Key Words: hypothyroidism, combination therapy, addition of LT3, Epistemonikos, GRADE.
INTRODUCTION
The usual supplementation for hypothyroidism is based on monotherapy with levothyroxine. However, some patients persist with symptoms attributable to the deficit of
thyroid hormone. It has been suggested that the a combined treatment with liothyronine and levothyroxine would provide a greater benefit.
METHODS
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.
RESULTS AND CONCLUSIONS
We identified three systematic reviews including twelve primary studies overall, all of which were randomized trials. We concluded that the addition of liothyronine to the treatment of hypothyroidism has minimal or no effect on fatigue and quality of life. It probably does not improve mood, pain or function cognitive, and it would not reduce body weight.
Hypothyroidism is a common disease, characterized by a deficiency of endogenous thyroid hormone, which affects 0.5 to 4.1% of the world population [1]. The standard treatment of hypothyroidism, regardless its etiology, is monotherapy with levothyroxine (LT4), the synthetic form of thyroxine, adjusted for the concentration of thyroid stimulating hormone (TSH). Despite achieving normal TSH, approximately 5-10% of patients report residual symptoms of hypothyroidism [2].
The active thyroid hormone is triiodothyronine (T3). Eighty percent comes from the peripheral conversion of thyroxine (T4) to T3, mainly in the liver, and the remaining 20% is produced by the thyroid gland together with T4 [3], in a T3: T4 ratio of 1:5 [1]. Considering physiology, a treatment relying exclusively on LT4 would be deficient since optimum levels of T3 are not reached. Supplementation with T3 may be necessary in patients with hypothyroidism treated exclusively with LT4.
The objective of this summary was to evaluate the effects of the combination of LT4 and liothyronine (LT3) as a treatment for hypothyroidism.
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.
Key messages
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What is the evidence. |
We found three systematic reviews [3], [4], [5] that included 12 primary studies reported in 13 references [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], all corresponding to randomized trials. |
What types of patients were included* |
All trials included patients with hypothyroidism in previous treatment with LT4 with stabilized thyroid hormone levels prior to the intervention, most of them for more than two months. One trial [8] did not mention the time with stable thyroid hormone levels. Another trial [13] included patients with an indeterminate long time of previous hormonal stabilization. Regarding the etiology of hypothyroidism, three trials [14], [16], [17] exclusively included patients with hypothyroidism due to chronic thyroiditis, while in the rest of the trials patients with hypothyroidism of different etiologies were included: chronic thyroiditis, post-thyroidectomy (for cancer) and post-radiation [5]. Regarding the gender of the included patients, two trials [8], [10] included only women and one trial [6] conducted separate analyses: one with the total population and another excluding the male population [7]. In the rest of the trials, both women and men were included, the former constituting the vast majority of patients, except in one of the trials [17]. The age of the patients ranged between 18 and 76 years. |
What types of interventions were included* |
All trials evaluated the combined treatment with LT4 + LT3 as an intervention. Regarding the dose used in the intervention, seven trials [6], [8], [9], [11], [12], [14], [17] used the usual dose of LT4 minus 50 ug/day; one trial [16] used the usual dose minus 25 ug/day, and another [13] used the daily dose minus a 5%. In the remaining three trials [10], [15], [18] an arbitrary dose of LT4 (75 ug/day, ≥50 ug day and 80 ug/day respectively) was used. The doses of LT3 varied. All trials compared the intervention against the standard treatment (LT4). Nine trials [6], [8], [9], [11], [12], [13], [14], [16], [17] administered the usual dose, in two trials [10], [18] 100 ug/day and in one trial [15] ≥100ug/day. |
What types of outcomes |
The trials evaluated multiple outcomes, which were grouped by the systematic reviews as follows:
The average follow-up of the trials was 12 weeks, with a range between 5 and 39 weeks. |
* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.
The information on the effects of the combined treatment of hypothyroidism with LT3 + LT4 versus monotherapy with LT4 in hypothyroidism is based on 12 randomized controlled trials.
Four trials assessed pain (936 patients) [12], [14], [15], [17], seven trials assessed quality of life (1068 patients) [9], [10], [12], [13], [14], [15], [17], 11 evaluated mood (1563 patients) [6], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], six assessed fatigue (350 patients) [6], [10], [11], [13], [16], [17] and 11 evaluated adverse effects (1247 patients) [6], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. None of the systematic reviews presented data that could be re-analyzed and incorporated into a meta-analysis for body weight and cognitive function outcomes, so a narrative summary was prepared based on the results as reported by the reviews.
The summary of findings is as follows:
Follow the link to access the interactive version of this table (Interactive Summary of Findings – iSoF) |
To whom this evidence does and does not apply |
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About the outcomes included in this summary |
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Balance between benefits and risks, and certainty of the evidence |
|
Resource considerations |
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What would patients and their doctors think about this intervention |
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Differences between this summary and other sources |
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Could this evidence change in the future? |
|
Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.
Follow the link to access the interactive version: Combination therapy with thyroxine-triiodothyronine versus thyroxine monotherapy for hypothyroidism
The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.
After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.
This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)
Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).
Potential conflicts of interest
The authors do not have relevant interests to declare.
INTRODUCCIÓN
La suplementación habitual del hipotiroidismo se basa en la monoterapia con levotiroxina, sin embargo, algunos pacientes persisten con síntomas atribuibles al déficit de hormona tiroidea. Debido a esto se ha planteado que el uso de un tratamiento combinado con liotironina y levotiroxina otorgaría un mayor beneficio.
MÉTODOS
Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.
RESULTADOS Y CONCLUSIONES
Identificamos tres revisiones sistemáticas que en conjunto incluyeron 12 estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que la adición de liotironina al tratamiento del hipotiroidismo tiene un efecto mínimo o nulo sobre fatiga y calidad de vida. Probablemente tampoco mejora estado de ánimo, dolor ni función cognitiva, y no reduciría el peso corporal.
Citation: Fischman A, Domínguez J. Combined therapy with levothyroxine and liothyronine for hypothyroidism. Medwave 2018;18(8):e7375 doi: 10.5867/medwave.2018.08.7375
Submission date: 27/11/2018
Acceptance date: 4/12/2018
Publication date: 14/12/2018
Origin: This article is a product of the Evidence Synthesis Project of Epistemonikos Fundation, in collaboration with Medwave for its publication.
Type of review: Non-blinded peer review by members of the methodological team of Epistemonikos Evidence Synthesis Project.
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