Abstract

Background: Levothyroxine (LT4) is the standard treatment for hypothyroidism, but the optimal dosing for older adults remains unclear. Both higher and lower doses of LT4 may have differential effects on cardiovascular and bone health, with potential risks in ageing populations. We plan an emulated target trial aimed at assessing the impact of lower versus higher LT4 doses on cardiovascular events and bone health outcomes in older individuals with hypothyroidism.
Methods: We will utilise real-world data from a large, observational cohort of older adults with hypothyroidism residing in the United Kingdom from the Primary care-based THIN (The Health Improvement Network) electronic health records database. We will emulate a randomised trial comparing lower (≤1.0 µg/kg/day) versus higher (>1.0 µg/kg/day) LT4 doses. The primary outcomes will be vascular events (including myocardial infarction, stroke, and heart failure) and bone health outcomes (fragility fractures or a diagnosis of osteoporosis). Secondary outcomes include all-cause mortality and healthcare utilisation rates. We will employ inverse probability of treatment weighting (IPTW) to adjust for relevant confounders and emulate randomisation. Cox proportional hazard models (weighted by IPTWs) will be used to estimate treatment effects on outcomes. The study period will be from 2006 to 2021, with follow-up durations ranging up to 10 years. Sensitivity analyses will be performed to confirm the robustness of the findings.
Dissemination and ethics: No ethical approval is needed to use this retrospective anonymised database. The results will be disseminated during conferences and through publication in a peer-reviewed scientific journal.
Conclusions: This emulated target trial of observational data from Primary Care will evaluate if higher doses of LT4 are associated with increased risks of cardiovascular events and bone health events, as well as higher mortality, compared to lower doses. The findings of this research will provide valuable information on whether lower LT4 doses may be safe and efficacious in this population, balancing effective thyroid hormone replacement with minimized cardiovascular and bone health risks. Based on the results of this research, further randomised trials will be planned to confirm these results and guide clinical practice.