medwireNews: A secondary analysis of the CANVAS trial supports the beneficial cardiovascular (CV) and renal effects of sodium-glucose cotransporter (SGLT)2 inhibition down to a low level of kidney function.
The likelihood of a CV or renal event in patients treated with canagliflozin versus placebo was similar across decreasing categories of estimated glomerular filtration rate (eGFR) for major adverse CV events (MACE), CV death, fatal or nonfatal myocardial infarction, hospitalization for heart failure, and the composite renal outcome.
The exception was fatal or nonfatal stroke, for which there was a significant trend favoring canagliflozin in patients with lower renal function. Stroke rates progressively decreased with declining renal function in patients given canagliflozin, whereas the reverse was true for those given placebo.
“While it is unclear why treatment heterogeneity was observed for the outcome of stroke, qualitatively similar findings have been reported with empagliflozin, supporting the need for better understanding of this finding,” say Vlado Perkovic (The George Institute for Global Health, Sydney, New South Wales, Australia) and study co-authors.
CANVAS included 10,142 patients with type 2 diabetes, 2039 (20.1%) of whom had an eGFR below 60 mL/min per 1.73 m2, with 554 of these having an eGFR below 45 mL/min per 1.73 m2 (patients with eGFR <30 mL/min per 1.73 m2 were excluded at baseline).
Perkovic and team stress that the risk for all outcomes rose with declining kidney function, “underscoring the fact that [chronic kidney disease] is a cause, consequence, and risk multiplier of cardiovascular disease.”
They believe that the CV and renal benefits of canagliflozin likely outweigh the amputation risk seen in CANVAS. For every 1000 patients, treatment with canagliflozin rather than placebo resulted in 15 more amputations, but 23 fewer MACE, 16 fewer heart failure hospitalizations, and 17 fewer composite renal outcomes, with the absolute benefits tending to be larger at lower levels of renal function.
“These benefits are also likely to be clinically important, especially as they occurred in addition to standard of care that included [renin-angiotensin system] blockade in approximately 80% of participants,” say the researchers.
Treatment with canagliflozin preserved eGFR across all baseline categories of renal function, with the annual difference versus placebo ranging from 1.05 to 1.47 mL/min per 1.73 m2, the team reports in Circulation.
And the risk for adverse events with canagliflozin versus placebo, including amputations, fractures, and adverse renal outcomes, was also unaffected by baseline kidney function.
The researchers found a progressively smaller effect of canagliflozin on glycated hemoglobin levels with declining renal function, with reductions versus placebo falling from 0.76% to 0.35% for patients with eGFRs of at least 90 and less than 45 mL/min per 1.73 m2, respectively.
They note this is “[o]ne of the hallmark characteristics of this class of agents” and say it “is likely to be mediated by reduced available nephron mass, and therefore, diminished glucose reabsorption capacity” in patients with reduced renal function.
However, patients achieved similar reductions in bodyweight and blood pressure across the eGFR categories.
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