Smoking enhances absorption of insulin but reduces glucodynamic effects in individuals using the Lilly‐Dura inhaled insulin system

Abstract

To quantify the pharmacokinetic (PK) and glucodynamic (GD) impact of smoking on inhaled and subcutaneous (SC) insulin administration in healthy subjects. This study employed the euglycemic clamp procedure in a four-period, four-way randomized crossover design. Eight smoking and eight non-smoking healthy males were given SC insulin on two occasions and human insulin inhalation powder (HIIP) on two other occasions. Smokers exhibited greater insulin exposure (AUC(0-t')) than non-smokers, following both routes of insulin administration (HIIP, P = 0.003, 58% increase; SC, P = 0.006, 24% increase). The maximum insulin concentration (C(max)) following HIIP was greater in smokers by 172% (P = 0.001) compared with non-smokers. The glucodynamic effects were greater in smokers following HIIP, consistent with the insulin concentration difference observed. However, maximum glucose response (R(max)) following SC was decreased by 36% (P = 0.001) and obtained later [time of maximum glucose response (TR(max)); P < 0.001] in smokers than in non-smokers. Smokers appeared less sensitive to insulin [total glucose infused during the clamp procedure normalised by total insulin exposure (G(tot))/AUC(0-t')] than non-smokers following both SC (P = 0.001) and inhaled (P = 0.011) routes of administration. Smokers had substantially increased peak HIIP insulin concentration, but the glucodynamic effect was partially offset, most likely because of increased insulin resistance.