Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies

Heba Alwan*, Fanny Villoz, Martin Feller, Robin P.F. Dullaart, Stephan J.L. Bakker, Robin P. Peeters, Maryam Kavousi, Douglas C. Bauer, Anne R. Cappola, Bu B. Yeap, John P. Walsh, Suzanne J. Brown, Graziano Ceresini, Luigi Ferrucci, Jacobijn Gussekloo, Stella Trompet, Massimo Iacoviello, Jae Hoon Moon, Salman Razvi, Isabela M. BensenorFereidoun Azizi, Atieh Amouzegar, Sergio Valdés, Natalia Colomo, Nick J. Wareham, J. Wouter Jukema, Rudi G.J. Westendorp, Ki Woong Kim, Nicolas Rodondi, Cinzia Del Giovane

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)


Objective: Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. Methods: We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. Results: Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses. Conclusions: This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Significance statement: Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.

Original languageEnglish
Pages (from-to)S35-S46
JournalEuropean Journal of Endocrinology
Issue number5
Publication statusPublished - 1 Nov 2022

Bibliographical note

Funding Information:
Research?Institute?for?Diseases?in?the?Elderly?(RIDE);?the?Ministry?of? Education,?Culture?and?Science;?the?Dutch?Ministry?for?Health,?Welfare? and?Sports;?the?European?Commission?(DG?XII);?and?the?Municipality? of?Rotterdam.?The?Prevention?of?Renal?and?Vascular?End-Stage?Disease? (PREVEND)?394?study?has?been?made?possible?by?grants?from?the?Dutch? Kidney?Foundation?(E.033).?The?InChianti?study?was?supported?as?a?target? project?ICS?110.1jRS97.71?by?the?Italian?Ministry?of?Health,?and?in?part?by? the?US?NIA,?contracts?263-MD-9164-13?and?263-MD-821336.?The?Busselton? Health?Study?had?no?financial?support?to?disclose.?All?agencies?had?no?role? in?the?design?and?conduct?of?the?study,?collection,?management,?analysis,? or?interpretation?of?the?data,?or?preparation,?review,?or?approval?of?the? manuscript.?The?ELSA-Brasil?baseline?study?and?the?4-year?follow-up?was? supported?by?the?Brazilian?Ministry?of?Health?(Science?and?Technology? Department)?and?the?Brazilian?Ministry?of?Science?and?Technology? (Financiadora?de?Estudos?e?Projetos?and?CNPq?National?Research?Council)? (grants?of?baseline:?0106?0010.00?RS,?01?06?0212.00?BA,?01?06?0300.00?ES,? 01?06?0278.00?MG,?01?06?0115.00?SP,?01?06?0071.00?RJ;?grants?of?4-year? follow-up?01?10?0643-03?RS,?01?10?0742-00?BA,?01?12?0284-00?ES,?01?10? 0746-00?MG,?01?10?0773-00SP,?01110093-01RJ);?and?by?the?FAPESP?–? Fundação?de?Amparo?à?Pesquisa?do?Estado?de?São?Paulo?(2015/17213-2).? ACG,?ISS,?SMB,?BBD,?MIS,?PAL?and?IMB?are?recipients?of?a?scholarship?from? National?Research?Council?(CNPq).?The?Tehran?Thyroid?Study?(TTS)?was? funded?by?the?Research?Institute?for?Endocrine?Sciences,?Shahid?Beheshti? [email protected]?Study?has?been? funded?by?CIBERDEM?(Ministerio?de?Economía,?Industria?y?Competitividad-ISCIII),?Instituto?de?Salud?Carlos?III?(PI11-02755,?PI14/00710,?PI14/01104,? PI14/00970,?PI14/00874,?PIE14/00031,?PI20/01322),?Consejería?de?Salud?y? familias?(PI-0144-2018).

Funding Information:
This systematic review and IPD analysis were funded by a grant from the Swiss National Science Foundation (SNSF 32003B-200606) to Nicolas Rodondi. The HABC study was supported in part by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01- AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459, and by the Intramural Research Program of the NIH, National Institute on Aging. The Cardiovascular Health Study (CHS) is supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG032317, and K24 AG 042765 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, R01 AG066671 and UL1 TR000128. The Health In Men Study is supported by research grants from the National Health and Medical Research Council of Australia. The European Prospective Investigation of Cancer (EPIC)-Norfolk study was supported by research grants from the Medical Research Council UK and Cancer Research UK. The Leiden 85 plus Study was partly funded by an unrestricted grant from the Dutch 375 Ministry of Health, Welfare and Sports (1997.2001). The original PROSPER study was supported by an unrestricted, investigator-initiated grant from Bristol-Myers Squibb. The Rotterdam Study was funded by the following: Erasmus MC and Erasmus University, Rotterdam, the Netherlands; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Dutch Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The Prevention of Renal and Vascular End-Stage Disease (PREVEND) 394 study has been made possible by grants from the Dutch Kidney Foundation (E.033). The InChianti study was supported as a target project ICS 110.1jRS97.71 by the Italian Ministry of Health, and in part by the US NIA, contracts 263-MD-9164-13 and 263-MD-821336. The Busselton Health Study had no financial support to disclose. All agencies had no role in the design and conduct of the study, collection, management, analysis, or interpretation of the data, or preparation, review, or approval of the manuscript. The ELSA-Brasil baseline study and the 4-year follow-up was supported by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos and CNPq National Research Council) (grants of baseline: 0106 0010.00 RS, 01 06 0212.00 BA, 01 06 0300.00 ES, 01 06 0278.00 MG, 01 06 0115.00 SP, 01 06 0071.00 RJ; grants of 4-year follow-up 01 10 0643-03 RS, 01 10 0742-00 BA, 01 12 0284-00 ES, 01 10 0746-00 MG, 01 10 0773-00SP, 01110093-01RJ); and by the FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/17213-2). ACG, ISS, SMB, BBD, MIS, PAL and IMB are recipients of a scholarship from National Research Council (CNPq). The Tehran Thyroid Study (TTS) was funded by the Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences of Iran. The [email protected] Study has been funded by CIBERDEM (Ministerio de Economía, Industria y Competitividad- ISCIII), Instituto de Salud Carlos III (PI11-02755, PI14/00710, PI14/01104, PI14/00970, PI14/00874, PIE14/00031, PI20/01322), Consejería de Salud y familias (PI-0144-2018).

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