Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes
Li, J., Woodward, M., Perkovic, V., Figtree, G. A., Heerspink, H. J. L., Mahaffey, K. W., de Zeeuw, D., Vercruysse, F., Shaw, W., Matthews, D. R. & Neal, B., Jan-2020, In : JACC. Heart failure. 8, 1, p. 57-66 10 p.
http://hdl.handle.net/11370/86b33fdf-d28d-4301-8703-b4579e21de9e
Final publisher's version, 340 KB, PDF document
https://doi.org/10.1016/j.jchf.2019.08.004
JingWei Li
Mark Woodward
Vlado Perkovic
Gemma A. Figtree
Hiddo J. L. Heerspink
Kenneth W. Mahaffey
Dick de Zeeuw
Frank Vercruysse
Wayne Shaw
David R. Matthews
Bruce Neal
Groningen Kidney Center (GKC)
Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Objectives: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study–Renal; NCT01989754). Background: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain. Methods: The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. Results: Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). Conclusions: A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.
JACC. Heart failure
Published - Jan-2020
canagliflozin, heart failure, mediation analysis, renal outcomes, BASE-LINE CHARACTERISTICS, CARDIOVASCULAR ASSESSMENT, EMPAGLIFLOZIN, DAPAGLIFLOZIN, MECHANISMS, RATIONALE, DESIGN