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 μg/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.

Keywords: clinical trial; combination therapy; hypothyroidism; levothyroxine; liothyronine; patient-reported outcomes.

FIG. 1.

Relative roles of the D1 and D2 pathways in the TSH feedback mechanism during treatment with LT4. In LT4-treated thyroidectomized patients to achieve normal serum TSH levels, the D2 pathway contributes with ∼80% of the circulating T3 (6). Studies performed in rats revealed how plasma T4 is taken up by the hypothalamic tanycytes and the pituitary thyrotrophs, and locally converted to T3 through the D2 pathway (8). The net effect of the D2 activity in these two sites is a reduction in TSH secretion. As the goal of therapy with LT4 is to normalize serum TSH, a progressive increase in LT4 dose increases circulating T3 levels (predominantly through D2) and simultaneously reduce TSH secretion (predominantly through D2). Studies performed in rodents demonstrated that the D2 pathway is negatively regulated by T4, that is, D2 is ubiquitinated by WSB-1 and inactivated as it converts T4 to T3 (7). However, this process occurs at a much slower rate in the hypothalamus (4). Also in pituitary thyrotrophs, the loss of D2 activity caused by T4 is a much slower process (5). As a result, D2-mediated T3 production is a more efficient process in the hypothalamus/pituitary unit when compared with other D2-containing tissues. Thus, while increasing the LT4 replacement dose to treat hypothyroidism, normalization of serum TSH levels will occur before full normalization of serum T3 levels. The role played by D1 is secondary, mainly because its affinity for T4 is three orders of magnitude less than D2, and its expression is positively regulated by plasma T3. Thus, D1 activity was never fully normalized in LT4-treated hypothyroid rats, only when a combination of LT4 and LT3 was used was serum T3 restored (4). D1, type 1 deiodinase; D2, type 2 deiodinase; LT4, levothyroxine; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin; WSB-1, gene encoding the WD repeat and SOCS box-containing protein 1.

FIG. 2.

Depiction of the four types of thyroid hormone signaling.

FIG. 3.

Transporters allowing thyroid hormone entry into cells.

FIG. 4.

Transporters allowing thyroid hormone entry into the brain. Adapted with permission from Groeneweg et al. (41).

FIG. 5.

Thyroid hormone profiles for 24 hours after administering either LT4 or LT4/LT3 in 10 patients with hypothyroidism with mean values of (a) fT3, (b) fT4, and (c) TSH shown. Reprinted with permission from Saravanan et al. (57).