Reviewed by Dr. Laurette Femnou Mbuntum
Neal, Bruce, et al. New England Journal of Medicine (2017)

Canagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor that is used as a second line oral agent in patients with diabetes and has been shown to reduce hyperglycemia, blood pressure, albuminuria, and body weight. This study includes analysis of data from the original CANVAS (Canagliflozin Cardiovascular Assessment Study) study as well as the renal arm, CANVAS-R. Participants were 10,142 men and women with type 2 diabetes with hemoglobin A1c between 7% and 10.5%. They were either at least 30 years old with known symptomatic atherosclerotic cardiovascular disease or at least 50 years old with two or more cardiovascular risk factors. There was a required eGFR of at least 30 ml per minute per 1.73 m2 of body-surface area. Patients in the CANVAS arm were randomized to receive placebo, canagliflozin 300 mg daily, or canagliflozin 100mg daily. In the CANVAS-R arm, patients were randomized to receive canagliflozin 100 mg daily with an optional increase in dose to 300 mg daily after 12 weeks vs placebo. Further diabetes management was in accordance with local best practices.

The primary outcome was a composite outcome, which included death from cardiovascular causes, nonfatal myocardial infarction, and stroke. Rates of primary outcome events were lower in the treatment group compared to the placebo, 26.9 vs. 31.5 events per 1000 patient-years (hazard ratio, 0.86; 95% CI, 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). There was no difference between the treatment and placebo groups for the secondary outcomes of death from any cause and death from cardiovascular causes. Progression of albuminuria occurred less frequently in the treatment group than the control, and regression of albuminuria occurred more frequently in the treatment group than the control. Regarding the safety profile of canagliflozin, there was a higher risk of limb amputation in treatment group (6.3 vs. 3.4 participants with amputation per 1000 patient-years; hazard ratio of 1.97; 95% CI, 1.41 to 2.75).  This trial also demonstrated the known risks of increase in bone fractures, genital infections, and volume depletion.

Cardiovascular disease and renal impairment commonly co-exist in patients with long standing type 2 diabetes. SGLT2 inhibitors are receiving a lot of attention because of their favorable effects on cardiovascular outcomes. Similar to the EMPA-REG trial, the CANVAS study showed improvement in the primary composite end point of cardiovascular death, non-fatal MI, and stroke. The number needed to treat in CANVAS is around 220, compared to 63 for EMPA-REG. This higher number needed to treat could be due to the fact that the CANVAS trial included high risk patients without proven CV disease in addition to patients with known CV disease. This second positive study suggests that the cardiovascular benefit is a class effect of SGLT2 inhibitors. In addition, the study shows that canagliflozin slows the progression of albuminuria in patients with baseline albuminuria and can even reverse the process. Currently, ACE inhibitors are the main drugs used in diabetic patients with proteinuria. The CANVAS trial suggests that SGLT2 inhibitors could be considered as an alternative in diabetic patients with proteinuria and contraindications to ACE inhibitors. SGLT2 inhibitors alone are likely not adequate to treat hyperglycemia in diabetes as monotherapy, given the relatively small reduction in hemoglobin A1C (-0.58%). However, for patients who are experiencing macro and microvascular complications of diabetes including renal dysfunction and cardiovascular disease, they should be considered preferentially as second line agents, particularly for those patients who are already close to A1C goals. However, canagliflozin is very expensive, costing about $486 for a one month supply of the 100 mg dose and $517 for a one month supply of the 300 mg dose. Additionally, one must consider the side effect profile of canagliflozin, including amputations with a number needed to harm of 344.