Regulatory Decision Summary for Invokana

Benefits
Invokana (canagliflozin) had benefit when added on to sitagliptin and metformin in patients who were inadequately controlled with sitagliptin and metformin. This was based on a 26-week, double-blind, phase 4 study (DIA4004) that randomized 213 adult patients with T2DM to treatment with either canagliflozin or placebo. Treatment with canagliflozin (100 mg up-titrated to 300 mg at Week 6) in subjects with T2DM who were inadequately controlled on maximally or near-maximally effective doses of metformin ≥1,500 mg/day and on sitagliptin 100 mg, provided clinically and statistically significant glycemic improvements on the primary endpoint (Hemoglobin A1c [HbA1c] reduction). Statistically significant superiority relative to placebo was also demonstrated on all pre-specified secondary endpoints: reduction of fasting plasma glucose (FPG), reduction in body weight from baseline, proportion of subjects achieved HbA1c <7.0%, and reduction in systolic blood pressure (SBP).

Harms
Treatment with canagliflozin (100 mg up-titrated to 300 mg) added on to metformin and sitagliptin was well tolerated overall. The incidence of adverse events, as well as the incidence of adverse events leading to discontinuation in canagliflozin group was comparable to the placebo group. A higher incidence of drug-related adverse events was observed in the canagliflozin group compared to placebo. This was driven by well characterized adverse drug reactions associated with canagliflozin and Sodium-glucose co-transporter 2 (SGLT2) inhibitors (in particular, genital infection and osmotic diuresis adverse events). Genital infections (female and male) observed with canagliflozin were mild or moderate in intensity, treatable and did not generally lead to discontinuation of treatment. Adverse events related to osmotic diuresis (polyuria, pollakiuria, thirst) were numerically increased in the canagliflozin group but comparable to placebo. Canagliflozin was associated with a numerically higher incidence of hypoglycemia compared to placebo. No severe hypoglycemia was observed with the addition of canagliflozin to metformin and sitagliptin.

The product monograph (PM) is adequately labelled with all identified safety issues.

Uncertainties
As canagliflozin was not investigated as an add-on to any other DPP-4 inhibitor but sitagliptin, the proposed indication was restricted to the use of canagliflozin as add-on to metformin and sitagliptin.

Canagliflozin 100 mg is the starting dose in Canada, however, the benefit-harm-uncertainty for this dose in the patient population under investigation was not fully established in the provided study. In the current study, the majority of subjects were up-titrated to canagliflozin 300 mg and a small number of subjects were maintained on canagliflozin 100 mg for the duration of the trial. The efficacy and safety of canagliflozin 100 mg was considered to be acceptable based on: the previously established efficacy and safety of canagliflozin 100 mg in patients with similar disease characteristics in phase 3 studies, the manner of dosing approximated Canadian dosing instructions, and an analysis of a patient subgroup taking background metformin and sitagliptin (n = 314) from a Phase 4 CANVAS study.

Patients with renal impairment were excluded from this study, as per metformin contraindications. The mean baseline estimated glomerular filtration rate (eGFR) was 90.5 mL/min/1.73 m². Canagliflozin is contraindicated in patients with an eGFR <45 mL/min/1.73 m² and should not be initiated in patients with an eGFR <60 mL/min/1.73 m²; however, a risk from off label use cannot be excluded. Elderly patients (≥65 years), who are more likely to have reduced renal function, were also limited in this study.

Overall
The overall benefit-harm-uncertainty profile of canagliflozin, when added on to sitagliptin and metformin in patients who were inadequately controlled with sitagliptin and metformin, is positive.