SGLT2 Inhibitors for the Treatment of Diabetes

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SGLT2 Inhibitors for the Treatment of Diabetes
John P.H. Wilding, DM, FRCP
Medscape Today

Introduction
The optimal treatment of hyperglycemia in type 2 diabetes remains a major clinical challenge. This was highlighted by the results of intensive treatment in the Veterans Administration Diabetes Trial (VADT), the Action in Diabetes and Vascular Disease (ADVANCE) trial, and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, results of which were presented and discussed at the recent American Diabetes Association (ADA) meeting in San Francisco. Although the ADVANCE trial suggested benefit for microvascular -- but not macrovascular -- outcomes, ACCORD showed increased risk for cardiovascular death when very intensive treatment was initiated in high-risk patients with longstanding disease. The VADT suggested benefits of intensive control in disease of short duration but potential risk in longstanding disease. These studies also showed that although very tight glycemic targets (A1C of 6.5%) can be met using currently available agents, it is often at the expense of side effects, particularly increases in body weight and hypoglycemia. This has promoted a debate as to whether these side effects might at least in part explain the increases in mortality seen with such intensive interventions.

Despite these concerns, there remains a significant unmet need for new agents that will help patients with diabetes reach treatment targets, particularly if this can be achieved without increasing the risk for weight gain or hypoglycemia. Of the new classes of oral agents that are currently in clinical development, those that induce renal glucosuria by targeting the renal sodium-glucose transporter-2 (SGLT2) appear to hold real promise.

Rationale for SGLT2 Inhibition in Diabetes Treatment
It has been known for many years that induction of glucosuria using a nonselective inhibitor of renal and intestinal glucose transport, such as phlorizin, was able to improve control of diabetes in animal models, but these nonselective inhibitors were unsuitable for clinical development as drugs. More recent understanding of the physiology of renal glucose transport and the genetics of rare syndromes of renal glucosuria has allowed the development of drugs that selectively target the SGLT2 transporter.

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