Volume X, No. I January/February 2007 Mandy C. Leonard, Pharm.D., BCPS Assistant Director, Drug Information Service Editor Use of Inhaled Human Insulin in Patients with Diabetes Mellitus Meghan K. Lehmann, Pharm.D., BCPS by Linda Ghobrial, Pharm.D. Drug Information Specialist Editor I ntroduction: Diabetes mellitus is a concentration >200 mg/dL in the pres- Dana L. Travis, R.Ph. Drug Information Pharmacist metabolic disease characterized by ence of symptoms, or a 2-hour OGTT 2 Editor hyperglycemia and abnormal carbo- value of >200 mg/dL. The diagnosis hydrate, fat, and protein metabolism. is then confirmed by measuring any David A. White, B.S., R.Ph. Diabetes has a very high prevalence one of the three criteria on a subse- Restricted Drug Pharmacist 2 Associate Editor worldwide. There are approximately quent day. 20.8 million (7%) people in the 1 Marcia J. Wyman, Pharm.D. United States who have diabetes. Classification: Most patients with D rug Information Pharmacist Diabetes results from defects in insu- diabetes mellitus are classified as hav- Associate Editor lin secretion, sensitivity, or both. Al- ing either type 1 or type 2. Type 1 Amy T. Sekel, Pharm.D. though the exact cause remains un- diabetes (previously known as juve- D rug Information Pharmacist clear, genetics and environmental fac- nile diabetes) accounts for about 10% IAnss otchiaiste IEsdsituoer tors such as obesity and lack of exer- of all diabetes cases and is usually cise appear to be involved. diagnosed in children and young David Kvancz, M.S., R.Ph., FASHP 2 Chief Pharmacy Officer adults. In these patients, insulin is Diagnosis: The diagnosis of diabetes not produced because of immune- Morton Goldman, Pharm.D., BCPS mellitus is based on one of three crite- mediated destruction of pancreatic Director, Pharmacotherapy Services ria: fasting plasma glucose (FPG), cells. In comparison, type 2 diabetes, In This Issue: casual elevated glucose levels that which accounts for almost 90% of • Inhaled Insulin occur in conjunction with symptoms, diabetes cases, is characterized by or an abnormal oral glucose tolerance both insulin resistance and insuffi- • Formulary Update 2 2 test (OGTT). Fasting plasma glucose cient insulin production. There are is defined as the glucose level taken other uncommon causes of diabetes after no caloric intake for at least which include endocrine disorders 2 Drug Information Service 8 hours. Casual glucose levels are (e.g., Cushing’s syndrome), gesta- (216) 444-6456, option #1 defined as the glucose level taken at tional diabetes mellitus, disease of the any time of the day without regard to pancreas (e.g., pancreatitis) and some Comprehensive information about meals. In the OGTT test, blood medications (e.g., glucocorticoids, medications, biologics, nutrients, glucose levels are measured 2 hours pentamidine, and interferon alfa).2 and drug therapy after drinking a glucose-rich beverage that contains 75 grams of glucose. Complications: It is well known that Formulary Information This test is completed after a fast with the long-term complications of diabe- normal FPG defined as <100 mg/dL tes include both microvascular and Medication Inservices 3 and impaired fasting glucose (IFG) macrovascular complications. Exam- between 100 and 125 mg/dL.2 ples of microvascular complications Diabetes mellitus is defined as FPG include retinopathy, neuropathy, and >126 mg/dL, a casual plasma glucose nephropathy. Macrovascular compli- cations include coronary heart disease, stroke, and periph- lease a constant amount of insulin over a 24-hour period.4 eral vascular disease.3 Good glycemic control has been There are also insulin mixtures available that contain fixed shown to decrease the risk of long-term complications in ratios of rapid- or short-acting insulin with intermediate insu- both type 1 and type 2 diabetic patients.3 lin (e.g., Novolin® 70/30) to reduce the number of injections patients may need to take each day.4 However, in an effort to Management: The goal of treatment is to ameliorate mimic normal physiologic insulin response in the body, insu- symptoms of hyperglycemia, reduce the onset and progres- lin mixtures are used less often resulting in more daily insulin sion of microvascular and macrovascular complications, injections. Attempts to treat diabetes by delivering insulin reduce mortality, and improve quality of life. The Ameri- through non-invasive means have led to the development of a can Diabetes Association (ADA) recommends a hemo- new formulation of insulin. globin A1c (HbA1c) of <7%, preprandial plasma glucose of 90-130 mg/dL, and postprandial glucose <180 mg/dL.4 Inhaled Insulin: Since its first use in 1922, there have been These goals can be difficult to achieve in type 1 diabetics as numerous efforts towards painless administration of insulin.7 well as in type 2 diabetics who do not respond to non- Until now, alternative insulin administration routes have pharmacologic