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Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy
Author(s) -
Perkins Bruce A.,
Soleymanlou Nima,
Rosenstock Julio,
Skyler Jay S.,
Laffel Lori M.,
Liesenfeld KarlHeinz,
Neubacher Dietmar,
Riggs Matthew M.,
Johnston Curtis K.,
EudyByrne Rena J.,
Elmokadem Ahmed,
George Jyothis T.,
Marquard Jan,
Nock Valerie
Publication year - 2020
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13945
Subject(s) - empagliflozin , medicine , insulin , diabetes mellitus , population , placebo , type 2 diabetes , diabetic ketoacidosis , endocrinology , alternative medicine , environmental health , pathology
Abstract Aim To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE‐3 by modelling and simulation analyses. Materials and methods Independent of data from EASE‐3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient‐level, exposure‐response modelling in the EASE‐2 clinical study. A primary semi‐mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE‐3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE‐3 but not EASE‐2) included a lower 2.5 mg dose. A placebo‐corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses. Results The simulated 26‐week mean HbA1c change was −0.41% without insulin dose adjustment and −0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the –0.29% HbA1c change that would have been observed had the EASE‐2 population received a 2.5 mg dose for 26/52 weeks. Conclusions The HbA1c benefit of low‐dose empagliflozin directly observed in the EASE‐3 trial was confirmed by two modelling and simulation approaches.