Levothyroxine Therapy in Older Adults With Subclinical Hypothyroidism: The TRUST-2 Randomized Clinical Trial

Background

Subclinical hypothyroidism, defined as elevated thyroid-stimulating hormone (TSH) with normal free thyroxine levels, affects 8-18% of adults over age 65. Whether levothyroxine replacement therapy improves clinical outcomes in this population remains controversial. The original TRUST trial suggested no benefit at 1 year, but questions remained regarding longer-term outcomes. The TRUST-2 trial extended follow-up and powered the study for cardiovascular and cognitive endpoints.

Methods

This multicenter, double-blind, placebo-controlled trial randomized 2,104 adults aged 65 years and older with persistent subclinical hypothyroidism (TSH 4.6-19.9 mIU/L) from 32 centers across the United States and Europe. Participants were randomized 1:1 to levothyroxine (starting dose 25-50 mcg, titrated to normalize TSH) or matching placebo. The co-primary endpoints were change in the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) score and a composite of cardiovascular events (myocardial infarction, stroke, heart failure hospitalization, or cardiovascular death) over 3 years. Secondary endpoints included cognitive function assessed by a comprehensive neuropsychological battery.

Results

At 3 years, mean TSH normalized to 3.1 mIU/L in the levothyroxine group versus 6.4 mIU/L in the placebo group. No significant difference was observed in the ThyPRO composite score (between-group difference, -0.4 points; 95% CI, -2.1 to 1.3; P=0.64). The cardiovascular composite event rate was 7.2% in the levothyroxine group versus 7.8% in the placebo group (HR 0.92; 95% CI, 0.70-1.21; P=0.55). No significant differences were observed in cognitive function decline, including memory (P=0.73), executive function (P=0.88), and processing speed (P=0.61). In prespecified subgroup analysis, participants with TSH above 10 mIU/L showed a trend toward cardiovascular benefit (HR 0.68; 95% CI, 0.42-1.10; P=0.12). Adverse events were similar between groups, with atrial fibrillation occurring in 3.8% of levothyroxine-treated versus 3.2% of placebo-treated participants.

Conclusions

Levothyroxine replacement therapy in older adults with subclinical hypothyroidism and TSH below 20 mIU/L did not improve quality of life, prevent cardiovascular events, or preserve cognitive function over 3 years. Routine levothyroxine treatment for mild subclinical hypothyroidism in elderly patients is not supported by this evidence.