Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes
Year: 2019
Type: article
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.
Source: JACC Heart Failure
Institutions: Army Medical University, Chinese PLA General Hospital, UNSW Sydney, The George Institute for Global Health, Xinqiao Hospital, George Institute for Global Health, Chinese People's Liberation Army, Johns Hopkins University, The George Institute for Global Health, University of Oxford, The University of Sydney, Royal North Shore Hospital, University Medical Center Groningen, University of Groningen, Stanford Medicine, Stanford University, Janssen (Belgium), Janssen Research & Development (United States), Oxford Centre for Diabetes, Endocrinology and Metabolism, Imperial College London
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
Funders: Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Astellas Pharma US, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Roche, Sanofi, Medtronic, Gilead Sciences, University of California, AbbVie, Boehringer Ingelheim, Heart Research Australia, Novo Nordisk, Astellas Pharma, European Association for the Study of Diabetes, Servier, Mitsubishi Tanabe Pharma Corporation, Sanofi Australia, National Institutes of Health, Johnson and Johnson, Stanford Bio-X, Medical Research Council, National Health and Medical Research Council, Relypsa, Janssen Research and Development, Janssen Pharmaceuticals
OpenAlex ID: W2982570836