Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes

Abstract

Metformin is typically the first pharmacologic treatment recommended for type 2 diabetes mellitus (T2DM), but many patients do not achieve glycemic control with metformin alone and eventually require combination therapy with other agents. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was assessed in a comprehensive Phase 3 clinical development program consisting of ~10,000 participants, of which ~80% were on background therapy that consisted of metformin alone or in combination with other antihyperglycemic agents (AHAs; e.g., pioglitazone, sulfonylurea, and insulin). In addition, the efficacy and safety of canagliflozin and metformin as the initial combination therapy and canagliflozin monotherapy were assessed versus metformin in treatment-naïve patients with T2DM. Across studies in patients with T2DM who were on metformin alone or in combination with other AHAs, canagliflozin 100 and 300 mg provided improvements in glycated hemoglobin for up to 104 weeks. Canagliflozin was also associated with reductions in body weight and systolic blood pressure when added to background therapy consisting of metformin alone or with other AHAs. Canagliflozin was generally well tolerated, with increased incidence of adverse events (AEs) related to the mechanism of SGLT2 inhibition (i.e., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs). Consistent with its insulin-independent mechanism of action, canagliflozin was associated with low rates of hypoglycemia when background therapy did not include sulfonylurea or insulin. Due to its favorable efficacy and safety profile, these results suggest that adding canagliflozin to a background regimen consisting of metformin or implementing treatment with a fixed-dose regimen of canagliflozin and metformin would provide an effective and safe treatment regimen for T2DM management.

Funding: Janssen Global Services, LLC.

Keywords: Canagliflozin; Efficacy; Metformin; Safety; Sodium glucose co-transporter 2 inhibitor; Type 2 diabetes mellitus.

Fig. 1

Changes from baseline in HbA1c in Phase 3 studies of canagliflozin in combination with metformin ± other AHAs [–32]. ^a p < 0.001 versus PBO; ^b p = 0.001 versus MET; ^c p = 0.001 versus CANA 100 mg; ^d p = 0.001 versus CANA 300 mg; ^e Noninferiority p = 0.001 versus MET. AHA antihyperglycemic agent, CANA canagliflozin, GLIM glimepiride, HbA1c glycated hemoglobin, LS least squares, MET metformin, PBO placebo, PIO pioglitazone, SE standard error, SITA sitagliptin, SU sulfonylurea

Fig. 2

Changes from baseline in body weight in Phase 3 studies of canagliflozin in combination with metformin ± other AHAs [–32]. ^a Absolute changes from baseline in kg are shown in parentheses; ^b p < 0.001 versus PBO; ^c p < 0.001 versus SITA 100 mg; ^d p < 0.0001 versus GLIM; ^e p = 0.001 versus MET; ^f p = 0.016 versus MET; ^g p = 0.002 versus MET. AHA antihyperglycemic agent, CANA canagliflozin, GLIM glimepiride, LS least squares, MET metformin, PBO placebo, PIO pioglitazone, SE standard error, SITA sitagliptin, SU sulfonylurea

Fig. 3

Changes from baseline in systolic BP in Phase 3 studies of canagliflozin in combination with metformin ± other AHAs [–32]. ^a p < 0.001 versus PBO; ^b p < 0.001 versus SITA 100 mg; ^c p = NS versus MET; ^d p < 0.01 versus PBO; ^e p < 0.025 versus PBO. AHA antihyperglycemic agent, BP blood pressure, CANA canagliflozin, GLIM glimepiride, LS least squares, MET metformin, NS not significant, PBO placebo, PIO pioglitazone, SE standard error, SITA sitagliptin, SU sulfonylurea