Thomas A Zelniker1, David A Morrow2, Ofri Mosenzon3, Erica L Goodrich2, Petr Jarolim4, Sabina A Murphy2, Deepak L Bhatt2, Lawrence A Leiter5, Darren K McGuire6, John Wilding7, Christoph Bode8, Basil S Lewis9, Ingrid Gause-Nilsson10, Anna Maria Langkilde10, Martin Fredriksson10, Itamar Raz3, Marc S Sabatine2, Stephen D Wiviott2. 1. Division of Cardiology, Medical University of Vienna, Vienna, Austria. 2. TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 3. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel. 4. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 5. Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada. 6. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 7. Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK. 8. Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 9. Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel. 10. BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Abstract
AIMS: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. METHODS AND RESULTS: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). CONCLUSION: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.
AIMS: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. METHODS AND RESULTS: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026). CONCLUSION: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.
Authors: Milton Packer; James L Januzzi; Joao Pedro Ferreira; Stefan D Anker; Javed Butler; Gerasimos Filippatos; Stuart J Pocock; Martina Brueckmann; Waheed Jamal; Daniel Cotton; Tomoko Iwata; Faiez Zannad Journal: Eur J Heart Fail Date: 2021-06-21 Impact factor: 17.349
Authors: David D Berg; Stephen D Wiviott; Benjamin M Scirica; Thomas A Zelniker; Erica L Goodrich; Petr Jarolim; Ofri Mosenzon; Avivit Cahn; Deepak L Bhatt; Lawrence A Leiter; Darren K McGuire; John P H Wilding; Per Johanson; Anna Maria Langkilde; Itamar Raz; Eugene Braunwald; Marc S Sabatine; David A Morrow Journal: Diabetes Care Date: 2021-09-17 Impact factor: 19.112
Authors: Denis A Lebedev; Elena A Lyasnikova; Elena Yu Vasilyeva; Nikolai P Likhonosov; Maria Yu Sitnikova; Alina Yu Babenko Journal: J Diabetes Res Date: 2021-11-05 Impact factor: 4.011
Authors: Dominika Klimczak-Tomaniak; Marie de Bakker; Elke Bouwens; K Martijn Akkerhuis; Sara Baart; Dimitris Rizopoulos; Henk Mouthaan; Jan van Ramshorst; Tjeerd Germans; Alina Constantinescu; Olivier Manintveld; Victor Umans; Eric Boersma; Isabella Kardys Journal: Sci Rep Date: 2022-02-18 Impact factor: 4.379
Authors: Felix Hofer; Ulrike Pailer; Patrick Sulzgruber; Christian Gerges; Max-Paul Winter; Robert P Giugliano; Michael Gottsauner-Wolf; Martin Hülsmann; Niema Kazem; Lorenz Koller; Robert Schönbauer; Alexander Niessner; Christian Hengstenberg; Thomas A Zelniker Journal: ESC Heart Fail Date: 2022-05-20