Introduction: Patients with diabetes often require add-on therapy due to the progressive nature of this disease. Recently, the American Diabetes Association recommended using diabetes medications with complimentary mechanisms of action in triple-therapy combinations if dual therapy is not sufficient. Canagliflozin’s mechanism of action as an SGLT2 inhibitor is distinct from that of current anti-hyperglycemic agents, making it a potentially advantageous add-on therapy.
Methods: This phase 3 study compared the change in hemoglobin A1C in 755 patients randomized to canagliflozin 300 mg or sitagliptin 100 mg daily, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in addition to background therapy with metformin plus sulfonylurea. The patients all were inadequately controlled on the background therapy.
Results: After 52 weeks, the median A1C decreased significantly by -1.03% from baseline with canagliflozin versus -0.66% with sitagliptin. Other differences between the two groups included a greater decrease in fasting plasma glucose level (-1.7 vs -0.3 mmol/L); body weight (-2.5% vs 0.3%); and systolic blood pressure (-5.1 vs +0.9 mm Hg; P<0.001 for all comparisons).
The rate of treatment discontinuation was higher in the canagliflozin group than in the sitagliptin group (44.4% vs 32.6%), with the most common reason for dropouts being failure to meet prespecified glycemic targets (22.5% vs 10.6%) as the study design did not allow for use of glycemic rescue therapy.
The incidence of serious adverse events and adverse-event related discontinuations were relatively low in both groups. The canagliflozin 300 mg group had a higher incidence of genital mycotic infections (15.3% vs 4.3% in women; 9.2% vs 0.5% in men) and osmotic diuresis-related adverse events (pollakiuria: 1.6% vs 1.3%; polyuria: 0.8% vs 0%) compared with the sitagliptin group.
Conclusion: The findings suggest that this agent may be beneficial in patients inadequately controlled with metformin plus a sulfonylurea who require a third agent.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
The progression of diabetes often requires escalation of pharmacotherapy to meet treatment goals. It is the standard of care to move from monotherapy to combination therapy by adding a second agent and eventually a third one. The usual progression of diabetes medications in clinical algorithms is dictated by an individual’s response to antecedent treatment. In most third-party payer coverage rules, generic medications must fail to achieve treatment goals before patented medications may be considered for coverage. Therefore, in this study, Schernthaner and colleagues studied the addition of one of two patented drugs to a regimen that is very common in clinical practice: the combination of metformin and a sulfonylurea, two classes of generic medications.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral agents with antihyperglycemic properties. DPP-4 is a gut enzyme that breaks down glucagon-like intestinal peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). DPP-4 activity in patients with type 2 diabetes mellitus causes long-term loss of both GLP-1 and GIP activity. Therefore, inhibition of DPP-4 raises the levels of GLP-1 and GIP in the circulation. Boosting the levels of GLP-1 with DPP-4 inhibition has the major physiological effect of restoring first phase insulin release in people with diabetes. In addition, DPP-4 inhibition also causes a decrease in glucagon release from the pancreas, which is likely due to increased insulin production and a delay in gastric emptying. The combined effects result in a lowering of the level of glycemia.
In this trial, sitagliptin—the first of the DPP-4 inhibitors to come to market—was compared head to head to canagliflozin. Both medications achieved further lowering of the A1C level, and canagliflozin did better than sitagliptin. Both drugs had similar rates of hypoglycemic reactions when added to the hypoglycemic effect of a sulfonylurea. As has been repeatedly shown, canagliflozin significantly lowered body weight and blood pressure, which are additional benefits of this medication. On the other hand, owing to the glucosuria that results from canagliflozin’s mechanism of action, genital mycotic infections and side effects from osmotic diuresis were more common with canagliflozin.
Based on these findings, canagliflozin is a safe and effective drug to add as third-line therapy for type 2 diabetes.