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

doi:10.1016/j.jchf.2019.08.004

JACC: Heart Failure

Volume 8, Issue 1, January 2020, Pages 57-66

https://doi.org/10.1016/j.jchf.2019.08.004 Get rights and content

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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.

Central Illustration

Key Words

canagliflozin

heart failure

mediation analysis

renal outcomes

Abbreviations and Acronyms

BMI

body mass index

confidence interval

DBP

diastolic blood pressure

eGFR

estimated glomerular filtration rate

FPG

fasting plasma glucose

GGT

gamma glutamyltransferase

HbA_1c

hemoglobin A_1c

HDL-C

high-density lipoprotein cholesterol

hazard ratio

LDL-C

low-density lipoprotein cholesterol

MDRD

Modification of Diet in Renal Disease

NHE3

sodium hydrogen exchanger-3

SBP

systolic blood pressure

SGLT2

sodium glucose cotransporter 2

total cholesterol

triglyceride

UACR

urinary albumin:creatinine ratio

Cited by (0)

: Supported by Janssen Research & Development. Drs. Li and Woodward are employees of the George Institute. Dr. Perkovic has received research support from the Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant); and has been a member of the steering committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, and Pfizer; and has served on advisory boards and/or as a speaker at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, and Vitae. Dr. Figtree has received research support from the cofunded Australian National Health and Medical Research Council and Heart Foundation fellowship and Heart Research Australia; and has received compensation from Janssen for serving on the adjudication panel of the CANVAS Program. Dr. Heerspink has served as a consultant for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, and Mitsubishi Tanabe; and has received research support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen. Dr. Mahaffey has received research grants/contracts from Afferent, Amgen, Apple, Inc., AstraZeneca, Cardiva Medical, Inc., Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, National Institutes of Health (NIH), Novartis, Sanofi, St. Jude, and Tenax; and has served as a consultant for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, and University of California, San Francisco (UCSF). Dr. de Zeeuw has served on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; and has served on steering committees for AbbVie and Janssen; and has served on data safety and monitoring committees for Bayer. Drs. Vercruysse and Shaw are employees of Janssen Research & Development. Dr. Matthews has received research support from Janssen; and has served on advisory boards and as a consultant for Novo Nordisk, Novartis, Eli Lilly, Sanofi, Janssen, and Servier; and has given lectures for Novo Nordisk, Servier, Sanofi, Eli Lilly, Novartis, Janssen, Mitsubishi Tanabe, and Aché Laboratories; and currently serves as president of the European Association for the Study of Diabetes (EASD). Dr. Neal has received research support from the Australian National Health and Medical Research Council principal research fellowship; and has served on advisory boards and/or as a consultant for Janssen and Merck Sharpe & Dohme, with any consultancy, honoraria, or travel support paid to his institution. The George Institute for Global Health holds multiple additional commercial contracts with a diverse range of entities.