Combined SGLT1 and SGLT2 Inhibitors and Their Role in Diabetes Care
Combined SGLT1 and SGLT2 Inhibitors and Their Role in Diabetes Care
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DOI：
10.1089/dia.2018.0081
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发表时间：
2018-06-01
影响因子：
5.4
通讯作者：
Kordonouri, Olga
中科院分区：
文献类型：
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作者：
Danne, Thomas;Biester, Torben;Kordonouri, Olga
1 型钠-葡萄糖协同转运蛋白 (SGLT1) 是胃肠道中吸收葡萄糖和半乳糖的主要转运蛋白。抑制会减弱并延迟餐后血糖 (PPG) 的波动。 2 型钠-葡萄糖协同转运蛋白 (SGLT2) 在肾脏中表达，可重吸收 90% 的滤过葡萄糖。因此，双重 SGLT1 和 SGLT2 抑制（与选择性 SGLT2 抑制相比）即使在肾功能下降的患者中也可能导致较低的 PPG 和显着的 A1c 降低。 Sotagliflozin 是一种口服有效的胰岛素依赖性 SGLT1 和 SGLT2 双重抑制剂。针对成人 1 型糖尿病 (T1DM) 和 2 型糖尿病 (T2DM) 的 2 期和 3 期临床研究发布的初步数据显示，血糖控制有所改善，并达到了 A1c 以外的疗效终点，安全性与 SGLT 类别一致：体重、收缩压显着降低，在较低估计肾小球滤过率水平下保持疗效，且低血糖未增加。糖尿病酮症酸中毒 (DKA) 伴异常轻度至中度血糖升高（血糖正常的 DKA）的风险增加与使用所有已批准的 SGLT2 抑制剂有关。引发 DKA 的因素包括胰岛素减少、热量和液体摄入量低、并发疾病和饮酒。然而，通过适当的患者教育，DKA 是可以检测和控制的。使用 sotagliflozin 时，DKA 发生率并不高于 T1DM 的预期背景发生率，但在数值上高于安慰剂。 Sotagliflozin 是第一个为治疗成年 T1DM 患者而开发的口服 SGLT1 和 SGLT2 抑制剂，与胰岛素联合使用，有潜力解决 T1DM 和可能的 T2DM 患者未满足的需求，并具有良好的获益/风险状况。
The sodium-glucose cotransporter type 1 (SGLT1) is the primary transporter for absorption of glucose and galactose in the gastrointestinal tract. Inhibition blunts and delays postprandial glucose (PPG) excursion. Sodium-glucose cotransporter type 2 (SGLT2) is expressed in the kidney, where it reabsorbs 90% of filtered glucose. Thus, a dual SGLT1 and SGLT2 inhibition (compared with selective SGLT2 inhibition) could result in lower PPG and robust A1c reduction even in patients with reduced kidney function. Sotagliflozin is an oral potent dual inhibitor of the insulin-independent SGLT1 and SGLT2. Preliminary data released from phase 2 and 3 clinical studies in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) showed improved glycemic control, and met efficacy endpoints beyond A1c with a safety profile consistent with the SGLT class: significant reduction in body weight, systolic blood pressure, and efficacy maintained in lower estimated glomerular filtration rate levels with no increased hypoglycemia. Increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild-to-moderate glucose elevations (euglycemic DKA) is associated with the use of all the approved SGLT2 inhibitors. Factors that trigger DKA include insulin reductions, low caloric and fluid intake, intercurrent illness, and alcohol use. However, DKA is detectable and manageable with proper patient education. With sotagliflozin, DKA rates were not higher than the expected background rate in T1DM, but numerically higher than placebo. Sotagliflozin is the first oral SGLT1 and SGLT2 inhibitor developed for the treatment of adult patients with T1DM, in adjunct with insulin, and has the potential to address unmet needs for patients with T1DM and possibly T2DM, with a favorable benefit/risk profile.