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Effect of canagliflozin on HF not easily explained
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In a new analysis from the CANVAS trial, researchers identified 14 biomarkers with significant mediating effects on the efficacy of canagliflozin for HF among patients with type 2 diabetes, with erythrocyte concentration, serum urate and urinary albumin-to-creatinine ratio having the strongest effect.
“Our analyses provide support for most of the previously hypothesized mechanisms for the prevention of heart failure with SGLT2 inhibitors, but the extent to which each truly mediates the beneficial effect of canagliflozin on heart failure remains uncertain,” JingWei Li, PhD, of the department of cardiology at People’s Liberation Army General Hospital, Beijing, and The George Institute for Global Health, University of New South Wales, Sydney, and colleagues wrote.
Meaningful biomarkers
According to a multivariate analysis included in a report published in the Journal of the American College of Cardiology, erythrocyte concentration, serum urate and urinary albumin-to-creatinine ratio accounted for an estimated 102% (95% CI, 42-480) of the cumulative mediation effect of canagliflozin (Invokana, Janssen) on HF.
Moreover, researchers identified 11 mediators based upon early changes in biomarker levels in a multivariable model. They reported that early changes in hemoglobin, serum urate and HbA1c had a significant mediating effect with an estimated mediation value of 75% (95% CI, 47-101).
“Some of the mediators, such as markers of plasma volume, are highly plausible based upon the known causes of heart failure,” Li and colleagues wrote. “Others, such as systolic BP, were not identified as strong or consistent mediators despite long-established effects of BP-lowering agents on heart failure and clear effects of canagliflozin on blood pressure. Others still, such as blood lipid levels, were identified as weak mediators, but with no known mechanism of action. The most consistent finding across all the analyses was of strong mediating effects for the markers of volume and hematopoiesis and for mediating effects of uric acid. Mediating effects for albuminuria in many of the models highlights a likely central role for the cardio-renal axis in mediating the effects of canagliflozin on heart failure.”
In other findings, there were 13 mediators identified based upon average levels.
The inclusion of erythrocyte concentration, serum urate and urinary albumin-to-creatinine ratio in the analysis resulted in an estimated overall mediation of 94% (95% CI, 85-103), according to the researchers.
Better targeting needed
“Sodium-glucose cotransporter 2 inhibitors provide significant protection against heart failure,” the researchers wrote. “This benefit was not anticipated when the trials of these agents were initially designed. Mediation analyses can provide insights into the mechanism by which drug effects are achieved and may enable the better targeting of therapy to patient groups most likely to benefit.”
Researchers analyzed the mediating effects of 19 biomarkers by comparing the HRs for the effect of randomized treatment from an unadjusted model and a model adjusting for the biomarker of interest. Researchers later assessed the joint effects the strongest mediating biomarkers in a multivariable analysis.
“Assessments of the joint effects of mediators resulted in over 100% of the effect explained with only three mediators included, and this highlights the limited capacity to explore and control for double counting of a mechanistic pathway that is captured by more than one biomarker,” the researchers wrote. “Finally, it is not possible to be sure that the effects identified are truly part of the mechanistic pathway for heart failure prevention by canagliflozin rather than an epiphenomenon associated with both the effects of canagliflozin and the future risk of heart failure.” – by Scott Buzby
Disclosures: The study was supported by Janssen. Li and another author report being employees of The George Institute. Please see the study for all other authors’ relevant financial disclosures.
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