Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba-shi, Chiba, 260-8679, Japan.
Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
Sci Rep. 2024 Oct 21;14(1):24695. doi: 10.1038/s41598-024-76256-6.
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 (E) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher E 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.
本研究旨在评估钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2is）在 2 型糖尿病（T2DM）患者中的剂量-反应关系——坎格列净、达格列净、恩格列净、伊格列净、鲁格列净和托格列净——能否基于其促进尿糖排泄（UGE）的能力进行统一解释。从随机对照试验的文献中收集了各种剂量的 SGLT2i 降低 HbA1c 的信息，并根据 I 期研究的每日 UGE 数据进行了归一化。归一化剂量后，大多数 SGLT2i 的 HbA1c 降低的剂量反应关系用统一的非线性混合效应模型表示，估计的最大 HbA1c（%）降低（E）为 0.796 点，而协变量分析表明，坎格列净的 E 比其他药物高 1.33 倍。其他协变量包括基线 HbA1c 水平、体重、病程、既往治疗和肾功能。本研究的结果将影响临床实践中的药物选择和调整。与 SGLT2is 一样，在疗效不易评估但在早期临床试验中评估了适当的药效学标志物的情况下，类似的方法可指导 III 期试验中基于策略和证据的剂量选择。
