Canagliflozin may have lower risk of cardiovascular events compared to placebo, industry-funded study finds

The study found a higher risk of amputation of toes, feet, or legs with canagliflozin than with placebo, with most amputations occurring at the toe or metatarsal.


Patients treated with canagliflozin had a lower risk of cardiovascular events but a greater risk of amputation compared to those who received placebo, according to two combined, industry-funded trials.

The Canagliflozin Cardiovascular Assessment Study (CANVAS) integrated data from two trials at 667 centers in 30 countries involving 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks.

Patients were either 30 years of age or older with a history of symptomatic atherosclerotic cardiovascular disease or 50 years of age or older with two or more of the following risk factors for cardiovascular disease:

  • duration of diabetes of at least 10 years,
  • systolic blood pressure higher than 140 mm Hg while receiving one or more antihypertensive agents,
  • current smoking,
  • microalbuminuria or macroalbuminuria, or
  • high-density lipoprotein cholesterol level of less than 1 mmol per liter (38.7 mg/dL).

The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results appeared in the June 12 New England Journal of Medicine. The study was funded by Janssen Research and Development.

Compared to the placebo group, significantly fewer participants in the canagliflozin group died from cardiovascular causes or had a nonfatal myocardial infarction or nonfatal stroke: 26.9 vs. 31.5 events per 1,000 patient-years (hazard ratio [HR], 0.86; 95% CI, 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority) The effects on the primary outcome were nearly the same when imputation for missing events was performed (HR, 0.85; 95% CI, 0.75 to 0.97).

Progression of albuminuria occurred less frequently among participants receiving canagliflozin than the placebo group (89.4 vs. 128.7 events per 1,000 patient-years; HR, 0.73; 95% CI, 0.67 to 0.79). Regression of albuminuria also occurred more frequently among those receiving canagliflozin than the placebo group (293.4 vs. 187.5 participants with regression per 1,000 patient-years; HR, 1.70; 95% CI, 1.51 to 1.91).

There were fewer serious adverse events among participants taking canagliflozin compared to placebo (104.3 vs. 120.0 events per 1,000 patient-years; HR, 0.93; 95% CI, 0.87 to 1.00). Adverse events leading to discontinuation did not differ significantly between groups (35.5 vs. 32.8 events per 1,000 patient-years; HR, 1.13; 95% CI, 0.99 to 1.28). There was a higher risk of amputation of toes, feet, or legs with canagliflozin than with placebo (6.3 vs. 3.4 participants with amputation per 1,000 patient-years, HR, 1.97; 95% CI, 1.41 to 2.75). Among those undergoing amputation, 71% had their highest amputation at the toe or metatarsal.

The study authors said that the beneficial effects on cardiovascular and renal outcomes are similar to previous research on this drug class, but that a trend toward a reduction in stroke with the drug in this study differs from previous results and additional data will be required to clarify the differing results. They also noted that the higher risk of amputation is a new finding and that “care is warranted in the use of canagliflozin in patients at risk for amputation.”