Sodium-Glucose Co-Transport Inhibitors

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_lc 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.