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Canagliflozin and Cardiovascular, and Renal Events In Type 2 Diabetes

Canagliflozin may reduce the risk of major cardiovascular complication, but amputation risk is increased.

SGLT-2 inhibitors are effective 2nd line agents in the treatment of type 2 diabetes. They can also help lower blood pressure, weight, and albuminuria, and reduce the risk of cardiovascular complications. However, this class of anti-diabetic drugs has also been linked to increasing risk of urinary tract infections, diabetic ketoacidosis and fractures. Canagliflozin (Invokana) became the first SGLT-2 inhibitor approved in the US, and it has been commonly prescribed since then as either add-on therapy or monotherapy. The need for a study to properly evaluate the risk vs benefits of this medication has laid out the CANVAS Program (Canagliflozin Cardiovascular Assessment Study), which was designed to assess drug safety in patients with diabetes who have cardiovascular comorbidities.

The CANVAS Program was a set of two randomized, double-blind placebo-controlled trials (CANVAS and CANVAS-R) with a large pool of over 10,000 participants. It included patients over 30 years old who have had type 2 diabetes and with atherosclerosis or patients over 50 years old with cardiovascular risk factors such as: hypertension and COPD. Participants in CANVAS followed 1:1:1 randomization ratio for canagliflozin 300 mg, canagliflozin 100 mg, and placebo. The participants in CANVAS-R were randomly assigned in a 1:1 ratio to receive canagliflozin 100 mg daily to be titrated up 300 mg, or matching placebo. The urinary albumin-to-creatinine ratio was measured every 26 weeks in CANVAS-R after 3 months, then annually in CANVAS. Measurement of eGFR was performed at least every 26 weeks in both trials. Primary outcome was a composite of mortality from cardiovascular causes, nonfatal MI, or nonfatal stroke. Secondary outcomes were death from any cause, including cardiovascular causes, progression of albuminuria, and hospitalization for heart failure.

Patients in the canagliflozin group had significantly less incidences of the primary outcome event vs placebo (26.9 vs. 31.5 participants with an event per 1000 patient-years; hazard ratio of 0.86). Estimates for secondary outcomes, including death from any cause or cardiovascular causes, were not found to be significant. Progression of albuminuria occurred less frequently in the group of participants taking canagliflozin versus the ones assigned to placebo (89.4 vs. 128.7 participants with an event per 1000 patient years; hazard ratio of 0.73). Regression of albuminuria also occurred more frequently among those assigned to canagliflozin than among those assigned to placebo (293.4 vs. 187.5 participants with regression per 1000 patient-years; hazard ratio of 1.70). The composite outcome of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes occurred less frequently among participants in the canagliflozin group as compared to the placebo group (5.5 vs. 9.0 participants with the outcome per 1000 patient-years; hazard ratio of 0.60).

However, this trial revealed some potential risks among those who were treated with canagliflozin. 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 1000 patient-years, hazard ratio of 1.97). The highest risk of amputation occurred among patients who had a history of amputation or peripheral disease, but the relative risk of amputation with canagliflozin as compared with placebo was similar across these subgroups. Among the findings, there were no higher risks of hypoglycemia, hyperkalemia, acute kidney injury, pancreatitis or DVT with canagliflozin when compared with placebo. Also, there was a higher rate of fractures with canagliflozin than with placebo (15.4 vs. 11.9 participants with fracture per 1000 patient-years; hazard ratio of 1.26); however, there was no reference to osteoporosis risk or Vitamin D deficiency. These findings were later reflected by the FDA adding a warning to canagliflozin’s package insert regarding the increasing the risk of amputation and bone fractures.

Participants with type 2 diabetes and history of cardiovascular disease who were treated with canagliflozin had significantly lower incidences of the primary cardiovascular outcome than participants who were given a placebo. This includes death related to cardiovascular causes, nonfatal MI, and nonfatal stroke. This study also suggested that canagliflozin may have a renoprotective effect by reducing albuminuria. The increased rate of amputation was a new finding without any possible explanation and patients who are at risk of amputations should be aware of it. This study had a strength of a large randomized population size in two combined trials with a median follow-up of over 3 years.

Practice Pearls:

  • The use of canagliflozin in patients with T2D may reduce the risk of cardiovascular mortality, nonfatal MI. and nonfatal strokes.
  • Canagliflozin treatment may increase the risk of amputation in patients with diabetes.
  • Canagliflozin may help reduce albuminuria in patients with diabetes who have kidney disease.


Bruce Neal, M.B, ChB, PhD. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657


Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy