Charité Research Organisation GmbH, Berlin, Germany.
National Research Council Institute of Clinical Physiology, Pisa, Italy.
Diabetes Care. 2022 Sep 1;45(9):2118-2126. doi: 10.2337/dc21-2166.
Inhibiting sodium-glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.
Using a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.
Changes from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.
Changes from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).
抑制钠-葡萄糖共转运蛋白（SGLTs）可改善 2 型糖尿病（T2D）患者的血糖和心血管结局。我们研究了选择性 SGLT2 抑制和 SGLT1 和 SGLT2 双重抑制对多种参数的差异影响。
我们采用双盲、平行分组设计，将 40 例伴有高血压的 T2D 患者随机分为两组，分别接受双重 SGLT1 和 SGLT2 抑制剂索格列净 400mg 或选择性 SGLT2 抑制剂恩格列净 25mg 治疗，同时给予预先存在的降压治疗，疗程 8 周。在内部检测点，通过混合餐耐量试验（MMTT）和其他实验室及临床评估，研究 24 小时内代谢、肠道、心血管和尿参数的变化。
与恩格列净相比，索格列净和恩格列净治疗均能使血糖和血压控制、肠道、尿液和代谢参数以及心血管生物标志物得到相似程度的改善。在早餐 MMTT 期间，索格列净显著降低餐后血糖、胰岛素和葡萄糖依赖性胰岛素释放肽（GIP）的曲线下面积（AUC）增量值，显著增加餐后胰高血糖素样肽 1（GLP-1）的 AUC 增量值，这与索格列净对肠道 SGLT1 的抑制作用一致。这些变化在午餐和晚餐 MMTT 期间减弱。两种治疗均使 14 小时 MMTT 期间的 GIP AUC 较基线水平显著降低；这种作用最明显的是在一天第一餐开始时给予索格列净。未观察到严重不良事件。
与恩格列净相比，索格列净和恩格列净治疗后，血糖和血压控制、心血管生物标志物和其他参数的变化无显著差异。然而，与恩格列净相比，索格列净可抑制早餐后肠道 SGLT1，表现为餐后血糖、胰岛素、GIP 和 GLP-1 AUC 变化更大，特别是早餐后。需要进一步研究以评估短暂 SGLT1 抑制和肠促胰岛素反应差异的临床意义（NCT03462069）。
