Canagliflozin is the second agent under development in the class of drugs known as the sodium-glucose cotransporter-2 (SGLT2) inhibitors for glycaemic control in type 2 diabetes. These agents result in increased urinary glucose excretion thus decreasing plasma glucose.
This randomised, double-blind, active-controlled, phase 3 non-inferiority trial assessed the efficacy and safety of canagliflozin compared with glimepiride as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. The study was conducted at 157 centres in 19 countries and included people with type 2 diabetes aged 18-80 years and glycated haemoglobin A1c (HbA1c) of 7.0–9.5%. Participants were also receiving stable metformin therapy (≥2000 mg per day or ≥1500 mg per day if unable to tolerate a higher dose) for at least 10 weeks. They were randomised (1:1:1 ratio) to either canagliflozin 100 mg or 300 mg, or glimepiride titrated up to 6 mg or 8 mg per day) orally once daily. The primary endpoint measure considered in the study was the change in HbA1c from baseline to week 52 with a non-inferiority margin of 0.3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, the researchers evaluated superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0.0%.
The primary analysis was based on a last observation carried forward (LOCF) approach in the modified intention-to-treat population (all randomised patients receiving at least one dose of study drug). Overall, 1450 of 1452 of participants randomised received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485), and therefore made up the modified intention-to-treat group. The results found:
• For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0.01% [95% CI −0.11 to 0.09]), and canagliflozin 300 mg was superior to glimepiride (-0.12% [-0.22 to −0.02]).
• 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group.
• In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, greater number of genital mycotic infections was observed:
- women: 26 [11%] and 34 [14%] vs. five [2%]; men: 17 [7%] and 20 [8%] vs. three [1%])
- urinary tract infections (31 [6%] for both canagliflozin doses vs. 22 [5%]), and
- osmotic diuresis-related events (pollakiuria [increased urinary frequency]: 12 [3%] for both doses vs. one [<1%]; polyuria [increased urinary volume]: four [<1%] for both doses vs. two [<1%]).
The researchers discuss several limitations of their study, including:
• As the study included patients with HbA1c values of 7.0 - 9.5%, it is not possible to make conclusions about the comparison of these drugs in patients with more severe hyperglycaemia.
• Although the study ran over 52 weeks, long term data would allow a better understanding of the comparative benefits and risks of the drugs and the durability of response. It would also allow an assessment of whether favourable effects observed on cardiovascular risk factors translate into cardiovascular benefits
The researchers conclude, “Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin.”
In a related Comment article, the authors discuss the results of the study and note that the United States Food and Drug Administration (FDA) conditionally approved canagliflozin in March 2013. Approval needed five post-marketing studies, including a long-term cardiovascular safety study and a bone safety study. Although the authors acknowledge the results of the study as encouraging, they note that:
• The position of the SGLT2 inhibitors in the present stepwise treatment approach for type 2 diabetes is unclear.
• Long-term safety concerns, including cardiovascular, cerebrovascular, and cancer safety, and class-related adverse effects on bone health in a high-risk population, need close surveillance even after approval
• It is unknown if the increased frequency of genitourinary infections would be acceptable for patients with diabetes, who are prone to such infections.
Canagliflozin has been filed for approval in the EU for the treatment of adult patient with type 2 diabetes. NICE issued technology appraisal guidance (TAG) on the use of dapagliflozin (the first drug in this class) in June 2013, which recommends dapagliflozin:
• In a dual therapy regimen in combination with metformin as an option for treating type 2 diabetes, only if it is used as described for dipeptidyl peptidase 4 (DPP 4) inhibitors in Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87).
• In combination with insulin with or without other antidiabetic drugs as an option for treating type 2 diabetes.
NICE guidance does not support the use of dapagliflozin in a triple therapy regimen in combination with metformin and a sulfonylurea for treating type 2 diabetes, except as part of a clinical trial.