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

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

doi:10.1016/j.jchf.2019.08.004

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

JACC Heart Fail. 2020 Jan;8(1):57-66. doi: 10.1016/j.jchf.2019.08.004. Epub 2019 Oct 29.

Authors

Affiliations

¹ Department of Cardiology, People's Liberation Army General Hospital, Beijing, China; Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China; George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
² George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; University of Oxford, Oxford, United Kingdom; Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.
³ George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁴ Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.
⁵ George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁶ Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California.
⁷ University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁸ Janssen Research and Development, Beerse, Belgium.
⁹ Janssen Research & Development, Raritan, New Jersey.
¹⁰ Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, United Kingdom.
¹¹ George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Imperial College London, London, United Kingdom. Electronic address: bneal@georgeinstitute.org.au.

PMID: 31676303
DOI: 10.1016/j.jchf.2019.08.004

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.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Canagliflozin / therapeutic use*
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / physiopathology
Female
Glomerular Filtration Rate / drug effects
Glomerular Filtration Rate / physiology
Heart Failure / etiology*
Heart Failure / prevention & control
Humans
Male
Middle Aged
Risk Factors
Sodium-Glucose Transporter 2 Inhibitors / therapeutic use
Ventricular Function, Left / drug effects
Ventricular Function, Left / physiology

Substances

Sodium-Glucose Transporter 2 Inhibitors
Canagliflozin

Associated data

ClinicalTrials.gov/NCT01989754