant to DPP-4 inhibition) Exenatide GLP-1 agonist GLP-1 analog 53% homology to human GLP-1 SC BID Human GLP-1 derivative, 97% homology to human GLP-1 Low risk of hypoglycemia Mainly PPG effects SC once-daily Side effects: nausea; rare reports of Reduces FPG and PPG hemorrhagic or necrotizing pancreatitis Less nausea, greater BG Exenatide QW reductions than exenatide Long-acting-release (LAR) formula of Low risk of hypoglycemia exenatide A1C reduced by 8% to 175% SC once per week and weight by 25 to 3 kg More effective than twice-daily form, similar safety and weight loss, less nausea Drucker DJ et al Lancet 26;368: Exendin-4 was originally isolated from the salivary secretions of the Gila monster The Gila monster eats large amounts of food, but does that quite seldom These lizards eat as few as four times each year, storing large amounts of fat in their tails and living off that in longer periods of time When the lizard eats, the exendin-4 in the spit of the animal "wakes" pancreatic islet activity, giving rise to beta-cell activity, insulin release and control of glucose and fat metabolism Exenatide is a synthetic version of Exendin-4 Exenatide 3 was the 6 first 9 12 incretin mimetic Time After Meal (h) 1

2 Effect of Exenatide on Fasting Plasma Glucose and Insulin in Type 2 Diabetes Effect of Exenatide on Post-prandial Glucose and Glucagon in Type 2 Diabetes Plasma Glucose (mmol/l) Placebo 5 µg/kg exenatide 1 µg/kg exenatide 2 µg/kg exenatide Serum Insulin (pmol/l) Placebo 5 µg/kg exenatide 1 µg/kg exenatide 2 µg/kg exenatide Plasma Glucose (mmol/l) Placebo Exenatide 1 µg/kg Exenatide or Placebo Standardized Breakfast Plasma Glucagon (pg/ml) Placebo Exenatide 1 µg/kg Exenatide or Placebo Standardized Breakfast Time (h) Time (h) Time (min) Time (min) Evaluable population (n=12) Mean ± SE n=2 Mean ± SE Data from: Kolterman OG, et al J Clin Endocrinol Metab 23; 88: Data from Kolterman OG, et al J Clin Endocrinol Metab 23; 88: Exenatide: Effects on Glycemic Control in Combination With Current Oral Therapies Exenatide: Clinical Pharmacology Indication: Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Metabolism: Predominantly eliminated by glomerular filtration Drug Interactions: Use caution in patients taking Oral meds requiring rapid absorption Meds dependent on threshold concentrations for efficacy such as contraceptives and antibiotics advise pt to take these meds at least 1hr before exenatide If drugs are to be administered with food, pts should be advised to take them with a meal or snack when exenatide is not administered Exenatide: Clinical Pharmacology Effectiveness: 5mcg BID 1mcg BID A1C -4% -8% FBG -8 mg/dl -1 mg/dl PPG -63 mg/dl -71 mg/dl Administration: Available in pre-filled pens (5 µg, 1 µg) for SC injection Each pen delivers 6 doses (3 day BID dosing) Administered anytime within 6-minute period before the morning and evening meal (DO NOT give after meals) Exenatide: Clinical Pharmacology Precautions: Acute Pancreatitis Post-marketing data has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis After initiation and dose increases, observe patients carefully for signs and symptoms of pancreatitis Medications Known to Cause Hypoglycemia Patients receiving a sulfonylurea may require a lower dose of the sulfonylurea to reduce the risk of hypoglycemia Renal Impairment Should not be used in patients with severe renal impairment (CrCl < 3 ml/min) or end-stage renal disease Used with caution in patients with renal transplantation Exenatide may induce nausea and vomiting with transient hypovolemia, and therefore worsen renal function Caution should be applied when initiating or escalating the dose from 5 mcg to 1 mcg in patients with moderate renal impairment (CrCl 3 to 5 ml/min) 2

