Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism

Abstract

Importance: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism.

Objective: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older.

Design, setting, and participants: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018.

Exposures: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial).

Main outcomes and measures: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9).

Results: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants).

Conclusions and relevance: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older.

Trial registration: ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mooijaart reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. Dr Du Puy reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. Dr Stott reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. Dr Rodondi reported receiving grants from the Swiss National Science Foundation and the Velux Foundation (EU FP7-HEALTH-2011) during the conduct of the study. Dr Poortvliet reported receiving grants from Netherlands Organisation for Health Research and Development (ZonMw) and the European Union FP7-HEALTH-2011 programme during the conduct of the study. Dr van Heemst was supported by the European Commission–funded project THYRAGE (Horizon 2020 research and innovation programme under grant agreement 666869). Dr Collet reported receiving grants from the Swiss National Science Foundation during the conduct of the study. Dr Langhorne reported receiving grants from University of Glasgow during the conduct of the study. Dr J Gussekloo reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Patient Flow of the Participants in a Study of the Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism

The difference in the number of participants randomized was due to a chance occurrence and, in part, to the failure to stratify randomization by age in the Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial (TRUST). The 12-month window was defined as between 334 and 397 days after randomization. IEMO indicates Institute for Evidence-Based Medicine in Old Age.

Figure 2.. Thyrotropin Levels of Participants in a Study of the Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism

Mean follow-up duration was 17 months. The boxes indicate the first and third quartiles and the median, the whiskers extend to the highest and lowest values within 1.5 × interquartile range, and the dots represent outliers.