Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes
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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.
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Hematocrit increase and uric acid decrease have been identified as important determinants of the heart failure benefits of these drugs in trials of patients with type 2 diabetes.
“both have been identified as important determinants of the heart failure benefits of these drugs in trials of patients with type 2 diabetes.”
From Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial (2021) · cites this paper as [33]
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- Authors
- 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.
- Affiliations
- Army Medical University (CN)
- Johns Hopkins University (US)
- UNSW Sydney (AU)
- The University of Sydney (AU)
- University Medical Center Groningen (NL)
- Stanford Medicine (US)
- Janssen (Belgium) (BE)
- Janssen Research & Development (United States) (US)
- University of Oxford (GB)
- Corresponding author
- Neal, Bruce
- ORCID
- Venue
- JACC: Heart Failure
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 8
- Issue
- 1
- Pages
- 57-66
- ISSN
- 2213-1779 (ISSN-L)
- OpenAlex
- W2982570836
- Cited by
- 144
- References
- 31
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 16 · 2023: 32 · 2022: 27 · 2021: 22 · 2020: 26 · 2019: 1
- FWCI
- 15.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- JACC Heart Failure (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Roche
- Servier
- National Institutes of Health
- Medtronic
- Mitsubishi Tanabe Pharma Corporation
- Bristol-Myers Squibb
- Janssen Research and Development
- Sanofi Australia
- Eli Lilly and Company
- Gilead Sciences
- Novo Nordisk
- Novartis
- European Association for the Study of Diabetes
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- Janssen Pharmaceuticals
- Johnson and Johnson
- National Health and Medical Research Council
- Merck
- University of California
- Astellas Pharma US
- AbbVie
- Pfizer
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- canagliflozin, heart failure, type 2 diabetes, SGLT2 inhibitors, mediation analysis, biomarkers, erythrocyte concentration, hemoglobin levels, serum uric acid, urinary albumin-creatinine ratio, serum bicarbonate, CANVAS Program
- MeSH terms
- Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Diabetes Mellitus, Type 2, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Middle Aged, Risk Factors, Ventricular Function, Left
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