Sodium glucose transporter 2 inhibition: A new approach to diabetes treatment (抑制钠葡萄糖转运体2:一种新的糖尿病治疗方法)

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A vexing aspect of the treatment of type 2 diabetes is the potential of both insulin and the sulfonylureas to cause hypoglycemia, with increasing recognition of the association of hypoglycemia with adverse outcome.[1] It is hypoglycemia rather than normalization of glycemic control that appears (for certain individuals) to be undesirable. Although in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study intensive glycemic treatment was associated with an increase in mortality, there was actual reduction in mortality with excellent control, with the dilemma that those diabetic patients in worse control initially appeared to have greater risk of both hypoglycemia and mortality.[2-4] Thus, the appearance of a new therapeutic class not intrinsically associated with hypoglycemia should be greeted with cautious optimism.

Glucose is present in the glomerular filtrate and is, under usual circumstances, completely reabsorbed by a group of transport proteins in the renal tubular epithelium, with sodium glucose transporter (SGLT)-2 quantitatively the most important.[5] Recent observations have shown that diabetic patients upregulate the expression of this and other renal glucose transporters,[6] presumably to compensate for and reduce glycosuria. A number of orally absorbed small molecules can inhibit this transporter, leading to glycosuria at even modestly elevated glucose concentrations, a phenomenon that was used experimentally nearly three decades ago in studies demonstrating that glucose toxicity is a reversible contributor to both insulin resistance and impaired insulin secretion.[7] Glucose excretion with administration of these SGLT2 inhibitors increases in degree as glucose levels rise, whereas the agents do not increase glycosuria to a major degree at eu- or hypoglycemic levels. In addition, by causing osmotic diuresis, these agents may have benefits in lowering blood pressure, and the glucose lost in the urine can lead to weight reduction.

What are the clinical data? A number of SGLT2 inhibitors are being studied, including dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin. A series of Phase 3 clinical trials of dapagliflozin presented to the US Food and Drug Administration showed dose-related glucose-lowering of similar efficacy to that of sulfonylureas and metformin,[8] with a study of dapagliflozin added to metformin showing a glucose-lowering effect equal to that of glipizide, but with less than one-tenth as much hypoglycemia.[9] In a meta-analysis of clinical studies, dapagliflozin was associated with significant weight loss and with a reduction in systolic blood pressure without increasing hypoglycemia.[10] Dapagliflozin is approved for the treatment of type 2 diabetes in the European Union. Canagliflozin, which has recently been approved in the US, similarly lowers glucose, blood pressure, and body weight in a dose-related manner.[11] In a study of type 2 diabetic patients treated with metformin plus sulfonylurea, canagliflozin at the highest dose lowered HbA1c to a greater extent than did sitagliptin.[12] Empagliflozin[13] and ipragliflozin[14] have been less well studied, but appear to similarly lower glucose levels in monotherapy and in combination with metformin.[15]

It was thought that inhibition of the major intestinal glucose transporter SGLT1 would lead to undesirable gastrointestinal side effects, but interesting preliminary evaluation of LX4211, which inhibits SGLT1 as well as SGLT2, showed that in addition to similar glucose-lowering efficacy to that of the SGLT2 inhibitors, LX4211increased levels of both glucagon-like peptide-1 (GLP-1) and peptide YY, suggesting that by increasing the delivery of glucose to the distal small intestine there may be L-cell stimulation.[16] In fact, because of the higher drug concentrations in the gastrointestinal tract, the SGLT2 inhibitors may also act on gastrointestinal SGLT1, with studies of canagliflozin showing that it lowers postprandial glucose in association with a reduction in gastrointestinal glucose absorption, and reduces renal glucose reabsorption.[17]

However, there are a number of potential adverse effects to be considered in the use of SGLT2 inhibitors. By increasing glycosuria, they can predispose to both urinary infection and fungal genital tract infection,[10, 18, 19] and concerns have been raised as to potential for the development of bladder and breast cancers with dapagliflozin;[8] such effects did not appear to occur with canagliflozin.[20] Although diuresis is beneficial in the treatment of hypertension, some treated patients may become dehydrated with the agent,[20] which could lead to initial adverse cardiovascular effects, although there is no overall evidence of cardiac safety effects. Given the dependence of the glycosuria on glucose in the glomerular filtrate, there is limited benefit with renal insufficiency. Finally, a dose-related 4–8 mg/dL (0.1–0.2 mmol/L) elevation in low-density lipoprotein–cholesterol (LDL-C) was observed with canagliflozin.[20]

We are left then with a fascinating group of agents exhibiting the benefits of glucose lowering without hypoglycemia risk, with weight loss and the potential for blood pressure lowering. Concerns include urinary infection, genital tract micotic infection, the potential for volume depletion, very limited evidence of increased malignancy with dapagliflozin, and with mild but definite LDL-C increases with canagliflozin, and the lesser efficacy of these agents with renal insufficiency. Just as we now routinely give combinations of multiple blood pressure-lowering agents in the treatment of hypertension, can we foresee a time when multiple oral agents can be given to type 2 diabetic patients, with a low risk of hypoglycemia and weight gain, allowing stable long-term glycemic control?

