CANVAS program analysis: Canagliflozin benefits patients with T2DM and poor kidney function

ORLANDO – The cardioprotective benefits of canagliflozin as demonstrated in patients with type 2 diabetes mellitus are similar across varying levels of kidney function, according to an analysis of data from the CANVAS program.

The findings suggest that it may be time to reconsider limitations on usage of the sodium-glucose transporter 2 inhibitor in patients with poor kidney function, Dick de Zeeuw, MD, PhD, said at the annual scientific sessions of the American Diabetes Association.

Despite the smaller glycemic effects in patients with reduced estimated glomerular filtration rate (eGFR) seen in CANVAS (CANagliflozin cardioVascular Assessment Study), the relative effects on the primary – and most other – cardiovascular outcomes in CANVAS were similar in patients with low (less than 60 mL/min per 1.72 m² [2,029 patients]) versus high (greater than 60 mL/min per 1.72 m² [8,101 patients]) eGFR, and across four eGFR subgroups (less than 45 mL/min per 1.72 m² [554 patients], 45-60 mL/min per 1.72 m² [1,485 patients], 60-90 mL/min per1.72 m² [5,625 patients], and 90 or greater mL/min per 1.72 m² [2,684 patients]), reported Dr. de Zeeuw of the University Medical Center Groningen, the Netherlands.

An exception was a possible finding of heterogeneity of treatment effect for the exploratory outcome of stroke, he noted.

As expected, the effects of canagliflozin versus placebo on the surrogate marker of HbA_1c was significantly smaller with lower renal function, with reductions of 0.35%, 0.45%, 0.57%, and 0.76% across the four eGFR subgroups, respectively.

“But most interestingly, the three other cardiovascular risk markers show no difference in the effect of canagliflozin when we compare them for the four different eGFR groups,” he said, explaining that reductions in systolic blood pressure, body weight, and albuminuria were “very consistent” across the groups.

For the CANVAS 3-point major cardiac adverse event primary endpoint, which included a composite of cardiovascular death, nonfatal MI, or nonfatal stroke (and which was reduced by 14% [hazard ratio, 0.86] with canagliflozin treatment in the primary CANVAS analysis), no significant heterogeneity for treatment effect was noted between the high versus low eGFR groups or the four eGFR groups (P = .08 and .33, respectively), Dr. de Zeeuw said.

“If anything, there was more effect in the low eGFR group than in the high eGFR group [HRs, 0.92 and 0.70, respectively; 0.65, 0.71, 0.95, and 0.84 for the four eGFR groups, respectively]”, he added, noting that the same was true for the cardiovascular death and MI components of the primary endpoint.

For stroke, however, possible heterogeneity by baseline kidney function was noted. In the primary CANVAS analysis, canagliflozin was associated with a nonsignificant 13% reduction in stroke risk (HR, 0.87), and the hazard ratios for low versus high eGFR in the current analysis were 0.50 and 1.01, respectively, and in the four eGFR groups they were 0.32, 0.56, 0.89, and 1.42 , respectively (P = .01 for both comparisons).

For the secondary endpoints of hospitalizations for heart failure and renal function (a composite of eGFR, end-stage kidney disease, or renal death), which both were important outcomes in the CANVAS program with each showing highly significant reductions with canagliflozin treatment versus placebo in the primary analysis (HRs, 0.67 and 0.60), no heterogeneity by eGFR was seen in the current analysis.

As for safety outcomes, which included serious adverse events, adverse events leading to treatment discontinuation, amputation, fractures, and renal safety (serious renal-related adverse events, serious acute kidney injury, and serious hyperkalemia), no heterogeneity was seen in the outcomes across eGFR groups, he said.

“The CANVAS program ... is a composite of two cardiovascular safety trials that have been conducted over the past [8+] years,” Dr. de Zeeuw said, noting that participants included patients with type 2 diabetes mellitus and cardiovascular disease or high cardiovascular risk who were treated with either 300 mg or 100 mg of canagliflozin or with placebo after a 2-week placebo run-in.

The outcomes favored canagliflozin across all endpoints, and particularly for the secondary endpoints of hospitalization for heart failure and the composite of renal outcomes.

“The interest [in terms of the current analysis] is that this drug supposedly works better in those that have a functioning kidney and a filtering kidney, where the tubule is actually the target of this drug. It was anticipated that there would be less effect of this drug on low renal functions,” he said, adding that although the effect on HbA_1c is progressively attenuated with declining renal function, as expected, the effects on other cardiovascular risk markers were, surprisingly, very comparable across the eGFR subgroups.

“And with that, more importantly, the effect on the hard outcomes – like the primary outcomes, most of the CV outcomes [maybe except stroke], the renal and safety outcomes – are very consistent across the different kidney function levels,” he said, adding that these beneficial findings in patients with 30-45 eGFR who are at high cardiovascular and renal risk suggest that reconsideration of the current limitation on the use of canagliflozin inhibitors to patients with eGFR above 45 is warranted.

The CANVAS program was sponsored by Janssen Research & Development. Dr. de Zeeuw is a consultant and/or speaker for AbbVie, Astellas, Bayer, Boehringer Ingelheim, Fresenius, Janssen, and Mitsubishi Tanabe.