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)
Article first published online: 30 JUN 2013
© 2013 Wiley Publishing Asia Pty Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine
Journal of Diabetes
Volume 5, Issue 3, pages 225–227, September 2013
How to Cite
Bloomgarden, Z. (2013), 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). Journal of Diabetes, 5: 225–227. doi: 10.1111/1753-0407.12065
- Issue published online: 5 AUG 2013
- Article first published online: 30 JUN 2013
- Accepted manuscript online: 29 MAY 2013 02:06AM EST
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. 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. Recent observations have shown that diabetic patients upregulate the expression of this and other renal glucose transporters, 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. 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, 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. 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. 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. 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. Empagliflozin and ipragliflozin have been less well studied, but appear to similarly lower glucose levels in monotherapy and in combination with metformin.
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. 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.
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; such effects did not appear to occur with canagliflozin. Although diuresis is beneficial in the treatment of hypertension, some treated patients may become dehydrated with the agent, 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.
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。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。
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）。
- 8US Food and Drug Administration. FDA briefing document NDA 202293: Dapagliflozin tablets, 5 and 10 mg, Sponsor: Bristol-Myers Squibb. Advisory Committee Meeting July 19, 2011. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm262994.pdf (accessed 27 May 2013).
- 12Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care. 2013; 36: PMID: 23564919. [Epub ahead of print]., , et al.
- 17Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study. Diabetes Care. 2013; 36: PMID: 23412078. [Epub 14 February 2013]., , et al.
- 20US Food and Drug Administration. FDA briefing document NDA 204042. Invokana (canagliflozin) Tablets, Applicant: Janssen Pharmaceuticals, Inc. Endocrinologic and Metabolic Drugs Advisory Committee Meeting January 10, 2013. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolic%20DrugsAdvisoryCommittee/UCM334550.pdf (accessed 27 May 2013).