Invokana reduced cardiovascular events in patients with type 2 diabetes and CVD. The medication also showed possible kidney benefits by retarding albuminuria rise and estimated GFR decline. Unexpectedly, higher rates of toe and metatarsal amputations were seen in adults receiving invokana vs. placebo. More research is needed to confirm or elucidate the mechanism of such adverse events. About 10,000 participants were followed for 3.5 years.

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ORIGINAL Study

June 2017

Background: Canagliflozin is a sodium–glucose cotransporter 2 inhibitor (SGLT-2 inhibitor) that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes.

Methods: The CANVAS Program integrated data from two trials involving a total of 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. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Results:

The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease.

The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; P<0.001 for noninferiority; P=0.02 for superiority).

Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73, P < 0.05) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; P<0.05).

Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; P<0.5); amputations were primarily at the level of the toe or metatarsal.

Conclusions:

In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of CV events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.

More from the publication:

Type 2 diabetes mellitus is associated with a substantial risk of cardiovascular and renal disease. The use of inhibitors of sodium–glucose cotransporter 2 (SGLT2) results in favorable effects on biomarkers, including glycemia, blood pressure, weight, intrarenal hemodynamics, and albuminuria, and may also reduce the risk of serious cardiovascular complications, kidney disease, and death.

The CANVAS Program, comprising two sister trials, was designed to assess the cardiovascular safety and efficacy of canagliflozin and to evaluate the balance between any potential benefits of the drug and the risks associated with it, such as genitourinary infection, diabetic ketoacidosis, and fracture.

The Canagliflozin Cardiovascular Assessment Study (CANVAS) was initiated in December 2009, before the approval of canagliflozin by the Food and Drug Administration (FDA), with the initial goal of showing cardiovascular safety. The first approval of the compound by the FDA occurred in March 2013, with interim data from CANVAS.

Patients with type 2 diabetes and established cardiovascular disease or at high risk for cardiovascular events who were treated with canagliflozin had significantly lower rates of the primary cardiovascular outcome than patients assigned to placebo. All three components of the primary outcome — death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke — showed point estimates of effect that suggested benefit, although the individual effects did not reach significance. The results also showed that patients treated with canagliflozin had a lower risk of hospitalization for heart failure, progression of albuminuria, and substantive loss of kidney function than patients who received placebo, although on the basis of the prespecified hypothesis testing sequence these findings are not considered statistically significant.

Several established effects of SGLT2 inhibitors on intermediate outcomes may contribute to cardiovascular and renal protection. Although pleiotropic effects have been inferred, improved glycemic control, lowering of blood pressure, decrease in intraglomerular pressure, reduction in albuminuria, and amelioration of volume overload are all plausible protective mechanisms.

The possible benefit of canagliflozin use with respect to renal outcomes is supported by the magnitude of the effects observed, the consistency of the observation across renal outcomes, and the consistency of the findings with other recently reported data. Prespecification, confirmation, and adjudication of the renal outcomes in this trial program add support to the possibility that SGLT2 inhibition may have an important kidney-protective effect in type 2 diabetes. Since most renal events were based on changes in eGFR, more data are required to confirm the effects on kidney failure. Definitive evidence about the effects of canagliflozin on clinical kidney outcomes are likely to be provided by the ongoing Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation trial.

The adverse effects observed in this program of two integrated trials are generally consistent with the known safety profile of canagliflozin and other SGLT2 inhibitors. The increased rate of amputation is a new finding for which the mechanism is unknown, and care is warranted in the use of canagliflozin in patients at risk for amputation. An increase in bone fractures has been described previously with canagliflozin, but the excess in bone fracture seen in CANVAS was not observed in CANVAS-R. There is no clear explanation for the difference in fracture risk between the two trials, which included directly comparable patient groups and assessed the same intervention.

In summary, the trial program showed that among patients with type 2 diabetes who had an increased risk of cardiovascular disease, patients treated with canagliflozin had a significantly lower risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than those who received placebo but a greater risk of amputation.