MON-383 - Early Levothyroxine Initiation, Cardiovascular Outcomes, and Mortality in Subclinical Hypothyroidism

Background: The clinical benefit of levothyroxine therapy in subclinical hypothyroidism remains uncertain. Previous studies have yielded inconsistent results, often limited by heterogeneous exposure definitions and time-related biases. In addition, few studies have focused on patients with higher thyrotropin (TSH) levels or evaluated the impact of early treatment initiation.

Objective: To evaluate whether initiation of levothyroxine therapy within 1 year after identification of TSH level between 7.5–19.9 mIU/L, compared with no initiation within 1 year, is associated with reduced risk of all-cause mortality and cardiovascular outcomes in adults.

Methods: We conducted a propensity score–matched retrospective cohort study using the TriNetX Global Collaborative Network. Adults (≥18 years) with a TSH between 7.5–19.9 mIU/L were identified and classified using a landmark design based on levothyroxine initiation within 1 year of the index TSH measurement. A minimum TSH of 7.5 mIU/L was chosen to minimize the capture of transient TSH elevations. Patients were categorized into treatment and control groups and analyzed using an intention-to-treat approach. Individuals who died or experienced an outcome before or during the first year were excluded. Follow-up began at the landmark time and continued for up to 15 years. Propensity score matching was performed to balance baseline characteristics and TSH level. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for mortality and cardiovascular outcomes. Subgroup analyses were performed.

Results: After matching, 30,875 patients (mean age of 49±16 years, 68% females) were included in each group. Median follow-up was approximately 5 years. Levothyroxine initiation within 1 year was associated with a lower risk of all-cause mortality (4.5% vs 5.8%; HR, 0.83; 95% CI, 0.78–0.89) and major adverse cardiovascular events (MACE, 6.7% vs 8.2%; HR, 0.89; 95% CI, 0.84–0.94), including stroke (HR, 0.88), myocardial infarction (HR, 0.86), heart failure (HR, 0.82), and atrial fibrillation (HR, 0.80). Levothyroxine early initiation was also associated with lower risks of diabetes (HR, 0.71) and hypertension (HR, 0.79), with no significant association for dyslipidemia or fractures (p>0.05). Findings were generally consistent across sexes, age, and TSH strata, except for stroke, where the benefit was significant in younger adults (HR, 0.81) but not in those ≥65 years (HR, 1.02; p=0.862). No associations were observed for negative control outcomes (cataract surgery, knee replacement, and skin melanoma).

Conclusion: Despite the limitations of an observational study, this real-world matched cohort using a landmark design showed that early levothyroxine treatment was associated with lower risks of cardiovascular outcomes and mortality in adults with TSH levels of 7.5–19.9 mIU/L.

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