No Benefit of Levothyroxine Treatment in High-Burden Subclinical Hypothyroidism

tired man touching neck, thyroid
Hypothyroid symptoms and tiredness in patients with high-burden subclinical hypothyroidism are not improved with levothyroxine treatment.

Hypothyroid symptoms and tiredness in patients with high-burden subclinical hypothyroidism are not improved with levothyroxine (LT4) treatment, according to study results published in the Annals of Internal Medicine.

The benefit of LT4 for patients with subclinical hypothyroidism has been debated and may depend on disease burden. In a secondary analysis of the randomized placebo-controlled Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial (TRUST), investigators aimed to evaluate whether LT4 therapy improves symptoms in older patients (aged ≥65 years) with high symptom burden.

Symptom burden was evaluated using the Thyroid-Related Quality-of-Life Patient-Reported Outcome (ThyPRO; range, 0-100) and EuroQol Group 5-Dimension (EQ-5D; range, 0.00-1.00) questionnaires, as well as performance on a handgrip test. Patients with a high symptom burden were defined as those with a hypothyroid symptoms score >30 or a tiredness score >40 on the ThyPRO questionnaire, an EQ-5D Health Utility score <0.75, or a handgrip strength <20 kg. The primary outcomes for the analysis were changed in hypothyroid symptoms and tiredness scores at 1 year.

Of the 638 patients included in the study, 132 (20.7%) had a hypothyroid symptoms score >30 and 133 (20.8%) had a tiredness score >40. Within these high-burden groups, there was no statistically significant difference in the proportion of patients who achieved normal thyrotropin (TSH) levels in the treatment and placebo groups at 1 year.

Compared with the placebo group, similar levels of improvement were observed in LT4-treated patients with regard to hypothyroid symptoms score (between-group difference, -2.0; 95% CI, -5.5 to 1.5; P =.27) and tiredness score (between-group difference, 0.0; 95% CI, -4.1 to 4.0; P =.99). Baseline hypothyroid symptoms and tiredness scores did not modify the effects of LT4 treatment (Pinteraction = .20 and .81, respectively).

Similar results were seen in patients with EQ-5D scores <0.75 (n=152) and handgrip strength <20 kg (n=125).

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The researchers noted that the secondary analysis was not prespecified in the original TRUST trial protocol. In addition, the mean TSH level after 1 year of therapy was 3.6 mIU/L in all groups; more aggressive LT4 therapy may have led to increased benefit.

“[LT4] therapy, as compared with placebo, was not associated with an improvement in hypothyroid symptoms or tiredness in older adults with persistent [subclinical hypothyroidism] and high symptom burden at baseline,” the study authors concluded. “[T]hese results do not support routine [LT4] therapy among older adults with [subclinical hypothyroidism], including those with greater hypothyroid symptom burden and tiredness.”

Disclosure: Support for the study was partially provided by Merck.


de Montmollin M, Feller M, Beglinger S, et al. L-thyroxine therapy for older adults with subclinical hypothyroidism and hypothyroid symptoms: secondary analysis of a randomized trial [published online May 5, 2020]. Ann Intern Med. doi:10.7326/M19-3193