Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, Washington 99217, USA.
Drugs. 2010 Mar 5;70(4):377-85. doi: 10.2165/11318680-000000000-00000.
The kidney plays a major role in glucose homeostasis because of its role in gluconeogenesis and the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Approximately 180 g of glucose is filtered daily in the glomeruli of a normal healthy adult. Typically, all of this glucose is reabsorbed with <1% being excreted in the urine. The transport of glucose from the tubule into the tubular epithelial cells is accomplished by sodium-glucose co-transporters (SGLTs). SGLTs encompass a family of membrane proteins that are responsible for the transport of glucose, amino acids, vitamins, ions and osmolytes across the brush-border membrane of proximal renal tubules as well as the intestinal epithelium. SGLT2 is a high-capacity, low-affinity transporter expressed chiefly in the kidney. It accounts for approximately 90% of glucose reabsorption in the kidney and has thus become the focus of a great deal of interest in the field of diabetes mellitus. SGLT2 inhibitors block the reabsorption of filtered glucose leading to glucosuria. This mechanism of action holds potential promise for patients with type 2 diabetes mellitus (T2DM) in terms of improvements in glycaemic control. In addition, the glucosuria associated with SGLT2 inhibition is associated with caloric loss, thus providing a potential benefit of weight loss. Dapagliflozin is the SGLT2 inhibitor with the most clinical data available to date, with other SGLT2 inhibitors currently in the developmental pipeline. Dapagliflozin has demonstrated sustained, dose-dependent glucosuria over 24 hours with once-daily dosing in clinical trials. Although long-term safety data are lacking, studies to date have generally found dapagliflozin to be safe and well tolerated. Concerns related to SGLT2 inhibition include the fact that by their very nature they cause glucose elevation in the urine that can theoretically lead to urinary tract and genital infections, electrolyte imbalances and increased urinary frequency. Although studies to date have been promising in terms of these and other concerns, longer-term studies evaluating the usual safety and efficacy outcomes will need to be conducted. Similarly, head-to-head comparator trials are needed to determine the role of SGLT2 inhibitors in relation to the many other therapeutic options available for the treatment of T2DM. If significant reductions in haemoglobin A(1c) are associated with SGLT2 inhibitor therapy, and these agents are determined to be safe and well tolerated in the long term, they could become a major breakthrough in the T2DM treatment armamentarium.
肾脏在葡萄糖稳态中起着重要作用，因为它在葡萄糖生成和近端曲管中的肾小球滤过和重吸收葡萄糖方面发挥作用。在正常健康成年人的肾小球中，每天大约过滤 180 克葡萄糖。通常，所有这些葡萄糖都被重吸收，只有<1%的葡萄糖随尿液排出。葡萄糖从肾小管进入肾小管上皮细胞的转运是通过钠-葡萄糖协同转运蛋白（SGLTs）完成的。SGLTs 包括一组膜蛋白，负责将葡萄糖、氨基酸、维生素、离子和渗透物从近端肾小管的刷状缘膜以及肠上皮转运。SGLT2 是一种高容量、低亲和力的转运体，主要在肾脏中表达。它负责肾脏中约 90%的葡萄糖重吸收，因此成为糖尿病领域研究的热点。SGLT2 抑制剂可阻断滤过葡萄糖的重吸收，导致糖尿。这种作用机制为 2 型糖尿病（T2DM）患者提供了改善血糖控制的潜在希望。此外，与 SGLT2 抑制相关的糖尿与热量损失有关，从而提供了减肥的潜在益处。达格列净是目前临床数据最多的 SGLT2 抑制剂，其他 SGLT2 抑制剂目前正在开发中。在临床试验中，达格列净每日一次给药可在 24 小时内持续、剂量依赖性地产生糖尿。尽管缺乏长期安全性数据，但迄今为止的研究普遍发现达格列净安全且耐受良好。与 SGLT2 抑制相关的担忧包括这样一个事实，即它们通过其性质本身导致尿液中葡萄糖升高，理论上可能导致尿路感染和生殖器感染、电解质失衡和排尿频率增加。尽管迄今为止的研究在这些和其他方面都很有前景，但需要进行更长期的研究，以评估通常的安全性和疗效结果。同样，需要进行头对头比较试验，以确定 SGLT2 抑制剂在治疗 2 型糖尿病的众多其他治疗选择中的作用。如果 SGLT2 抑制剂治疗与血红蛋白 A1c 的显著降低相关，并且这些药物在长期内被确定为安全且耐受良好，它们可能成为 2 型糖尿病治疗手段的重大突破。
