Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing UK Population with Subclinical Hypothyroidism: Emulated Target Trial (ACEL-UK-ETT)

Background: Thyrotropin levels increase with age, but standard reference intervals do not account for this, potentially leading to overdiagnosis of subclinical hypothyroidism (SCH) and overuse of levothyroxine in older adults. Methods: Using data from The Health Improvement Network, this observational emulated target trial study assessed 10-year outcomes in adults over 50 years with SCH (thyrotropin 4.1–10.0mU/L, free thyroxine 10.0–24.0 pmol/L) who were prescribed levothyroxine versus those who were not. Subgroup analyses were limited to patients with age-specific thyrotropin levels. 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. Hazard ratios, adjusted through inverse probability of treatment weighting (IPTW) for age, sex assigned at birth, body mass index, Charlson comorbidity index, total cholesterol, hypertension, thyrotropin, hormonal medications, and smoking, were estimated. Findings: Between January 1, 2006, and January 1, 2022, 22,621 patients (median age [interquartile range]: 66 [59–75] years, 76.7% female) were identified; 62% received levothyroxine and 38% did not. Levothyroxine was associated with reduced cardiovascular (IPTW-adjusted hazard ratio [aHR]: 0.82; CI: 0.74–0.91; p < 0.0001) and all-cause mortality (aHR: 0.71; CI: 0.67–0.75; p < 0.0001), with no adverse effects on bone (aHR: 1.04; CI: 0.93–1.17; p = 0.45). Cardiovascular benefits were limited to patients with thyrotropin levels above the age-specific range and after at least five years of treatment. Interpretation: Long-term levothyroxine use in older adults with SCH was associated with lower long-term cardiovascular and all-cause mortality risks, with no significant harm to bone health. Age-specific thyrotropin levels should guide treatment decisions.