在2型糖尿病的治疗中比较棘手的问题是胰岛素与磺脲类药物均有可能导致低血糖,而与此同时人们又越来越多地认识到了低血糖与不良结果之间的关系[1]。令人讨厌的正是出现了低血糖(对于某些患者来说)而不是血糖控制正常。虽然在控制糖尿病心血管风险行动(Action to Control Cardiovascular Risk in Diabetes ACCORD)研究中,强化血糖控制与死亡率增加相关,但事实上极佳的血糖控制可以减少死亡率,同时令人困惑的是那些血糖控制更差的糖尿病患者最初出现低血糖与死亡的风险都更高[2-4]。因此,一种新型的、与低血糖没有本质关联的治疗药物出现后应该能够受到人们谨慎而乐观的欢迎。

葡萄糖可出现在肾小球滤过液中,并且通常情况下可被肾小管上皮细胞中的一组转运蛋白完全重吸收,其中钠葡萄糖转运体(SGLT)-2的数量是最重要的[5]。最近的观察结果显示糖尿病患者的SGLT2以及其他肾脏葡萄糖转运体的表达都得到了上调[6],可能是为了补偿与减少糖尿。许多口服吸收的小分子可以抑制该转运体,甚至在血糖浓度适度升高的情况下也可以导致糖尿,这种现象在约30年以前观察葡萄糖毒性导致胰岛素抵抗与胰岛素分泌受损的可逆作用研究中就已经被利用[7]。使用这些SGLT2抑制剂以后随着血糖水平的升高可以增加葡萄糖的清除程度,然而这些药物在正常或者低血糖水平下并不会大幅度地增加糖尿。另外,通过引起渗透性利尿,这些药物可能对降低血压有益,且尿糖丢失后可使体重减轻。

临床数据是什么?目前正在研究许多SGLT2抑制剂,包括达格列净、坎格列净、empagliflozin与ipragliflozin。一系列提交给美国食品与药物管理局的达格列净3期临床试验结果显示,它具有剂量依赖性的降糖作用,其疗效与磺脲类以及二甲双胍相类似[8],同时一项达格列净联合二甲双胍的研究结果显示其降糖疗效等同于格列吡嗪,但是低血糖的发生率不到它的十分之一[9]。一项临床研究Meta分析发现,达格列净与显著的体重减轻以及收缩压下降相关,同时低血糖的发生率却没有增加[10]。达格列净在欧盟已被批准用于治疗2型糖尿病。坎格列净最近在美国也已被批准使用,它同样具有剂量依赖性的降低血糖、血压与体重的作用[11]。在一项2型糖尿病患者使用二甲双胍联合磺脲类作为基础治疗的研究中,与加用西格列汀相比较,加用最高剂量坎格列净治疗的患者HbA1c下降程度更大[12]。Empagliflozin[13]与ipragliflozin[14]还没有被很好地研究,但是在单药治疗以及与二甲双胍的联合治疗中也表现出了相似的降糖作用[15]。

有人认为占较大比例的肠道内葡萄糖转运体SGLT1受到抑制后将导致胃肠道不良反应,但有趣的是通过初步评估LX4211,一种可以同时抑制SGLT1与SGLT2的药物,发现除了具有与SGLT2抑制剂相似的降糖疗效以外,LX4211还可以升高胰高血糖素样肽-1(GLP-1)与YY肽的水平,这表明它通过增强葡萄糖向远端小肠转运可能对L细胞具有刺激作用[16]。实际上,因为在胃肠道内的药物浓度较高,SGLT2抑制剂可能对胃肠道SGLT1也有作用,有关坎格列净的研究结果显示,它降低餐后血糖与减少胃肠道葡萄糖吸收,以及减少肾脏葡萄糖重吸收有关[17]。

然而,目前使用SGLT2抑制剂治疗也存在着许多潜在的不良作用。通过增加尿糖,它们有可能诱发尿路感染与生殖道真菌感染[10, 18, 19],对达格列净有可能导致膀胱癌与乳腺癌的担忧也逐渐增加8;但是坎格列净并没有出现这些不良作用20。虽然利尿对于治疗高血压是有益的,但有些患者用药后会出现脱水20,这将导致初期心血管不良作用,即使目前还没有整体的影响心脏安全性的证据。因为尿糖依赖于肾小球滤过液中的葡萄糖浓度,所以肾功能不全的患者获益有限。最后,使用坎格列净后可观察到低密度脂蛋白胆固醇呈剂量相关性升高4–8 mg/dL(0.1–0.2 mmol/L)[20]。

我们面前摆着一组令人感兴趣的药物,它们在降糖的同时又不会有低血糖的风险,不但具有减轻体重的作用并且还可能有降压作用。然而担心的事情包括尿路感染,生殖道真菌感染,可能导致血容量不足,以及极为有限的使用达格列净后恶性肿瘤增加的证据。使用坎格列净后低密度脂蛋白胆固醇会有轻度但是明确的升高,以及这些药物在患者肾功能不全时效果变差。正如我们现在治疗高血压时要常规联合使用多种降压药物,我们不禁要问,给予2型糖尿病患者多种口服药物进行治疗,即能减少低血糖与体重增加的风险,同时还能达到长期血糖稳定的日子还远吗?

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