Discontinuation of low dose levothyroxine therapy for older adults with subclinical hypothyroidism: a randomized, double-blinded, placebo-controlled study

The National Institute on Aging awarded the Biomedical Research Foundation $720,513 on August 15, 2026, under the Aging Research program (CFDA 93.866) to conduct a randomized, double-blinded, placebo-controlled trial evaluating the discontinuation of low-dose levothyroxine therapy in older adults with subclinical hypothyroidism.

The study will enroll 138 adults aged 65 years and older currently receiving levothyroxine 50 micrograms to assess the effects of discontinuation on patient-important outcomes and quantify the cost-effectiveness of deprescribing. The trial addresses a critical evidence gap: while levothyroxine use in older patients with subclinical hypothyroidism is widespread despite lacking demonstrated clinical benefit and generating out-of-pocket costs and lifestyle burden, patient and clinician concerns about potential harm from discontinuation have hindered deprescribing efforts. The research will also quantify downstream levothyroxine-associated cost impacts to support discontinuation strategies.

Performance will occur in Arkansas with a period of performance from August 15, 2026, through July 31, 2031. The assistance type is a Project Grant.

Abstract

The overuse of levothyroxine (LT4) in older patients with subclinical hypothyroidism (SCH) is both widespread and harmful, necessitating urgent action to deprescribe LT4 for those unlikely to benefit from the medication and who may only experience harm. This proposal aims to address a critical barrier to routine LT4 discontinuation in older patients with SCH: the lack of high-quality evidence regarding the effect of LT4 discontinuation on patient well-being. Despite lack of clinical benefit on patient important outcomes and clinical practice recommendations against the use of LT4 in older patients with SCH, treatment initiation is frequent. LT4 administration necessitates lifestyle adjustments, such as taking IT separately from food or multivitamins, and frequent clinic appointments for monitoring, incurring substantial out-of-pocket health costs. Given the lack of clear benefits and the associated personal and healthcare burden of LT4 use in older patients with SCH, there is an urgent need to deprescribe LT4. However, patients and clinicians often express concern about the potential worsening of patients' well-being after discontinuation, acting as a significant barrier to deprescription. Additionally, the impact of LT4 discontinuation on downstream LT4-associated costs remains unknown, highlighting the important need of understanding these costs to support discontinuation strategies. To address these knowledge gaps, we propose a multicenter, noninferiority, patient-, clinician-, and researcher-blinded, placebo-controlled, randomized trial. This trial aims to evaluate the effects of LT4 discontinuation on patient-important outcomes in patients aged ≥65 years with SCH and quantify the cost- effectiveness of LT4 discontinuation. We will enroll 138 adults aged ≥65 years receiving LT4 ≤50 MCG/D for SCH across three sites. Participants will be randomized 1:1 stratified by site, SEX, and autoimmunity status to continue LT4 or receive placebo, with outcome assessments on thyroid-related symptoms, health-related quality of life, cognition, thyroid hormone levels, lipid levels, and adverse events conducted at baseline, 2, and 6 months. Furthermore, we will evaluate predictors for normal thyroid function after LT4 discontinuation. Moreover, we will conduct a model-based cost-effectiveness analysis using a 3-year time horizon. Utilizing parameter values from literature review and trial-based estimates, we will simulate outcomes (e.g., change in health-related quality of life) for patients who discontinue LT4 compared to those who continue LT4. We anticipate that this trial will produce high certainty evidence regarding the effects of discontinuing LT4 on the well-being of older adults with SCH. The results of this study will help overcome barriers to the adoption of LT4 discontinuation in clinical practice by quantifying its effect on patient well-being and providing estimates of cost-effectiveness, thus facilitating the development of strategies to support LT4 discontinuation.