Canagliflozin is a selective sodium glucose-cotransporter 2 (SGLT-2) inhibitor which blocks the reabsorption of glucose in the kidneys and promotes excretion of excess glucose in the urine. It has recently been licensed in the US for use as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus; it is not however approved in the EU.
The purpose of this double-blind Phase III study (CANTATA-D2; n=755) was to compare canagliflozin to sitagliptin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with metformin plus sulfonylurea. The primary endpoint was change from baseline in HbA1C at 52 weeks - canagliflozin was found to be non-inferior, and following subsequent testing superior, to sitagliptin with respect to this endpoint (mean difference between groups of -0.37%; 95% CI -0.50 to -0.25). Canagliflozin was also associated with improvements in various secondary endpoints studied, including body weight (improvement versus slight increase with sitagliptin), glucose levels (greater reductions in pre-meal levels versus sitagliptin) and fasting plasma glucose.
The overall incidence of adverse events was similar for canagliflozin and sitagliptin, although canagliflozin was associated with higher rates of genital mycotic infections (mainly mild or moderate; treated with conventional antifungals) and osmotic diuresis–related adverse events (polyuria). The incidence of hypoglycaemia was similar for the two groups. The authors note that the overall rate of study discontinuation (38.5%) was high, but that this was expected given the absence of glycaemic rescue therapy in this study.
The authors conclude that SGLT-2 inhibitors may present a new therapeutic option for diabetes, providing a mechanism of action that is complementary to those of other oral antidiabetic drugs. Based on the overall profile of canagliflozin observed in this study, they suggest that it may be a beneficial option when a third agent is needed.
The study was limited by its relatively short duration considering that diabetes is a chronic condition – longer-term studies will therefore be required to evaluate the durability of the effects of canagliflozin. In addition the findings may not be generalisable to patients using other antidiabetic regimens or those with milder or more severe HbA1c at baseline. Further studies utilising other active comparators are required to help evaluate the relative benefits of canagliflozin with agents commonly used as third agents in combination with metformin and sulfonylurea in clinical practice.
NICE guidance on canagliflozin is currently in development, and final guidance is due to be issued in February 2014. Dapagliflozin is currently the only SGLT-2 inhibitor licensed in the UK.