Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing United Kingdom population (ACEL-UK): Cohort Study.

Context: Thyroid stimulating hormone (TSH) levels tend to rise with age, but standard reference intervals do not reflect this, potentially leading to overdiagnosis of subclinical hypothyroidism (SCH) and excessive levothyroxine (LT4) prescriptions in older adults.

Methods: A retrospective cohort study was conducted utilising data from United Kingdom Primary Care patients from The Health Improvement Network, to compare outcomes in adults over 50 years with SCH who were either prescribed or not prescribed LT4. The primary outcome was cardiovascular events (angina, myocardial infarction, peripheral vascular disease, stent procedures, or stroke). Secondary outcomes included bone events (fragility fractures or osteoporosis) and all-cause mortality. Time-varying hazard ratios adjusted for relevant factors were estimated.

Results: This study included 53,899 patients (baseline median age 67 years (IQR: 59-76); 68.5% female; median TSH 4.6mU/L (IQR: 4.1-5.4). Median follow-up duration was 10 years (IQR: 5.5-10.0). Of these, 19,952 (37%) received LT4 and 33,947 (63%) did not. LT4 therapy showed a protective effect against cardiovascular events (HR: 0.91; 95% CI: 0.87-0.97; p < 0.001) but increased risk of bone events (HR: 1.21; 95% CI: 1.14-1.28; p < 0.001) and all-cause mortality (HR: 1.17; 95% CI: 1.13-1.22; p < 0.001).

Conclusions: Our data suggests that LT4 therapy in older individuals with SCH is associated with a trade-off between the potentially beneficial effect on cardiovascular risk and the deleterious relationship with bone health and mortality risk. These risks need to be considered, mitigated and discussed when LT4 therapy is being deliberated in older patients with SCH.