Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE The Impact of Smoking on Inhaled Insulin 1 2 ANDERS HIMMELMANN, MD, PHD ASTRID H. PETERSEN, MSC this route of administration, which re- 2 2 JOHAN JENDLE, MD, PHD ULF L. DAHL, MSC semble profiles of rapid-acting analogs 1 3 ANDERS MELLEN´ , MD PER WOLLMER, MD, PHD (4,8). Patients with diabetes have similar smoking habits to smokers without dia- betes, with as many as 17–26% of diabetic patients smoking cigarettes (9). The long- OBJECTIVE — This study, one of the first to address issues of pulmonary insulin delivery in term adverse effects of cigarette smoking smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers. are well established (10), and smoking has additional acute effects on the lungs, RESEARCH DESIGN AND METHODS — In this randomized two-period crossover increasing the permeability of the al- efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, veolar-capillary barrier in animal models mean age 28 years, mean BMI 23.0 kg/m2), subjects received single doses of inhaled insulin (33.8 (11) and humans (12). The effects of these IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked smoking-related pulmonary changes on three cigarettes immediately before insulin administration (“acute smoking”); on the other dos- the delivery and absorption of inhaled ing day, smokers had not smoked since midnight (“nonacute smoking”). After inhalation, 6-h serum insulin and serum glucose profiles were determined. drugs are not yet fully understood. Smok- ing dramatically increases the rate of ab- RESULTS — Pharmacokinetic results for evaluable subjects were derived from serum insulin sorption of the ␤ agonist terbutaline (13) profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the and decreases subcutaneous absorption exogenous serum insulin curve from 0 to 6 h [AUC(0–6h)]) was significantly greater in smokers of insulin, increasing dosage require- Ϫ Ϫ (63.2 vs. 40.0 mU ⅐ l 1 ⅐ h 1, P ϭ 0.0017); peak concentration was both higher and earlier in the ments (14). Smoking also acutely impairs Ͻ smokers (maximal serum concentration of insulin [Cmax] 42.0 vs. 13.9 mU/l, P 0.0001; time insulin action leading to insulin resistance to maximal serum concentration of insulin [t ] 31.5 vs. 53.9 min, P ϭ 0.0003). The estimated max (15). intrasubject variability of AUC(0–6h) was 13.7 and 16.5% for nonsmokers and smokers, respec- tively. No safety issues arose. Because insulin has a narrow thera- peutic index, the AERx iDMS, an inhala- CONCLUSIONS — Absorption of inhaled insulin via the AERx iDMS was significantly tion-activated system with insulin strips, greater in smokers, with a higher AUC(0–6h)and Cmax and a shorter tmax. Intrasubject variability has been developed to enable liquid aero- of AUC(0–6 h) was low and similar in nonsmokers and smokers. These data prompt more sols of bolus insulin to be delivered into extensive investigation of inhaled insulin in diabetic smokers. the deep lung. It emits a fine particle aero- sol (mass median aerodynamic diameter Diabetes Care 26:677–682, 2003 of 2–3 ␮m) from single-use insulin strips by extruding the prepacked solution through hundreds of precisely laser- ntensive insulin therapy is the corner- native (3,4). Advances in aerosol technol- evaporated holes in a single-use nozzle. stone of glycemic control in diabetic ogy have resulted in the efficient delivery The dose will be selected in AERx units in I patients, reducing complications in of smaller-sized particles (for example, the final version of the AERx iDMS (1 type 1 and type 2 diabetic subjects (1,2). AERx insulin Diabetes Management Sys- AERx unit ϭϳ1 IU given subcutane- Despite improvements in regimens, in- tem [iDMS], Exubera, Aerodose, and ously) and 1-unit increments will be pos- convenient multiple insulin injections Technospheres). The clinical perfor- sible, with a clear dose response as shown can pose a barrier to good glycemic con- mance, reproducibility, and patient satis- in previous trials (8,16). Trials have dem- trol. Alternative routes for insulin admin- faction with these emerging systems are onstrated the efficacy and reproducibility istration have been determined, with currently being investigated (3,5–7) of insulin administered from AERx iDMS inhaled insulin emerging as a viable alter- based on the insulin profiles seen using compared with subcutaneous delivery, ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● with no safety concerns or serious adverse events (8,16). From 1Sahlgrenska University Hospital, Gothenburg, Sweden; 2Novo Nordisk A/S, Copenhagen, Denmark; and 3Lund University, Lund, Sweden. The present study was performed