Adverse Drug Events Related to Canagliflozin: A Meta-Analysis of Randomized, Placebo-Controlled Trials

Canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, was recently approved in United States for the treatment of type 2 diabetes mellitus in combination with diet and exercise. Two strengths were approved, 100 mg and 300 mg. The US label warns of a dose-dependent increase in volume depletion-related adverse reactions on the 300 mg dose. The purpose of this meta-analysis was to assess the dose response of canaglifozin on safety and tolerability outcomes. A search was performed through MEDLINE, EMBASE, and Cochrane Library for clinical trials comparing canagliflozin with placebo or active controls. Keywords include canagliflozin, and meta-analysis. Reference lists of relevant articles were also used as sources. Two reviewers extracted data and evaluated pertinent studies. Study characteristics, safety outcomes of interest, and risk of bias were collected, verified and further analyzed. Canagliflozin was studied as monotherapy in 2 trials (n=270) and as an add-on therapy in 10 studies (n=2525). Ten of the studies were included in the analysis of selected safety outcomes. Length of intervention ranged from 12 to 52 weeks. All studies were randomized, comparative to either placebo or active controls. Canagliflozin treatment, , increased the risk of vulvovaginal mycotic infection (RR 4.11; CI 3.01-5.60; P<0.01), pollakiuria (RR 2.89, CI 1.84- 4.53), polyuria (RR 3.87; CI 1.66-9.05), hypoglycemia (RR 1.22; CI 1.10-1.35) and hypovolemia (RR 2.04; CI 1.13- 3.68). There were no significant dose responses among observed safety outcomes with the exception of genital infections (RR 4.12; CI 2.47-6.87). Additionally, the canagliflozin treatment group experienced a 24% reduction in serious adverse events when compared to controls (RR 0.76; 0.62-0.93; P<0.01). This meta-analysis did not show a dose response effect of canaglifozin on treatment emergent adverse events in type 2 diabetics.