3 Exenatide: Clinical Pharmacology Precautions: Gastrointestinal Disease Is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea, the use of exenatide is not recommended in patients with severe gastrointestinal disease Immunogenicity Pts may develop antibodies to exenatide Antibody formation was associated with an attenuated glycemic response If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered Hypersensitivity Postmarketing reports of serious hypersensitivity reactions (eg anaphylaxis and angioedema) have been documented Exenatide: Clinical Pharmacology Adverse Effects: Nausea Jittery Dyspepsia Dosage: Vomiting Dizziness Hypoglycemia (with sulfyl use) Diarrhea Headache Weight Loss 5 µg BID within a 6-minute period before the morning and evening meals Based on clinical response dosage may be increased to 1 µg BID after 1 month of therapy Storage: Exenatide pens should be refrigerated at 36 º F to 46 º F After first use, your BYETTA Pen can be kept at a room temperature not to exceed 77 F (25 C) Pen should be discarded 3 days after first use, even if some drug remains in the pen Nausea Is Dose-dependent and Decreases Over Time Effect of Exenatide on Body Weight Incidence of Nausea (% ITT Subjects) >4-8 >8-12 >12-16 >16-2 >2-24 >24-28 >28 Treatment (wk) 1 µg 5 µg Placebo Buse JB, et al Diabetes Care 24;27: Buse JB, et al Diabetes Care 24;27: Exenatide Continued to Reduce Weight Mean Δ Weight (kg) Baseline Weight Placebo BID 98 kg 5 µg Exenatide BID 1 kg 1 µg Exenatide BID 1 kg Placebo-Controlled Open-Label Extension Time (wk) 82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc -1-2 Exenatide Continued to Reduce A1C Weight at 25 Years Mean Baseline A1C 83% 25-y completers; N = 241; Mean ± SE; Patients were not required to follow any specified diet or exercise plan Data on file, Amylin Pharmaceuticals, Inc Open-Label Extension Combined Time (y) Mean Δ A1C (%) -11 Exenatide 1 µg BID Time (y) Mean Baseline Weight 1 kg Mean Δ Weight (kg) -51 3

4 Long-Acting Release Technology Plasma Exenatide QW Levels Exenatide QW: Bydureon A long-acting formulation of exenatide Once weekly injection Biodegradable polymeric microspheres for extended release Detectable plasma concentrations of exenatide for weeks to months after a single dose Initial release (1 st 24 hours) Lag phase Extended release Plasma Exenatide (pmol/l) Mean C ss,ave = 717 pmol/l release of surface drug Bartus RT et al Science 1998;281: hydration diffusion degradation erosion Time (weeks) Data are Geometric mean ± 25-75th percentile range Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Exenatide QW Produced a Greater Change in A1C Proportion of Patients Achieving A1C Targets 77% Δ A1C (%) -15±1% -19±1% Proportion (%) 61% 49% 42% 25% 18% Time (weeks) Data are LS mean (SE); p<1, QW vs BID Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA 7% 65% 6% p=39, QW vs BID Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Exenatide QW Produced a Greater Change in A1C Exenatide QW Produced a Greater Change in FBG Δ FPG (mg/dl) -25 mg/dl -42 mg/dl 52-wk Evaluable Population (N=241); LS Mean (SE); p<5 between groups Data on file, Amylin Pharmaceuticals, Inc Buse JB, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Time (weeks) Data are LS mean (SE); p<5 QW vs BID Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA 4

5 Exenatide QW Produced a Greater Change in Levels of Fasting Plasma Glucagon Change in Body Weight at 3 Weeks Δ Glucagon (pg/ml) -6 mg/dl -18 mg/dl Δ Body Weight (kg) -36 kg -37 kg Time (weeks) Data are LS mean (SE); p<5 QW vs BID Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Data are LS mean (SE) Time (weeks) Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Change in Body Weight at 52 Weeks 52-wk Evaluable Population (N=241); LS Mean (SE) Data on file, Amylin Pharmaceuticals, Inc Buse JB, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Exenatide Extended-Release: Clinical Pharmacology Indications and usage BYDUREON is an extended-release formulation of exenatide, administered as an injection once every seven days (weekly) Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Not recommended as first-line therapy Should not be used in patients with type 1 diabetes Has not been studied with insulin and cannot be recommended Exenatide has been associated with acute pancreatitis Other antidiabetic therapies should be considered in patients with a history of pancreatitis Administration 2 mg per dose should be administered once every seven days (weekly) May be administered at any time of day, with or without meals Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA Exenatide Extended-Release: Clinical Pharmacology Administration Missed doses should be administered as soon as noticed, provided the next regularly scheduled dose is due at least three days later Thereafter, patients can resume their usual dosing schedule of once every seven days (weekly) If a dose is missed and the next regularly scheduled dose is due one or two days later, the patient should not administer the missed dose and instead resume injections with the next regularly scheduled dose The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before Administered as a subcutaneous injection in the abdomen, thigh or upper arm region Prior treatment with exenatide is not required when initiating exenatide extended-release therapy If the decision is made to start exenatide extended-release in an appropriate patient already taking exenatide, the exenatide should be discontinued Patients making the change may experience transient (approximately two weeks) elevations in blood glucose concentrations Exenatide Extended-Release: Clinical Pharmacology Contraindications Exenatide extended-release is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) Warnings Risk of Thyroid C-cell Tumors---In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures compared to controls It is unknown whether exenatide extended-release will cause thyroid C- cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies Acute Pancreatitis--- Exenatide has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis Observe patients carefully for signs and symptoms of pancreatitis Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA 5

