Exposure?response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes

摘要

Aims To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure?response (E?R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). Methods Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM ( n = 974; 1–100?mg once daily, duration ≤12 weeks) were used to develop E?R models for efficacy (glycosylated haemoglobin [HbA_1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies ( n = 748, 12 weeks) were used to evaluate tolerability E?R. Results The efficacy model predicted maximal decreases in FPG and HbA_1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8?m m (144?mg?dl?1) and 10–25?mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia ( n = 4), urinary tract infection ( n = 17) or genital/vulvovaginal-related ( n = 16) events, although low prevalence rates may have precluded more accurate evaluation. Conclusions E?R analyses indicated that 10 and 25?mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.