ETA2022 Oral Presentations Oral Session 6: Hypothyroidism (5 abstracts)
The optimal ranges of thyroid function based on the risk of cardiovascular disease and mortality: an individual participant data meta-analysis
Yanning Xu 1 , Arash Derakhshan 2 , Lea Wildisen 3 , Ola Hysaj 3 , Massimo Iacoviello 4 , Graziano Ceresini 5 , Luigi Ferrucci 6 , Giorgio Iervasi 7 , Alessandro Pingitore 7 , Bert Vaes 8 , Jacobijn Gussekloo 9 , Marco Medici 10 , Tessel Galesloot 11 , Robin P. F. Dullaart 12 , Stephan J.L. Bakker 13 , J. Wouter Jukema 14 , Stella Trompet 15 , Rudi Westendorp 16 , Till Ittermann 17 , Henry Völzke 18 , Marcus Dörr 19 , Börge Schmidt 20 , Dagmar Führer 21 , Nicholas J. Wareham 22 , Kristien Boelaert 23 , Salman Razvi 24 , Mark P. J. Vanderpump 25 , Axel Muendlein 26 , Heinz Drexel 27 , Isabela Bensenor 28 , Jose Sgarbi 29 , Douglas C. Bauer 30 , Howard A. Fink 31 , Connie M. Rhee 32 , Fereidoun Azizi 33 , Misa Imaizumi 34 , Bu B. Yeap 35 , Graeme Hankey 36 , Suzanne J. Brown 37 , John P. Walsh 37 , Tim Korevaar 38 , Nicolas Rodondi 39 , Anne R. Cappola 40 , Robin Peeters 41 , Layal Chaker 42 & for the Thyroid Studies Collaboration 43
1Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands, Department of Internal Medicine and Department of Epidemiology, Rotterdam, Netherlands; 2Erasmus University Medical Center, Erasmus MC, Erasmus University Medical Center, Rotterdam, Netherlands; 3Institute of Primary Health Care (Biham), University of Bern, Bern, Switzerland; 4Cardiology Unit, Emergency and Organ Transplantation Department, University of Bari, Bari, Italy; 5Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; 6Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States; 7National Council Research (Cnr) Institute of Clinical Physiology, Pisa, Italy; 8Institute of Health and Society, Université Catholique de Louvain, Brussels, Belgium; 9Department of Public Health and Primary Care and Department of Internal Medicine, Section Gerontology and Geriatrics Leiden University Medical Center, Leiden, The Netherlands; 10Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands; 11Department for Health Evidence, Radboud Institute for Health Sciences (T.E.G.), Radboud University Medical Center, Nijmegen, the Netherlands; 12University Medical Center, DIV. of Endocrinology, Department of Internal Medicine, Groningen, Netherlands; 13University Medical Center Groningen, University of Groningen, Division of Nephrology, Groningen, Netherlands; 14Leiden University Medical Center (Lumc), Netherlands Heart Institute, Utrecht, the Netherlands, Netherlands; 15Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands; 16University of Copenhagen, Copenhagen, Denmark; 17University Medicine Greifswald, Institut für Community Medicine - Ship/Klinisch-Epidemiologische Forschung, Institut für Community Medicine/Ship, University Greifswald, Greifswald, Germany; 18Universitätsmedizin Greifswald, Institut Für Community Medicine, Ship/Klinisch-Epidemiologische Forschung, Greifswald, Germany; 19Department of Internal Medicine B – Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Germany, Greifswald, Germany; 20Institute for Medical Informatics, Biometry and Epidemiology (B.S.), University Hospital Essen, University of Duisburg-Essen, Germany, Germany; 21Universitätsklinikum Essen, University Hospital Essen, Klinik für Endokrinologie und Stoffwechselerkrankungen, Essen, Germany; 22University of Cambridge, Mrc Epidemiology Unit, Cambridge, United Kingdom; 23College of Medical and Dental Scienc, University of Birmingham, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; 24Institute of Genetic Medicine, Newcastle Upon Tyne, United Kingdom; 25The Physicians’ Clinic, London, England; 26Vorarlberg Institute for Vascular Investigation and Treatment (Vivit), Feldkirch, Austria; 27Vorarlberg Institute for Vascular Investigation and Treatment (Vivit), Feldkirch, Austria; Division of Angiology, Swiss Cardiovascular Center, University Hospital of Berne, Switzerland, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Drexel University College of Medicine, Philadelphia, Pa, Usa;; 28Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil; 29Faculdade de Medicina de Marilia, Marilia, Brazil; 30Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco; 31Geriatric Research Education and Clinical Center, Va Healthcare