6 Exenatide Extended-Release: Clinical Pharmacology Warnings Hypoglycemia---Risk of hypoglycemia is increased when exenatide is used in combination with a insulin secretagogues Therefore, a lower doses of secretagogues may be required Renal Impairment--- Should not be used in patients with severe renal impairment (CrCl < 3 ml/ min) or end-stage renal disease Should be used with caution in patients with renal transplantation Exenatide may induce nausea and vomiting with transient hypovolemia, and therefore worsen renal function Caution should be applied when using in patients with moderate renal impairment (CrCl 3 to 5 ml/min) Gastrointestinal Disease---Not recommended in patients with severe gastrointestinal disease Immunogenicity ---Pts may develop antibodies to exenatide resulting in an attenuated glycemic response If worsening glycemic control or failure to achieve targeted glycemic control should occur an alternative antidiabetic therapy should be Exenatide Extended-Release: Clinical Pharmacology Warnings Hypersensitivity ---There have been postmarketing reports of serious hypersensitivity reactions (eg anaphylaxis and angioedema) in patients treated with exenatide Drug Interactions Exenatide slows gastric emptying and thus has the potential to reduce the rate of absorption of orally administered drugs Storage Should be stored in the refrigerator up to the expiration date or until preparing for use Each single-dose tray can be kept at room temperature for no more than a total of 4 weeks, if needed Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA Exenatide Extended-Release: Clinical Pharmacology Adverse Events With Overall Incidence 1% QW (N=148) % BID (N=145) % Nausea Vomiting Injection site pruritus 18 1 Upper respiratory tract 8 17 infection Diarrhea Constipation 11 6 Injection site bruising 5 1 Urinary tract infection patients withdrawn during lead-in not included 3-week Assessment Period Data on file, Amylin Pharmaceuticals, Inc Drucker DJ, et al Presented at ADA, 68th Scientific Sessions; 28; San Francisco, CA Exenatide Extended-Release BYDUREON must be administered immediately after the exenatide powder is suspended in the diluent and transferred to the syringe Bydureon Package Insert, Amylin Pharmaceuticals, Inc, San Diego, CA BYDUREON is provided in a single-dose tray containing: one vial of 2 mg exenatide, one vial connector, one prefilled diluent syringe and two needles (one provided as a spare) a Long-acting GLP-1 Analogue Glu Phe 7 9 C-16 fatty acid (palmitoyl) His Ala Glu Gly Thr Phe Thr Ser Glu Lys Ala Ala Gln Ile Ala Trp Leu Gly Val Acylation of GLP-1 leads to Self-association Albumin binding Glu Arg Leu Tyr Gly Arg Asp Ser 37 Gly Val Ser Based on natural GLP-1 (97% homology) Slow absorption from subcutaneous Long plasma half-life (Approx 14 hours) Once daily dosing Resistance to DPP-IV Mechanism of Action Stimulates insulin secretion in the presence of elevated glucose concentrations Suppresses glucagon secretion in a glucosedependent manner A single dose of liraglutide did not impair glucagon response to a low glucose concentration Delays gastric emptying Reduces the rate at which PPG appears in the circulation Knudsen et al J Med Chem 2;43: Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 6

7 Enhances Glucose-Dependent Insulin Secretion and Glucagon Suppression Indications and Usage GLP-1 receptor agonist indicated as an adjunct to diet and exercise in adults with type 2 DM Not recommended as first line therapy for patients inadequately controlled on diet and exercise Has not been studied sufficiently in patients with a history of pancreatitis Use caution in patients with history of pancreatitis Not for treatment of type 1 DM Has not been studied in combination with prandial insulin n = 1 patients with type 2 diabetes; mean (SE); p,5 Reproduced from Nauck MA we al Diabetologia 1993;36: Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 : Phase 3a Clinical Trial Program : Effect on A1C Reduction : Effect on FBG Reduction Dosage and Administration Administered subcutaneously once daily Any time of the day, independently of meals Injected in the abdomen, thigh or upper arm Injection site and timing can be changed without dose adjustment Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 7

