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Aim  To explain the subadditive efficacy typically observed with initial combination treatments for type 2 diabetes.    Methods  Individual subject data from 1186 patients with type 2 diabetes [mean glycated haemoglobin ( HbA1c ) = 8.8%] treated with metformin, canagliflozin or canagliflozin + metformin were used. The baseline  HbA1c  versus  ΔHbA1c  relationships for monotherapy arms were determined using analysis of covariance and then used to predict efficacy in the combination arms by modelling how applying one treatment lowers the ‘effective baseline  HbA1c ’ for a second treatment. The model was further tested using data from several published combination studies.    Results  The mean  ΔHbA1c  levels were −1.25, −1.33, −1.37, −1.77 and −1.81% with metformin, canagliflozin 100 mg, canagliflozin 300 mg, canagliflozin 100 mg/metformin and canagliflozin 300 mg/metformin, respectively. Using the monotherapy results, the predicted efficacy for the canagliflozin/metformin arms was within 10% of the observed values using the new model, whereas assuming simple additivity overpredicted efficacy in the combination arms by nearly 50%. For 10 other published initial combination studies, predictions from the new model [mean (standard error) predicted  ΔHbA1c  = 1.67% (0.14)] were much more consistent with observed values [ ΔHbA1c  = 1.72% (0.12)] than predictions based on assuming additivity [predicted  ΔHbA1c  = 2.19% (0.21)].    Conclusions  The less‐than‐additive efficacy commonly seen with initial combination treatments for type 2 diabetes can be largely explained by the impact of baseline  HbA1c  on the efficacy of individual treatments. Novel formulas have been developed for predicting the efficacy of combination treatments based on the efficacy of individual treatments and the baseline  HbA1c  of the target patients.

diabetes, obesity and metabolism

Apparent subadditivity of the efficacy of initial combination treatments for type 2 diabetes is largely explained by the impact of baseline HbA1c on efficacy