Address correspondence and reprint requests to Associate Professor Anders Himmelmann, MD, Depart- with a prototype of AERx iDMS to evalu- ment of Clinical Pharmacology, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. E-mail: ate the pharmacokinetics, safety, and tol- [email protected]. erability of inhaled insulin delivered to a Received for publication 14 August 2002 and accepted in revised form 11 November 2002. A.H.P. and U.L.D. hold stock in Novo Nordisk A/S. P.W. has received honoraria for speaking engage- smoking population, to assess the acute ments from and serves on an advisory panel for Novo Nordisk A/S. effects of smoking, and to compare these Abbreviations: AUC(0–6h), area under the exogenous serum insulin curve from 0 to 6 h; Cmax, maximal findings with those from healthy non- serum concentration of insulin; CV, coefficient of variation; iDMS, insulin Diabetes Management System; smoking volunteers. This is one of the MRT, mean residence time; tmax, time to maximal serum concentration of insulin. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion first studies to address these issues of pul- factors for many substances. monary insulin delivery in smokers. DIABETES CARE, VOLUME 26, NUMBER 3, MARCH 2003 677 Impact of smoking on inhaled insulin Table 1—Baseline characteristics Nordisk A/S; Aradigm Corporation) was administered to each volunteer via a rep- Smokers Nonsmokers resentative prototype AERx iDMS (Novo Nordisk A/S; Aradigm Corporation). The Sex (M/F) 11/16 7/9 insulin was administered at a revised dose Age (years) 27.7 Ϯ 5.7 27.7 Ϯ 5.2 of 33.8 IU (half a strip; previously calcu- Weight (kg) 71.7 Ϯ 10.0 71.3 Ϯ 7.4 lated to have an effect corresponding ap- BMI (kg/m2) 23.4 Ϯ 2.2 23.0 Ϯ 1.7 proximately to a single subcutaneous FVC (% predicted) 103 Ϯ 10.2 103 Ϯ 10.0 dose of 4.4 IU with this prototype) (8). Ϯ Ϯ FEV1 (% predicted) 97.9 9.2 96.0 8.3 Because of pronounced hypoglyce- FEV% (% predicted) 94.6 Ϯ 7.6 93.0 Ϯ 6.6 mia in one of the first two subjects tested, Ϯ Data are means SD. FEV1, forced expiratory volume during the first second; FEV%, forced expiratory four subjects initially received a lower in- volume %; FVC, forced vital capacity. sulin dose of 22.5 IU. The protocol was then amended when results from another study became available demonstrating a RESEARCH DESIGN AND and facilitated assessment of the effects of lower relative bioavailability of inhaled METHODS — The trial was con- acute smoking before insulin inhalation. insulin than perceived on original dose ducted in accordance with the Declara- Smokers were randomized to either not selection. As a result of this new data, all tion of Helsinki and was approved by the smoke from midnight until the end of subsequent subjects finally received a re- local ethics committee, and all subjects dosing day 1 (“nonacute smoking”), and vised dose of 33.8 IU. To ensure safety at gave their written informed consent be- then on dosing day 2 to smoke three cig- this higher dose, all subjects in whom in- fore entering the trial. arettes during the 30 min before insulin tolerable signs and symptoms of hypogly- dosing (“acute smoking,” to simulate the cemia (and/or duplicate blood glucose Volunteers extreme situation), or vice versa. Subjects readings on a HemoCue Glucometer of Healthy volunteers were current smokers were hospitalized and test conditions Յ2.0 mmol/l) were observed were treated or nonsmokers of either sex, with a mean were identical on both dosing days. with intravenous glucose infusion to raise age of 27.7 Ϯ 5.4 years and a mean BMI of Smoke inhalation did not differ between their blood glucose level to 2.5 mmol/l or 23.4 Ϯ 2.2 kg/m2 for smokers and 23.0 Ϯ smoking groups (acute and nonacute a level necessary to relieve symptoms, 1.7 kg/m2 for nonsmokers (Table 1). A smoking), and subjects used their own whereas the blood sampling continued total of 43 eligible volunteers had inhaled cigarettes and inhalation habits. as planned. This glucose infusion sty- insulin administered, and these individu- In the morning of each dosing day mied interpretation of pharmacodynamic als comprised 27 smokers and 16 non- and after an overnight fast, a single dose of parameters. smokers. Smokers were defined as inhaled human soluble insulin in dispos- After inhalation of the trial drug, sub- smoking, on average, Ն10 cigarettes a able insulin strips (67.5 IU/strip; Novo jects held their breath for 10 s and then day for at least 5 years. Nonsmokers were defined as not having smoked tobacco for at least the previous 3 years and as having an average total smoking history of Յ7 pack-years (e.g., one pack of 20 cigarettes a day for 7 years).