Abstract

Background: Subclinical hypothyroidism (SCH), characterised by mildly elevated thyrotropin (TSH) and normal free thyroxine (fT4) levels, is common in those over 50 years. As TSH naturally increases with age, applying uniform reference ranges often leads to more SCH diagnoses in older adults, some of whom are treated with levothyroxine (LT4). However, the long-term impact of LT4 on cardiovascular, bone, and mortality outcomes remains unclear in this population.

Methods: A retrospective cohort and target trial emulation (TTE) study were conducted using data from The Health Improvement Network, with a 10-year follow-up. Adults over 50 years with normal fT4 and slightly raised TSH levels were included. Adjusted hazard ratios (HRs) were estimated for cardiovascular, bone health, and all-cause mortality outcomes. Subgroup analyses explored outcomes by age-specific TSH levels.

Results: In the cohort study, LT4 use was linked to reduced cardiovascular risk (HR: 0.91, 95% CI: 0.87-0.97) but increased risks to bone health (HR: 1.21, 95% CI: 1.14-1.28) and all-cause mortality (HR: 1.17, 95% CI: 1.13-1.22). The TTE study confirmed cardiovascular benefit (HR: 0.78, 95% CI: 0.71-0.86) and elevated bone risk (HR: 1.21, 95% CI: 1.09-1.33), but showed reduced mortality with LT4 (HR: 0.82, 95% CI: 0.77-0.86).

Conclusion: LT4 may offer cardiovascular benefits in older SCH patients, but is associated with bone health risks. Contrasting mortality findings between study designs highlight the need for further research.

Funding: NIHR Applied Research Collaboration North East and North Cumbria (NIHR200173).