Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial

Corrado De Marco, Brian L Claggett, Simon de Denus, Michael R Zile, Thao Huynh, Akshay S Desai, Martin G Sirois, Scott D Solomon, Bertram Pitt, Jean L Rouleau, Marc A Pfeffer, Eileen O'Meara, Corrado De Marco, Brian L Claggett, Simon de Denus, Michael R Zile, Thao Huynh, Akshay S Desai, Martin G Sirois, Scott D Solomon, Bertram Pitt, Jean L Rouleau, Marc A Pfeffer, Eileen O'Meara

Abstract

Aims: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature.

Methods and results: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone.

Conclusions: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.

Trial registration: ClinicalTrials.gov NCT00094302.

Keywords: Biomarker; Diabetes; Heart failure; Preserved left ventricular function; Spironolactone.

Conflict of interest statement

C.D.M., M.R.Z., T.H., and M.G.S. declare no conflicts of interest. B.C. receives support from Amgen, Corvia, Boehringer Ingelheim, Novartis, and MyoKardia. S.d.D. declares research support through grants from Pfizer, AstraZeneca, Roche Molecular Science, and DalCor. A.S.D. declares research support from Alnylam, AstraZeneca, and Novartis and consulting fees from Abbott, Alnylam, AstraZeneca, Biofourmis, Boston Scientific, Boehringer‐Ingelheim, DalCor Pharma, Novartis, Relypsa, and Regeneron. S.D.S. has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, and Theracos and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Daiichi‐Sankyo, Gilead, GSK, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. B.P. received consulting fees from Bayer, Sanofi, AstraZeneca, Vifor/Relypsa, and Sarfez; has equity in Vifor/Relypsa and Sarfez; and has a pending patent related to site‐specific delivery of eplerenone to the myocardium (# 9931412 USA). J.L.R. reports consulting fees from AstraZeneca, Merck, Bayer, SanofiAventis, and Novartis. M.A.P. receives research support from Novartis. He serves as a consultant for AstraZeneca, Corvidia, GlaxoSmithKline, DalCor, Novartis, NovoNordisk, Pharmascience, and Sanofi and has equity in DalCor. E.O. reports consultation and speaker services, as a member of the Montreal Heart Institute Research Center, for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis; steering committee and national leader roles for clinical studies by American Regent, AstraZeneca, Cytokinetics, and Novartis; and clinical trial participation with Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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Source: PubMed

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