Publication

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.

Research output: Contribution to journalArticleAcademicpeer-review

APA

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. (2020). Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes. JACC. Heart failure, 8(1), 57-66. https://doi.org/10.1016/j.jchf.2019.08.004

Author

Li, JingWei ; Woodward, Mark ; Perkovic, Vlado ; Figtree, Gemma A. ; Heerspink, Hiddo J. L. ; Mahaffey, Kenneth W. ; de Zeeuw, Dick ; Vercruysse, Frank ; Shaw, Wayne ; Matthews, David R. ; Neal, Bruce. / Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes. In: JACC. Heart failure. 2020 ; Vol. 8, No. 1. pp. 57-66.

Harvard

Li, J, Woodward, M, Perkovic, V, Figtree, GA, Heerspink, HJL, Mahaffey, KW, de Zeeuw, D, Vercruysse, F, Shaw, W, Matthews, DR & Neal, B 2020, 'Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes', JACC. Heart failure, vol. 8, no. 1, pp. 57-66. https://doi.org/10.1016/j.jchf.2019.08.004

Standard

Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes. / Li, JingWei; Woodward, Mark; Perkovic, Vlado; Figtree, Gemma A.; Heerspink, Hiddo J. L.; Mahaffey, Kenneth W.; de Zeeuw, Dick; Vercruysse, Frank; Shaw, Wayne; Matthews, David R.; Neal, Bruce.

In: JACC. Heart failure, Vol. 8, No. 1, 01.2020, p. 57-66.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Li J, Woodward M, Perkovic V, Figtree GA, Heerspink HJL, Mahaffey KW et al. Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes. JACC. Heart failure. 2020 Jan;8(1):57-66. https://doi.org/10.1016/j.jchf.2019.08.004


BibTeX

@article{86b33fdfd28d43018703b4579e21de9e,
title = "Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes",
abstract = "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.",
keywords = "canagliflozin, heart failure, mediation analysis, renal outcomes, BASE-LINE CHARACTERISTICS, CARDIOVASCULAR ASSESSMENT, EMPAGLIFLOZIN, DAPAGLIFLOZIN, MECHANISMS, RATIONALE, DESIGN",
author = "JingWei Li and Mark Woodward and Vlado Perkovic and Figtree, {Gemma A.} and Heerspink, {Hiddo J. L.} and Mahaffey, {Kenneth W.} and {de Zeeuw}, Dick and Frank Vercruysse and Wayne Shaw and Matthews, {David R.} and Bruce Neal",
year = "2020",
month = jan,
doi = "10.1016/j.jchf.2019.08.004",
language = "English",
volume = "8",
pages = "57--66",
journal = "JACC. Heart failure",
issn = "2213-1779",
publisher = "ELSEVIER SCI LTD",
number = "1",

}

RIS

TY - JOUR

T1 - Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes

AU - Li, JingWei

AU - Woodward, Mark

AU - Perkovic, Vlado

AU - Figtree, Gemma A.

AU - Heerspink, Hiddo J. L.

AU - Mahaffey, Kenneth W.

AU - de Zeeuw, Dick

AU - Vercruysse, Frank

AU - Shaw, Wayne

AU - Matthews, David R.

AU - Neal, Bruce

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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.

KW - canagliflozin

KW - heart failure

KW - mediation analysis

KW - renal outcomes

KW - BASE-LINE CHARACTERISTICS

KW - CARDIOVASCULAR ASSESSMENT

KW - EMPAGLIFLOZIN

KW - DAPAGLIFLOZIN

KW - MECHANISMS

KW - RATIONALE

KW - DESIGN

U2 - 10.1016/j.jchf.2019.08.004

DO - 10.1016/j.jchf.2019.08.004

M3 - Article

VL - 8

SP - 57

EP - 66

JO - JACC. Heart failure

JF - JACC. Heart failure

SN - 2213-1779

IS - 1

ER -

ID: 119036124