Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document

Abstract

Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/ LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 lg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients

“…In patients with TRa mutations, low T4/T3 ratio is typical and symptoms of hypothyroidism with variable manifestations are seen. The consensus report on evidence-based use of L-T3/L-T4 combinations in treating hypothyroidism reported that there is dissatisfaction with the existing standard of care and that "a new well-designed adequately powered clinical trial of combination therapy" is needed because not all studies met the current standard requirements (130).…”

Thyroid Hormone Replacement in Total Thyroidectomized Patients: Symptomatic and Metabolic Effects of Levothyroxine Monotherapy

“…We can adequately correct biochemical euthyroidism in total thyroidectomized patients with levothyroxine (LT4) replacement therapy, but some of them still complain of disturbances in their psychological and physical well-being (1). The reason for this may be the absence of some T3 in their circulation (2). Our thyroid synthesizes 2 different thyroid hormones (TH): one of them is thyroxine (T4) which has 4 iodine atoms; the second one is its biologically active brother 105 with 3 iodine atoms called triiodothyronine (T3).…”

T3 therapy in hypothyroidism. Still more questions than answers

“…Likewise, those with low baseline serum total T3 levels while taking LT4 monotherapy should also be include. Noteworthy, they suggest that future combination therapy trials should consider including polymorphism genotyping, and should be adequately powered to study the effect of this polymorphism on trial outcomes (6). The recommended initial dose of LT4:LT3 is 13:1 to 20:1, a ratio that mimics the ratio of physiological thyroxine (T4) and T3 secretion by the human thyroid gland, representing a dose of 5 or 10 μg LT3 for patients taking 100 to 200 μg LT4.…”

“…The recommended initial dose of LT4:LT3 is 13:1 to 20:1, a ratio that mimics the ratio of physiological thyroxine (T4) and T3 secretion by the human thyroid gland, representing a dose of 5 or 10 μg LT3 for patients taking 100 to 200 μg LT4. If no improvement is seen after 3-6 months of treatment, assessed by questionnaires such as ThyPRO, treatment should be discontinued (6).…”