JingWei Li1, Mark Woodward2, Vlado Perkovic3, Gemma A Figtree4, Hiddo J L Heerspink5, Kenneth W Mahaffey6, Dick de Zeeuw7, Frank Vercruysse8, Wayne Shaw9, David R Matthews10, Bruce Neal11. 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.
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.
OBJECTIVES: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozincardioVascular Assessment Study; NCT01032629 and CANagliflozincardioVascular 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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