8 Mechanism of Protraction Self-association that delays absorption Plasma protein binding (>98%) Stability against metabolic degradation by DPP-4 enzymes Half-life of ~ 13 hours Once daily administration Once-daily Injection of Covers 24-h BG Profile in T2DM Plasma glucose (mmol/l) Placebo (6 µg/kg OD) n= Time after injection (hours) Injection (8) 24-h glucose AUC (mmol/l/h, mean ± SE) 2323 ± ± 14 (p = 1) Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Adapted from: Degn et al Diabetes 24;53: Dosage and Administration Should be initiated with a dose of 6 mg once daily for 1 week 6 mg dose is a starting dose intended to reduce GI symptoms, and is not effective for glycemic control After 1 week at 6 mg once daily, the dose should be increased to 12 mg once daily If the 12 mg does not result in acceptable glycemic control, the dose may be increased to 18 mg once daily Available in a pre-filled, multi-dose pen that delivers doses of 6 mg, 12 mg or 18 mg Boxed Warning Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Contraindications Do not use in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type Do not use in patients with a prior serious hypersensitivity reaction Warnings and Precautions Thyroid C-cell tumors in animals: Human relevance unknown Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid tumors In clinical trials, there have been 6 reported cases of thyroid C-cell hyperplasia among liraglutide treated patients and 2 cases in comparator-treated patients One comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1 ng/l suggesting preexisting disease Five of the six liraglutide treated patients had elevated calcitonin concentrations at baseline and throughout the trial One liraglutide and one non-liraglutide treated patient developed elevated calcitonin concentrations while on treatment Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 8

9 Warnings and Precautions Pancreatitis: In clinical trials, there have been 13 cases of pancreatitis among liraglutide treated patients and 1 case in a comparator (glimepiride) treated patient 9 cases of acute and 4 cases of chronic Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse After initiation, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting) Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Warnings and Precautions Serious hypoglycemia: Can occur when liraglutide is used with an insulin secretagogue (eg a sulfonylurea) or insulin Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia Renal failure: Postmarketing reports of acute renal failure and worsening of chronic renal failure in liraglutide treated patients A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea or dehydration Some of the reported events occurred in patients receiving medications known to affect renal function or hydration status Hypersensitivity Reactions: Postmarketing reports of serious hypersensitivity reactions (eg, anaphylactic reactions and angioedema) Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 Drug Interactions delays gastric emptying May impact absorption of concomitantly administered oral medications : Adverse Events Occurring in > 5% Victoza [package insert] Novo Nordisk; Princton, NJ; January 21 : Minor Hypoglycemic Events : Effect on Weight 9

10 Which Patients Are Most Likely to Benefit From a GLP-1 Agonist? Individuals who are relatively early in the disease process, and need sufficient benefit from an agent with good efficacy Persons who could benefit from monotherapy, but are not good candidates for metformin or a sulfonylurea Patients with hazardous occupations, for whom hypoglycemia is especially dangerous Overweight patients Who want to lose weight, especially if they have suboptimal glycemic control with oral therapy Who are reluctant to transition to insulin because of concerns about further weight gain and/or hypoglycemia Educating Patients About GLP-1 Agonists Main BG effect is post-prandial with modest benefit on fasting The disposable administration pen should be stored and used appropriately Following instructions about the timing of medication administration is important with exenatide (within 6 minutes prior to meal) Renal function should be assessed before initiating treatment and periodically thereafter Patients who will be taking a GLP-1 agonist with a sulfonylurea or insulin should be familiar with the symptoms and treatment of hypoglycemia If taken with certain other medications, changes to the timing of medication administration or the frequency of monitoring may be necessary The health care provider should be notified immediately if pancreatitis symptoms develop Nathan DM et al Diabetes Care 29;32: Pratley RE et al Rev Diabet Stud 28;5:73 94 GLP-1 Analogues Verses DPP-IV Inhibitors Drug Characteristics GLP Analogues DPP-IV Inhibitors Administration Injection Oral Tablet Effect on A1C 8-18% 5-11% Weight Change 3-5 kg No effect (neutral) Beta Cell Mass Effect (in animals) Robust increase Not as robust Type 2 DM Pathophysiology Increased glucagon secretion Increased hepatic glucose production Increased gastric emptying rate Neuroendocrine dysfunction Impaired incretin effect Decreased secretion of GLP1 Impaired response to GIP Decreased amylin secretion Pramlintide acetate Synthetic analog of human amylin Amylin is a 37-amino acid neuroendocrine hormone Amylin is synthesized by pancreatic beta cells and co-secreted with insulin in response to food intake Pramlintide vs Amylin Human amylin is not soluble and has a tendency to aggregate Pramlintide is a soluble non-aggregating equipotent amylin analogue Indications: Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy, with or without a sulfonylurea and/or metformin 1

