Introduction: Previous data has demonstrated the efficacy of the SGLT2 inhibitor canagliflozin over placebo in reducing hemoglobin A1C levels, fasting plasma glucose, and weight, while having a relatively low risk of producing hypoglycemia. The present study was designed to extend this research into a long-term, head-to-head trial comparing the efficacy of canagliflozin with the sulfonylurea glimepiride.
Methods: This multicenter, phase 3, trial involved 1,450 patients ages 18 to 80 years with inadequately controlled type 2 diabetes despite treatment with metformin. The patients were randomized to receive either canagliflozin at 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily for 52 weeks.
Results: At 52 weeks, canagliflozin 100 mg was noninferior to glimepiride at lowering the A1C level and the 300-mg dose was superior to glimepiride (least-squares mean difference, -0.12%). Both canagliflozin doses were linked to significant decreases in body weight, while a slight increase in weight was found in the glimepiride group (P<0.001 for both doses vs glimepiride).
The incidence of serious adverse effects was 5% in both canagliflozin groups and 8% in the glimepiride group. The canagliflozin groups had a slightly higher incidence of genital mycotic infections (women: 11% with 100-mg and 14% with 300-mg canagliflozin vs 2% with glimepiride; men: 7% and 8% vs 1% with glimepiride) and urinary tract infections (6% for both canagliflozin doses vs 5% with glimepiride). In addition, osmotic diuresis-related adverse events were more common in the canagliflozin groups; however, the frequency of these events was low in all groups (≤3%). The frequency of severe hypoglycemia was lower with canagliflozin, but was relatively low in all three treatment groups (≤3%)
Conclusion: Canagliflozin 100 mg and 300 mg improved glycemic control over 52 weeks as an add-on treatment to metformin in patients with type 2 diabetes. The 300-mg canagliflozin dose was superior to glimepiride in terms of efficacy and both doses of canagliflozin were well tolerated.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
In the current economic and political climate, the practice of medicine is shaped by restrictions of coverage and outright rationing of resources. Every third-party payer creates obstacles for the use of patented medications, which encourages the use of generic prescriptions. There is no due consideration for individual patient needs or preferences. Almost universally, metformin is the oral agent of choice for diabetes monotherapy. In the algorithms employed by third-party payers to determine coverage, when combination therapy is required to meet treatment goals, the second-line agent is frequently a sulfonylurea. This is largely a financial rather than a logical decision.
Medications that have an inherent risk of hypoglycemia should be used with due caution. Sulfonylureas, because of their beta-cell stimulation regardless of level of glycemia, make hypoglycemia a significant risk. And to prevent hypoglycemia, patients often have to increase their caloric intake (ie, avoid low glucose reactions by eating).
In this trial by Cefalu and colleagues, the sulfonylurea glimepiride was compared to canagliflozin as add-on therapy for patients inadequately controlled on metformin monotherapy. The authors found that canagliflozin 300 mg does a better job lowering blood glucose levels than glimepiride. There is a significant increase in genital mycotic infections with canagliflozin compared to glimepiride. However, serious adverse events were less frequent with either dose of canagliflozin than with glimepiride. Of particular note, the incidence of hypoglycemia was 6 times higher in the glimepiride group than in either of the canagliflozin groups.
A subset of patients in this study underwent body composition analysis with dual energy x-ray absorptiometry or computerized tomography. Treatment with canagliflozin at either dose resulted in significant decreases in intra-abdominal visceral fat, total body fat, and percent fat, compared to glimepiride. Thus, canagliflozin is an effective treatment for the underlying adiposopathy of patients with diabetes, and it is a better choice for second-line therapy than sulfonylureas.