Combination therapy with levothyroxine and liothyronine in hypothyroidism

A deficiency of thyroid hormone, known as hypothyroidism, is a common condition typically treated with levothyroxine. For some individuals who do not achieve the desired symptom relief with this treatment, it has been suggested that combination therapy with levothyroxine and liothyronine may be considered.

Reading time approx. 8 minutes Published: February 4, 2025 Publication type:

SBU Enquiry Service

Consists of structured literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. We assess the risk of bias in systematic reviews and when needed also quality and transferability of results in health economic studies. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed.

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Published: February 4, 2025 Report no: ut202501 Registration no: SBU 2024/649

Question

What systematic reviews have been published regarding combination therapy with levothyroxine and liothyronine for hypothyroidism?

Method

A systematic literature search was performed using the following databases: Medline and Scopus.

Two authors independently assessed the abstracts of all identified studies.

Risk of bias in relevant systematic reviews was assessed using an assessment tool based on AMSTAR.

Identified literature

Two relevant systematic reviews with moderate risk of bias were identified[1, 2]. The results and conclusions are presented in Table 1. In eight relevant systematic reviews, the risk of bias was considered to be high, therefore the results and conclusions are not reported[3-10].

Table 1 Systematic reviews with moderate risk of bias.
Included studies	Population, Intervention, Control	Outcome and Results
CI = confidence interval; LT3 = liotyronin; LT4 = levotyroxin; RCT = randomised controlled trial; SMD = standardised mean difference
Akirov et al., 2019 [1] A systematic review and meta-analysis of patient preferences for combination thyroid hormone treatment for hypothyroidism
7 RCT (n=425) Setting: Australia: 1 study Denmark: 1 study Lithuania: 2 studies Netherlands: 1 study Spain: 1 studyUSA: 1 study	Population: Patients with hypothyroidism (Autoimmune primary hypothyroidism; Surgically treated Graves disease; Toxic multinodular goiter; Thyroidectomy; Radioactive iodine treatment) Intervention: L-T3 (Liothyronine) / L-T4 (Levothyroxine) combination therapy Control: L-T4 monotherapy	Patient Preference of Therapy (questionnaire or interviews) Not statistically significant The pooled prevalence rate for preference of combination therapy over L-T4 was 46.2% (95% CI, 40.2 to 52.4%) (p=0.231 for the difference from chance)
Authors' conclusions: ”In conclusion, in this systematic review and meta-analysis of relatively short-term blinded RCTs, approximately 46% of adult hypothyroid patients preferred combination therapy with LT3 and L-T4 and L-T3 over L-T4 monotherapy; yet these findings were not distinguishable from chance.”
Millan-Alanis et al., 2021 [2] Benefits and Harms of Levothyroxine Monotherapy for Adult Patients with Hypothyroidism: Systematic Review and Meta-Analysis
18 RCT (n=1563) included in narrative synthesis. 11 RCT included in meta-analyses. Setting: Australia: 1 study Brazil: 1 study Canada: 1 study Denmark: 1 study Germany: 2 studies Iran: 1 study Lithuania: 2 studies Netherlands: 1 study Poland: 1 study Russia: 2 studies Spain: 1 study UK: 1 study USA: 3 studies	Population: Adult patients with hyperthyroidism (primary or central) Intervention: L-T3 (Liothyronine) / L-T4 (Levothyroxine) combination therapy. Control: L-T4 monotherapy.	Clinical status (Zulewski clinical score; Billewicz score, 5 RCTs)SMD 0.24 (favoring monotherapy), (95% CI, –0.03 to 0.51). Not statistically significant (p-value 0.15) Quality of Life (Short Form Health Survey, 3 RCTs)SMD –0.24 (favoring combined therapy), (95% CI, –0.53 to 0.28). Not statistically significant (p-value 0.56) Psychological distress (General Health Questionnaire; Symptoms checklist, 9 RCTs)SMD –0.06 (favoring combined therapy), (95% CI, –0.17 to 0.04). Not statistically significant (p-value 0.21) Depression (Beck Depression Inventory; Center for Epidemiological Studies Depression scale, 9 RCTs) SMD –0.15 (favoring combined therapy), (95% CI, –0.30 to 0.01). Not statistically significant (p-value 0.06) Fatigue (Piper Fatigue scale, 3 RCTs) SMD 0.13 (favoring monotherapy), (95% CI, –0.13 to 0.39). Not statistically significant (p-value 0.32) Patient preferences Preference for combined therapy: 43% (95% CI, 0.34 to 0.52) Preference for monotherapy: 0.23% (95% CI, 0.14 to 0.35) No therapy preference: 0.30 (0.21 to 0.41) No statistically significant difference
Authors' conclusion: “The body of evidence at low-to-moderate certainty demonstrates that there is no difference in clinical and surrogate outcomes between LT4/LT3 combined therapy and LT4 monotherapy for the treatment of adult patients with hypothyroidism with the exception that patients preferred the use of combined therapy. Adverse events and reactions appear to be similar across groups, however, this observation is only narrative.”

