Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion

Abstract

Abstract This study was aimed to evaluate whether the dose–response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)—canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin—can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Information on HbA1c reduction at various doses of each SGLT2i was collected from literatures on randomized controlled trials and was normalized based on the daily UGE data from phase I studies. After normalizing doses, the dose–response relationship of HbA1c reduction of most of SGLT2is was represented by a unified nonlinear mixed-effect model, with the estimated maximum HbA1c (%) reduction (Emax) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher Emax than those of the other drugs. Other covariates included baseline HbA1c levels, body weight, disease duration, prior treatment, and renal function. Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials.

Keywords

• Pharmacometrics
• SGLT2 inhibitor
• Model-based meta-analysis
• Diabetes