Abstract

Background: Subclinical hypothyroidism (SCH), characterised by slightly elevated thyroid stimulating hormone (TSH) levels and normal free thyroxine (fT4) levels, is prevalent in individuals aged over 50 years. Evidence suggests that TSH levels naturally increase with age. However, as uniform serum TSH reference ranges are applied across the adult lifespan, SCH diagnoses are more common amongst older people, with some individuals also commencing levothyroxine (LT4) treatment. It is unclear whether LT4 use or lack thereof, is associated with adverse cardiovascular, bone health and all-cause mortality outcomes in older people with SCH.
Methods: A systematic review and meta-analysis were performed to synthesise previous studies evaluating cardiovascular and bone health outcomes in patients over 65 years with SCH, comparing LT4 treatment with no treatment. A retrospective cohort study and a target trial emulation (TTE) study that used electronic healthcare records from The Health
Improvement Network were conducted with a 10-year follow-up, analysing subjects over 50 years with normal fT4 and slightly elevated TSH levels. Further analyses split subjects into age-specific TSH groups. Time-varying hazard ratios were estimated for cardiovascular, bone health and all-cause mortality outcomes among individuals prescribed LT4 compared to those not prescribed LT4.
Results: The systematic review and meta-analysis (7 articles, 5,887 participants) found no significant association between LT4 use and cardiovascular effects in individuals over 65 years with SCH (pooled HR: 0.89, 95% CI: 0.71, 1.12). Similarly, no association was found between bone health effects and LT4 use in individuals over 65 years with SCH (pooled OR: 0.99, 95% CI: 0.52, 1.88). However, in the cohort study LT4 showed a protective effect against cardiovascular events (HR: 0.91, 95% CI: 0.87, 0.97, p < 0.001, n = 53,899) but posed an increase in bone health (HR: 1.21, 95% CI: 1.14, 1.28, p < 0.001, n = 56,878) and all-cause mortality risks (HR: 1.17, 95% CI: 1.13, 1.22, p < 0.001, n = 60,787). In the TTE study, LT4 was similarly associated with reduced cardiovascular risk (HR: 0.78, 95% CI: 0.71, 0.86, p < 0.001, n = 17,755) and increased bone health risk (HR: 1.21, 95% CI: 1.09, 1.33, p < 0.001, n = 19,364). However, in contrast to the cohort study, the trial revealed reduced all-cause mortality risk among LT4 users (HR: 0.82, 95% CI: 0.77, 0.86, p < 0.001, n = 21,098).
Conclusion: The systematic review and meta-analysis found no significant association between LT4 use and cardiovascular and bone health outcomes in SCH participants over 65 years. Our findings in the cohort study and TTE study highlight the long-term protective cardiovascular effects of LT4 in individuals aged over 50 years with slightly elevated TSH levels and normal fT4 levels. Additionally, our findings revealed adverse bone health
outcomes associated with LT4 use in the same population. Whilst separate study designs, a cohort study and a TTE study, have yielded divergent conclusions regarding all-cause mortality, this work raises the question of bone protection for ageing SCH patients treated with LT4.
Funding: This project was funded by the National Institute for Health and Care Research Applied Research Collaboration North East and North Cumbria (NIHR200173). The views expressed are those of the author and not necessarily those of the National Institute for Health and Care Research or the Department of Health and Social Care.