and oral antihyperglycemic therapy and re- failed to deliver insulin in a reproducible and dose-dependent quire multiple daily insulin injections. Diabetic patients manner.7 The concept of pulmonary insulin administration requiring exogenous insulin have traditionally received it has become a reality with advances in technology and drug by either subcutaneous injection with disposable needles, formulation.8 Exubera®, insulin human [rDNA origin] inha- pen devices, or insulin pumps (i.e., portable devices that lation powder (Pfizer), was approved by the Food and Drug deliver rapid-acting insulin). Administration (FDA) on January 27, 2006, for the treatment of children aged 6 years or older and adult patients with Type 1 and some type 2 diabetic patients require both long- type 1 or type 2 diabetes mellitus.9 In patients with type 1 and short-acting insulins to provide basal insulin coverage diabetes, Exubera® is used in combination with a long-acting as well as coverage required during meal times. Over the insulin.9 In patients with type 2 diabetes, Exubera® can be last 2 decades, there has been an increase in the number of used as monotherapy or in combination with oral agents or insulin analogues available for patients with diabetes (see long-acting insulin.9 This article will review the background Table 1).4 Rapid-acting insulins have a faster onset of ac- of inhaled insulin, its efficacy and tolerability, as well as its tion and more predictable duration of action than regular directions for use and place in therapy. insulin and have been used more frequently to provide meal time insulin requirements. Insulin glulisine (Apidra®) was Pharmacology: The primary action of insulin, a polypeptide, recently approved as a rapid-acting insulin. Likewise, insu- is to regulate glucose metabolism. Insulin lowers blood glu- lin glargine (Lantus®) and insulin detemir (Levemir®) have cose concentrations by stimulating peripheral glucose uptake been introduced for basal insulin coverage since they re- by skeletal muscle and fat, and by inhibiting hepatic glucose Table 1. Insulin and Insulin Analogues5,6,9 Generic Brand Name Manufacturer Classification Onset Duration AWP Inhaled insulin Exubera®NF Pfizer Rapid 10-20 min 6-8 h $180.00† Insulin lispro Humalog®NF Eli Lilly Rapid 10-20 min 3-4 h $80.35‡ Insulin aspart Novolog®NF Novo Nordisk Rapid 10-20 min 3-5 h $83.70‡ Insulin glulisine Apridra®F Sanofi Aventis Rapid 10-20 min 3-4 h $77.63‡ Humulin R®NF Eli Lilly $54.24‡ Insulin regular Short 30 min 6-8 h Novolin R®F Novo Nordisk $56.55‡ Humulin N®NF Eli Lilly $54.24‡ Insulin NPH Intermediate 1-2 h 18-24 h Novolin N®F Novo Nordisk $56.55‡ Insulin detemir Levemir®F Novo Nordisk Long 3-4 h 6-23 h $83.70‡ Insulin glargine Lantus®F Sanofi Aventis Long 3-4 h 24 h $76.98‡ F= Formulary NF= Non-formulary AWP= Average Wholesale Price † = Kit (inhaler, chamber and release unit, 90- 1 mg blisters and 180- 3 mg blisters) ‡=10 mL vial production. Insulin also inhibits lipolysis and proteolysis, and (Cmax) were reduced by approximately 20 and 30%, respec- enhances protein synthesis.4 Once inside the gastrointestinal tively.9 In patients with unstable or poorly controlled lung tract, insulin is denatured. This is why insulin has only been disease, there are wide variations in lung function that could administered by either subcutaneous (SC) injection or intrave- affect absorption and increase the risk of hypoglycemia or nous infusion in the past.7 hyperglycemia.9 In asthmatic patients, absorption of inhaled insulin in the absence of treatment with a bronchodilator is Pharmacokinetics: The absorption of inhaled insulin a pproximately 20% lower than absorption noted in subjects depends on many factors. Each alveolus has a diameter of without asthma.9 Systemic insulin concentrations are ap- 0.06 to 0.2 mm and healthy adult lungs consist of about proximately 2-fold higher in patients with chronic obstructive 400 million alveoli, thus forming a surface area of approxi- pulmonary disease (COPD) compared to normal subjects.9 mately 100 m2.7 In order for a drug to reach the alveoli, the inhalation system must generate the optimal aerodynamic di- Select Clinical Trials: The efficacy of inhaled insulin was ameter of 1-3 µm.7 Particles larger than 5 µm linger in the studied in both type 1 and type 2 diabetic patients with oropharynx and upper airway whereas smaller particles are primary endpoints of changes in HbA1c, FPG, and postpran- lost during exhalation.7 The rate of drug absorption varies at dial glucose. Type 1 diabetic patients who were stable on different sites within the lung because of the variable thickness their current treatment were studied in two 24-week trials.11,12 of mucosal surfaces.7 The alveolar regions of the lungs are so Both studies compared the regimens of preprandial inhaled densely perfused with capillaries that five liters of blood pass insulin to preprandial regular insulin administered SC.