11 Mechanism of Action Pramlintide acting as an amylinomimetic Decreases postprandial glucagon secretion thereby reducing glucose output by the liver and reducing postprandial plasma glucose Increases satiety and reduces food intake Slows gastric emptying Pharmacokinetics Formulation Injection SymlinPen 6: 1 carton containing 2 x 15-mL disposable, multidose pen-injector devices for doses of 15 mcg, 3 mcg, 45 mcg, and 6 mcg SymlinPen 12: 1 carton containing 2 x 27-mL disposable, multidose pen-injector devices for doses of 6 mcg and 12 mcg Route subcutaneous Injection in the arm showed higher exposure with greater variability, compared to abdomen or thigh 6% bound to serum albumin or blood cells Half-life about 48 minutes Metabolism renal; one active metabolite has been identified (des-lys pramlintide) Excretion - renal Efficacy of Pramlintide Type 1 Diabetes Prescribing information summarizes data from 3 studies of pramlintide (3-6µg) in patients with type 1 diabetes (A1C ~ 9%) Efficacy of Pramlintide Type 2 Diabetes Prescribing information summarizes data from two trials in type 2 patients Placebo vs pramlintide 12 mcg (both with usual insulin regimen) Patient Selection Patient Selection Pramlintide should only be considered for insulin-using patients who: Have failed to achieve adequate glycemic control despite individualized insulin management Are receiving ongoing care under the guidance of a health care provider skilled in the use of insulin and supported by the services of a diabetes educator Patients meeting any of the following criteria should not be considered for pramlintide therapy: Poor compliance with current insulin regimen Poor compliance with SMBG Have an A1C > 9% Have recurrent severe hypoglycemia requiring assistance during the past 6 months Presence of hypoglycemic unawareness Confirmed diagnosis of gastroparesis Require medications that stimulate gastrointestinal motility Pediatric patients 11

12 Warnings and Precautions Contraindications When initiating pramlintide therapy, reduce short- or rapid-acting insulin dose by 5% including fixed mix insulins such as 7/3 Other glucose-lowering medications may require dosage adjustment as well Frequent glucose monitoring Pre- and post-meal Bedtime Hypersensitivity to pramlintide or any of its components Confirmed diagnosis of gastroparesis Hypoglycemic unawareness Adverse Effects Nausea, vomiting, dyspepsia, anorexia, headache, fatigue Nausea in about 1/3 to 1/2 patients Tolerance develops to the nausea and anorexia as therapy continues Lower incidence if pramlintide gradually titrated to recommended dosage Does not cause hypoglycemia alone Dosing and Administration Type 1 DM Reduce preprandial, rapid-acting or short-acting insulin doses, including fixed mix insulins by 5% Starting dose 15 mcg Increase dose by 15 mcg increments (3, 45, 6 mcg) when no clinically significant nausea has occurred for at least 3 days Maintenance dose 3 mcg or 6 mcg as tolerated Persistent nausea at the 45 or 6 mcg dose level requires a reduction to 3 mcg If the 3 mcg dose is not tolerated d/c therapy Administer dose immediately before major meals (25 calories or > 3g CHO) Dosing and Administration Dosing and Administration Type 2 DM Reduce preprandial, rapid-acting or short-acting insulin doses, including fixed mix insulins by 5% Starting dose 6 mcg Increase dose to 12 mcg when no clinically significant nausea has occurred for 3-7 days Maintenance dose 12 mcg as tolerated Persistent nausea at the 12 mcg dose level requires a reduction to 6 mcg Administer dose immediately before major meals (25 calories or > 3g CHO) Once target dose of pramlintide is achieved, both insulin using type 1 and type 2 patients should have their insulin dose adjusted to optimize glycemic control Administer into abdomen or thigh with injection sites rotated Do not use same site repeatedly Injection site selected should be distinct from insulin injection site (at least 2 inches away) Do not mix with insulin 12

13 Storage Unopened vials and pen-injectors should be refrigerated Opened (in-use) vials and pen-injectors may be kept either refrigerated or at room temperature for up to 28 days 13