Context: Subclinical hypothyroidism (SHypo) has been associated with atherosclerosis, but no conclusive clinical trials assessing the levothyroxine impact on carotid atherosclerosis exist.

Objective: To assess the impact of treatment of SHypo with levothyroxine on carotid atherosclerosis.

Design and Setting: Randomized, double-blind, placebo-controlled trial nested within the Thyroid Hormone Replacement for Subclinical Hypothyroidism trial.

Participants: Participants aged ≥65 years with SHypo [thyroid-stimulating hormone (TSH), 4.60 to 19.99 mIU/L; free thyroxine level within reference range].

Intervention: Levothyroxine dose-titrated to achieve TSH normalization or placebo, including mock titrations.

Main Outcome Measures: Carotid intima media thickness (CIMT), maximum plaque thickness measured with ultrasound.

Results: One hundred eighty-five participants (mean age 74.1 years, 47% women, 96 randomized to levothyroxine) underwent carotid ultrasound. Overall mean TSH ± SD was 6.35 ± 1.95 mIU/L at baseline and decreased to 3.55 ± 2.14 mIU/L with levothyroxine compared with 5.29 ± 2.21 mIU/L with placebo (P < 0.001). After a median treatment of 18.4 months (interquartile range 12.2 to 30.0 months), mean CIMT was 0.85 ± 0.14 mm under levothyroxine and 0.82 ± 0.13 mm under placebo [between-group difference = 0.02 mm; 95% CI, -0.01 to 0.06; P = 0.30]. The proportion of carotid plaque was similar (n = 135; 70.8% under levothyroxine and 75.3% under placebo; P = 0.46). Maximum carotid plaque thickness was 2.38 ± 0.92 mm under levothyroxine and 2.37 ± 0.91 mm under placebo (between-group difference -0.03; 95% CI, -0.34 to 0.29; P = 0.86). There were no significant interactions between levothyroxine treatment and mean CIMT, according to sex, baseline TSH (categories 4.6 to 6.9, 7.0 to 9.9, and ≥10 mIU/L), or established cardiovascular disease (all P for interaction ≥ 0.14).

Conclusion: Normalization of TSH with levothyroxine was associated with no difference in CIMT and carotid atherosclerosis in older persons with SHypo.