Canagliflozin most effective in higher-risk patients for cardiovascular, kidney outcomes
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Using the Kidney Disease: Improving Global Outcomes criteria, researchers found patients with type 2 diabetes who were at higher risk for adverse cardiovascular and kidney outcomes reaped the most benefits from canagliflozin.
“The [Kidney Disease: Improving Global Outcomes] KDIGO classification of chronic kidney disease is a useful tool for informing prognosis as it allows us to classify people according to their risk of kidney failure and other adverse outcomes,” Brendon L. Neuen, MBBS, MSc, of the George Institute for Global Health, UNSW Sydney, in Australia, said in a press release from the National Kidney Foundation. “However, it has not been widely used to estimate potential benefits with new treatments, such as SGLT2 inhibitors. We found that the KDIGO classification of chronic kidney disease is clinically useful for identifying people who might benefit most from treatment with canagliflozin in terms of protection against cardiovascular events and progression of kidney disease.”
Conducting a post hoc analysis of the Canagliflozin cardiovascular Assessment Study Program, researchers examined outcomes in 10,031 patients with type 2 diabetes and an eGFR of at least 30 mL/min/1.73 m2. All patients had been randomized to either canagliflozin or placebo treatment and were subsequently categorized based on the KDIGO classification system as being at low, moderate, high or very high risk of cardiovascular and/or kidney outcomes (58.6%, 25.8%, 10.6%, and 5% of patients in each category, respectively).
The primary outcome of the study was a composite of cardiovascular mortality, nonfatal myocardial infarction or nonfatal stroke, with researchers also considering hospitalization for heart failure, sustained 40% decline in eGFR, progression to end-stage kidney disease or mortality due to kidney disease.
Results showed the relative effect of canagliflozin on reducing major cardiovascular events (hazard ratio [HR] = 0.86), cardiovascular mortality or hospitalization for heart failure (HR = 0.78), as well as on reducing kidney outcomes, was similar across KDIGO risk categories.
However, further findings indicated absolute reductions in the primary outcome were greater for patients in higher KDIGO risk categories.
“The absolute effect of canagliflozin on eGFR slope varied across different time periods,” Neuen and colleagues wrote. “Treatment with canagliflozin resulted in an acute fall in eGFR within the first 13 weeks that was similar across KDIGO risk categories. From week 13 to the end of follow-up, the rate of decline in kidney function for placebo-treated participants increased across progressively higher KDIGO risk categories, and as a result, the absolute effect of canagliflozin on eGFR slope was greater in higher KDIGO risk categories.”
Co-author on the study, David Wheeler, MD, also commented on the utility of the findings in the press release.
“These data demonstrate that the widely used KDIGO classification for chronic kidney disease can be used to identify individuals who might derive greater absolute benefits with respect to cardiovascular and kidney protection with canagliflozin,” he said.
According to Wheeler, patients at high or very high risk should be prioritized for treatment with the drug.
“We must now ensure that people who might benefit most from treatment with SGLT2 inhibitors are able to access it,” Neuen added.
Perspective
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This post hoc analysis of the CANVAS trial from Neuen and colleagues provides some interesting insights into the relative and absolute risk reduction benefits of canagliflozin on several important cardiovascular and renal outcomes for participants with kidney disease based on their baseline KDIGO risk category. Their work shows that while the relative risk reduction effects of canagliflozin are similar across KDIGO risk categories for both cardiovascular and kidney outcomes, absolute risk reductions appear lower for individuals at lower KDIGO defined risk.
The clinical approach to patients with high-risk diabetic kidney disease on RAAS inhibition is currently fairly clear, the benefits of SGLT2 inhibitors commonly outweigh risks based on the results of the CREDENCE study but questions still remain in lower risk groups. As an example, if a patient with diabetic kidney disease has a 2% 5-year risk of developing ESKD and a similar risk of a cardiovascular event, does the absolute benefit of an SGLT2 inhibitor make sense given the risks of urinary tract infections and other more serious reported adverse events? We may see an evolution of shared decision-making for patients in this situation similar to what has been seen with statins for primary prevention of cardiovascular events with guidelines encouraging absolute risk assessment as a cornerstone of clinical practice.
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