Canagliflozin 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

OBJECTIVE

To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea.

RESEARCH DESIGN AND METHODS

In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports.

RESULTS

At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (−1.03% [−11.3 mmol/mol] and −0.66% [−7.2 mmol/mol], respectively; least squares mean difference between groups, −0.37% [95% CI, −0.50 to −0.25] or −4.0 mmol/mol [−5.5 to −2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin (P < 0.001). Overall AE rates were similar with canagliflozin (76.7%) and sitagliptin (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. Higher incidences of genital mycotic infections and osmotic diuresis–related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both groups.

CONCLUSIONS

Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.Patients with type 2 diabetes often require combinations of antihyperglycemic agents (AHAs) to maintain glycemic control because of the progressive nature of the disease (1,2). Metformin is the recommended first-line pharmacologic therapy for type 2 diabetes (1,2). For patients who do not achieve or sustain sufficient glycemic control with metformin, a second AHA is often added (2). With further decline in glycemic control (3,4), the addition of a third oral agent is increasingly common. Currently available classes of AHAs, such as dipeptidyl peptidase-4 inhibitors, peroxisome proliferator–activated receptor (PPAR)γ agonists, and sulfonylureas, have distinct risk/benefit profiles (2,5). A recent position statement by the American Diabetes Association and the European Association for the Study of Diabetes recommends individualization of treatment for patients and suggests the use of pharmacologic agents with complementary mechanisms of action in triple therapy combinations if A1C targets are not attained with dual combination therapy (2).Canagliflozin is an inhibitor of the sodium glucose cotransporter 2 (SGLT2) in development for the treatment of patients with type 2 diabetes (6–10). SGLT2 is responsible for the majority of glucose reabsorption in the kidney (11). Almost all glucose is reabsorbed from the tubules until renal tubular resorptive capacity is exceeded and urinary glucose excretion (UGE) ensues; the glucose concentration at which this occurs is referred to as the renal threshold for glucose. Canagliflozin lowers the renal threshold for glucose, markedly increasing UGE and thereby reducing blood glucose concentrations in patients with hyperglycemia. The increase in UGE results in a mild osmotic diuresis and also provides a net caloric loss (with most patients with type 2 diabetes losing an average of 80–120 g/day) (12). This mechanism of action, distinct from the mechanisms of glucose-lowering of current AHA classes and independent of insulin, should provide additive glycemic control across stages of type 2 diabetes and range of classes, including add-on to the combination of metformin and a sulfonylurea agent. This 52-week Canagliflozin Treatment and Trial Analysis–dipeptidyl peptidase-4 inhibitor (CANTATA-D2; second comparator trial) study evaluated the efficacy and safety of canagliflozin 300 mg compared with sitagliptin 100 mg as add-on therapy in subjects with type 2 diabetes inadequately controlled with metformin plus a sulfonylurea agent.