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  • Author: Antonio C. Bianco x
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Antonio C. Bianco Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Fla., USA

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Sabina Casula Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Fla., USA

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Current guidelines recommend that hypothyroid patients should be treated with levothyroxine, which in the vast majority of the cases leads to resolution of the symptoms and normalization of serum free T<sub>4</sub> (FT<sub>4</sub>), T<sub>3</sub> and TSH levels. However, a small group of hypothyroid patients remain symptomatic for neurocognitive dysfunction despite normal serum FT<sub>4</sub> and TSH, which could be explained by localized brain hypothyroidism. More than half of the T<sub>3</sub> in the brain is produced locally via the action of the type II deiodinase (D<sub>2</sub>) and variability/defects in this pathway could explain the residual symptoms. If this rationale is correct, adding liothyronine to the replacement therapy could prove beneficial. However, with a few exceptions, several clinical trials failed to identify any beneficial effects of combined therapy. More recently, the results of a large clinical trial revealed a better neurocognitive outcome with combined therapy only in hypothyroid patients carrying a polymorphism in the DIO2 gene. This obviously needs to be confirmed by other groups but it is tempting to speculate that combined levothyroxine and liothyronine has a place in the treatment of hypothyroidism, for some.

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Jacqueline Jonklaas Division of Endocrinology, Georgetown University, Washington, District of Columbia, USA

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Antonio C. Bianco Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, Illinois, USA

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Anne R. Cappola Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Francesco S. Celi Division of Endocrinology, Diabetes and Metabolism, Virginia Commonwealth University, Richmond, Virginia, USA

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Eric Fliers Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Center, Amsterdam, The Netherlands

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Heike Heuer Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Elizabeth A. McAninch Division of Endocrinology, Rush University, Chicago, Illinois, USA

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Lars C. Moeller Department of Endocrinology, Diabetes and Metabolism, University Duisburg-Essen, Essen, Germany

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Birte Nygaard Center for Endocrinology and Metabolism, Department of Internal Medicine, Herlev and Gentofte Hospitals, Herlev, Denmark

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Anna M. Sawka Division of Endocrinology, University Health Network and University of Toronto, Toronto, Ontario, Canada

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Torquil Watt Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

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Colin M. Dayan Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom

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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.

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