Effect of Thyroid Hormone Therapy on Fatigability in Older Adults With Subclinical Hypothyroidism: A Nested Study Within a Randomized Placebo-Controlled Trial

Abstract

Background: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.

Method: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.

Results: Among 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score [n = 88] or ≥13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).

Conclusions: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.

Trial registration: ClinicalTrials.gov NCT02500342.

Keywords: Fatigue; Levothyroxine; Thyroid disease.

© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Randomization and follow-up. 1The Pittsburgh Fatigability Scale (PFS) has two separate subscores for mental and physical fatigability, each ranging from 0 to 50 with higher scores indicating greater fatigability. 2Eleven participants in the levothyroxine group and 11 participants in the placebo group had a follow-up visit but did not answer the PFS-questions due to administrative reasons, n = 1 participant in the placebo group had a follow-up visit but did not answer the PFS-questions due to unknown reasons. These missing outcomes were accounted for in sensitivity analysis (Inverse probability weighting [IPW] analysis). 3Thirteen participants withdrew, in eight cases due to participants’ decision, in three cases due to adverse events, in one case due to physician recommendation for unknown reason and in one participant the reason is unknown. 4One participant died from a septic shock due to a colon perforation combined with a segmental pulmonary embolism left and one participant died from dehydration due to an aspiration pneumonia with acute hypoxemia and progression of cell carcinoma of the hypopharynx. Both deaths were not related to the medication. 5Participants with more than three missing questions or lacking information whether the activity has been done or not for a missing answer, as defined in the rules to analyze PFS (13,18).