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

Levothyroxine use was associated with a significant reduction in cardiovascular events in adults over 50 with subclinical hypothyroidism.

• IPTW-adjusted hazard ratio for cardiovascular events was 0.82 (CI: 0.74-0.91; p < 0.0001)
• Cardiovascular outcomes included angina, myocardial infarction, peripheral vascular disease, stent procedures, or stroke
• The cardiovascular benefit was observed over a 10-year follow-up period
• Adjustments were made for age, sex, BMI, Charlson comorbidity index, total cholesterol, hypertension, thyrotropin, hormonal medications, and smoking via IPTW

Levothyroxine use was associated with a significant reduction in all-cause mortality in older adults with subclinical hypothyroidism.

• IPTW-adjusted hazard ratio for all-cause mortality was 0.71 (CI: 0.67-0.75; p < 0.0001)
• The study population had a median age of 66 years (IQR: 59-75) and was 76.7% female
• 62% of the 22,621 patients received levothyroxine and 38% did not
• Data were drawn from The Health Improvement Network between January 1, 2006, and January 1, 2022

Levothyroxine use was not associated with adverse effects on bone health in older adults with subclinical hypothyroidism.

• IPTW-adjusted hazard ratio for bone events was 1.04 (CI: 0.93-1.17; p = 0.45), which was not statistically significant
• Bone outcomes were defined as fragility fractures or osteoporosis
• The null finding on bone health held over the 10-year follow-up period

The cardiovascular benefits of levothyroxine were limited to patients with thyrotropin levels above the age-specific reference range.

• Subgroup analyses were specifically limited to patients with age-specific thyrotropin levels
• SCH was defined as thyrotropin 4.1-10.0 mU/L with free thyroxine 10.0-24.0 pmol/L
• Standard reference intervals do not account for the known increase in thyrotropin levels with age, potentially leading to overdiagnosis of SCH in older adults
• The authors suggest age-specific thyrotropin levels should guide treatment decisions

The cardiovascular benefits of levothyroxine were only observed after at least five years of treatment.

• Cardiovascular benefits were temporally limited, requiring at least five years of levothyroxine treatment before becoming apparent
• The study employed a 10-year follow-up window to capture long-term outcomes
• This finding suggests short-term treatment may not confer cardiovascular benefit in this population

The study used an emulated target trial design with a large observational cohort of adults over 50 with subclinical hypothyroidism from a UK primary care database.

• 22,621 patients were identified from The Health Improvement Network between January 1, 2006, and January 1, 2022
• Median age was 66 years (IQR: 59-75) and 76.7% were female
• Inverse probability of treatment weighting (IPTW) was used to adjust for confounding
• The primary outcome was a composite of cardiovascular events; secondary outcomes were bone events and all-cause mortality

Thyrotropin levels increase with age and standard reference intervals do not account for this, potentially leading to overdiagnosis of subclinical hypothyroidism in older adults.

• The authors note this age-related increase may result in overuse of levothyroxine in older adults
• The study was motivated in part by the concern that age-unadjusted TSH thresholds misclassify normal aging as disease
• The study specifically examined adults over 50 years of age with TSH in the 4.1-10.0 mU/L range