Purpose: Our aim was to investigate the long-term efficacy and safety of canagliflozin, a sodium-glucose co-transporter 2 inhibitor, added to background sulfonylurea (SU) monotherapy for patients with type 2 diabetes mellitus.
Methods: The CANagliflozin cardioVascularAssessment Study (CANVAS) was a double-blind, placebo-controlled cardiovascular outcomes study that randomly assigned participants to receive placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. CANVAS included a prespecified SU substudy of patients taking background doses of SU monotherapy; data from the primary efficacy evaluation at 18 weeks have been published previously. We performed a retrospective analysis of the SU substudy at 52 weeks to measure long-term efficacy and safety of canagliflozin used with an SU. The primary objective of the long-term extension was to assess the change from baseline to 52 weeks in glycosylated hemoglobin (HbA1c).
Findings: A total of 215 patients were included in the 52-week extension study. Patients receiving both 100-mg and 300-mg doses of canagliflozin achieved a sustained reduction in HbA1c relative to patients receiving placebo (-0.61% [95% CI, -0.941% to -0.282%] and -0.66% [95% CI, -0.993% to -0.332%], respectively), regardless of baseline HbA1c, duration of diabetes, SU dose, estimated glomerular filtration rate, or body mass index. A sustained reduction in fasting plasma glucose was also found in both 100-mg and 300-mg groups, relative to the placebo group (-2.04 mmol/L [95% CI, -2.778 to -1.299 mmol/L] and -1.88 mmol/L [95% CI, -2.623 to -1.146 mmol/L], respectively). Weight was reduced significantly at 52 weeks in both 100-mg and 300-mg groups, relative to placebo (-1.9% [95% CI, -3.2% to -0.7%] and -2.0% [95% CI, -3.2% to -0.7%], respectively). Reduction in systolic blood pressure was also reported for both dose groups relative to the placebo group, but there was no clear difference in HDL-C, LDL-C, or triglyceride levels. Canagliflozin was generally well tolerated. While documented hypoglycemia occurred in 14% of patients on placebo, the frequency of hypoglycemia with the addition of canagliflozin was similar. There was an increased frequency of genital mycotic infections in both men (5.1%) and women (10.4%) in both canagliflozin groups combined, relative to the placebo group (0%), and their frequency increased in the higher-dose group. There was a slightly higher rate of renal impairment in those treated with canagliflozin versus placebo (2.1% vs 0%).
Implications: After 52 weeks, patients receiving canagliflozin added to background SU had sustained reductions in HbA1c and fasting plasma glucose, without increasing hypoglycemia and body weight; safety findings were generally consistent with the known safety profile of the drug. ClinicalTrials.gov identifier: NCT01032629.
Keywords: SGLT2 inhibitor; canagliflozin; cardiovascular disease; sulfonylureas; type 2 diabetes; weight loss.
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