System, Minneapolis, Minnesota; Department of Medicine, University of Minnesota, Minneapolis; 32Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, California; 33Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran, Tehran, Iran; 34Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima and Nagasaki, Japan; 35Medical School, University of Western Australia, Perth, Australia and Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia; 36Medical School, University of Western Australia, Australia; 37Medical School, University of Western Australia, Crawley, Western Australia, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia; 38Erasmus MC, Rotterdam, The Netherlands, Department of Internal Medicine, Academic Center For Thyroid Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands, Endocrinology, Rotterdam, Netherlands; 39Institute of Primary Health Care (Biham), University of Bern, Bern, Switzerland, Department of General Internal Medicine, Inselspital, University of Bern, Switzerland, University of Bern; 40Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa; 41Academic Center for Thyroid Diseases, Department of Endocrinology, Erasmus, Department of Internal Medicine,, Rotterdam, Netherlands; 42Erasmus Medical Center, Erasmus University Medical Center, Department of Internal Medicine and Epidemiology, Academic Center for Thyroid Diseases,, Rotterdam, Netherlands; 43For the Thyroid Studies Collaboration
Background and Objective: Thyroid function reference ranges are statistically defined by the 2.5th and 97.5th percentiles, which do not account for potential risk of clinical outcomes. We aimed to define the optimal ranges of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), based on the risk of cardiovascular disease (CVD) and mortality.
Methods: We performed an individual-participant data analysis and identified prospective cohorts with baseline TSH and FT4 concentrations as well as CVD outcomes and mortality through the Thyroid Studies Collaboration, supplemented with a systematic literature search. The primary outcome was a composite of incident CVD (coronary heart disease, stroke, heart failure), CVD mortality and all-cause mortality, while secondary analysis assessed these outcomes separately. In a one-step approach, we analyzed TSH and FT4 in percentiles, using cohort-stratified Cox proportional hazard models or cause-specific hazard models with nonlinear associations assessed by restricted cubic splines. For the two-step analysis, we used thyroid function quintiles and pooled estimates from each cohort using a random-effects model. All analyses were adjusted for age and sex, and further adjusted for cardiovascular risk factors (e.g. diabetes), and stratified by age (<70, ≥70 years) and sex.
Results: We included individual participant data on 123,892 participants from 26 cohorts (51.5% women median age of 60 years, median follow-up of 10.3 years). TSH was not associated with CVD events (P=0.18) and only marginally associated with the composite outcome (P=0.02) with individuals in the lowest quintile had a hazard ratio (HR) of 1.04 (0.99-1.08) compared to those in the third quintile. In contrast, FT4 was nonlinearly associated with the composite outcome as well as secondary outcomes in a J-shape pattern (all P<0.001). Participants with FT4 in the second quintile (i.e. 20th-40th percentiles) had the lowest risk of composite outcome while individuals with FT4 in the highest quintile had a HR of 1.18 (95%CI 1.08-1.29). Overall, compared to men and younger individuals, the FT4 concentrations with the lowest risk of the aforementioned outcomes were lower in women and older individuals. In individuals aged ≥70 years, ten-year absolute risk estimates of composite outcome increased more than 5% for women with FT4 concentrations >85th percentile while 5% and 10% for men with FT4 concentrations >75th and >90th percentiles respectively.
Conclusion: Overall TSH was not associated with CVD events. FT4 between the 20th and 40th percentiles represented the optimal health ranges based on the risk of cardiovascular disease and mortality, which has potential implications for treatment targets when managing clinical and subclinical thyroid disease.
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Endocrine Abstracts
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