References

Akirov A, Fazelzad R, Ezzat S, Thabane L, Sawka AM. A Systematic Review and Meta-Analysis of Patient Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism. Front Endocrinol (Lausanne). 2019;10:477. Available from: https://doi.org/10.3389/fendo.2019.00477.
Millan-Alanis JM, Gonzalez-Gonzalez JG, Flores-Rodriguez A, Singh Ospina N, Maraka S, Moreno-Pena PJ, et al. Benefits and Harms of Levothyroxine/L-Triiodothyronine Versus Levothyroxine Monotherapy for Adult Patients with Hypothyroidism: Systematic Review and Meta-Analysis. Thyroid. 2021;31(11):1613-25. Available from: https://doi.org/10.1089/thy.2021.0270.
Ma C, Xie J, Huang X, Wang G, Wang Y, Wang X, et al. Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. Nucl Med Commun. 2009;30(8):586-93. Available from: https://doi.org/10.1097/MNM.0b013e32832c79e0.
Chen Y, Tai HY. Levothyroxine in the treatment of overt or subclinical hypothyroidism: a systematic review and meta-analysis. Endocr J. 2020;67(7):719-32. Available from: https://doi.org/10.1507/endocrj.EJ19-0583.
de Lima Beltrao FE, Carvalhal G, de Almeida Beltrao DC, de Lima Beltrao FE, Ribeiro MO, Ettleson MD, et al. Treatment Preferences in Patients with Hypothyroidism: an Analysis of Eleven Randomized Controlled Trials. J Clin Endocrinol Metab. 2024;18:18. Available from: https://doi.org/10.1210/clinem/dgae651.
Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592-9. Available from: https://doi.org/10.1210/jc.2006-0448.
Hidalgo J, Lincango EP, Cordova-Madera S, Ruiz-Arellanos K, Wenczenovicz C, Ponce O, et al. Interventions to improve symptomatology in patients with hypothyroidism and persistent symptoms: A systematic review. Endocrine. 2024;84(3):864-73. Available from: https://doi.org/10.1007/s12020-024-03816-1.
Lan H, Wen J, Mao Y, Huang H, Chen G, Lin W. Combined T4 + T3 therapy versus T4 monotherapy effect on psychological health in hypothyroidism: A systematic review and meta-analysis. Clin Endocrinol (Oxf). 2022;97(1):13-25. Available from: https://doi.org/10.1111/cen.14742.
Nassar M, Hassan A, Ramadan S, Desouki MT, Hassan MA, Chaudhuri A. Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis. BMC Endocr Disord. 2024;24(1):90. Available from: https://doi.org/10.1186/s12902-024-01612-6.
Vargas-Uricoechea H, Wartofsky L. LT4/LT3 Combination Therapy vs. Monotherapy with LT4 for Persistent Symptoms of Hypothyroidism: A Systematic Review. Int J Mol Sci. 2024;25(17). Available from: https://doi.org/10.3390/ijms25179218.

Search strategies

Medline via OvidSP 19 September 2024

Title: Combination treatment with Levothyroxine and Liothyronine for patients with hypothyroidism
Search terms		Items found
/ = Term from the MeSH controlled vocabulary; .sh = Term from the MeSH controlled vocabulary; exp = Term from MeSH including terms found below this term in the MeSH hierarchy; .ti,ab = Title or abstract; .tw = Title or abstract; .kf = Keywords; .kw = Keywords, exact; .bt = Book title. NLM Bookshelf; .pt = Publication type; .ja = Journal abbreviation; .af = All fields; adjn = Adjacent. Proximity operator retrieving adjacent words, adj3 retrieves records with search terms within two terms from each other; * or $ = Truncation; “ “ = Citation Marks; searches for an exact phrase
Population:
1./td>	Exp Hypothyroidism/	39 955
2.	(hypothyr* or (thyroid ADJ3 (deficienc* or insufficienc)) or TSH deficienc).ti,bt,kf,ab.	45 493
3.	Or/1-2	56 585
Intervention:
4.	Triiodothyronine/	26 595
5.	(triiodothyronin* or T3 or liothyronin* or “L-triiodothyronin*”).ti,bt,kf,ab.	70 786
6.	Or/4-5	79 043
Study types: systematic reviews and meta-analysis
7.	((Systematic Review/ or Meta-Analysis/ or Cochrane Database Syst Rev.ja. or ((systematic adj4 review) or "meta analys" or metaanalys).ti,bt,ab.) not (editorial/ or letter/ or case reports/))	504 904
Combined sets:
8.	3 AND 6 AND 7	85
Final result
9.	3 AND 6 AND 7	85

Scopus via scopus.com 19 September 2024

Title: Combination treatment with Levothyroxine and Liothyronine for patients with hypothyroidism
Search terms		Items found
TITLE-ABS-KEY = Title, abstract or keywords (including indexed keywords and author keywords); ALL = All fields; W/n = Within. Proximity operator retrieving terms within n words from each other; PRE/n = Precedes by. Proximity operator, the first term in the search must precede the second by n words; LIMIT-TO (X) = Includes only results of specified type, e.g., publication type or time range; DOCTYPE = Publication type; “re” = review; “le” = letter; “ed” = editorial; “ch” = book chapter; “cp” = conference proceedings; * = Truncation; “ “ = Citation Marks; searches for an exact phrase
Population:
1.	TITLE-ABS-KEY (hypothyr*)	92 311
2.	TITLE-ABS-KEY (thyroid W/3 ( deficienc* OR insufficienc* ) )	3076
3.	TITLE-ABS-KEY ("TSH Deficienc*" )	289
4.	Or/1-3	93 680
Intervention:
5.	TITLE-ABS-KEY (triodothyronin*)	103
6.	TITLE-ABS-KEY (T3)	98 230
7.	TITLE-ABS-KEY (" L-triiodothyronin*")	893
8.	TITLE-ABS-KEY (liothyronine*)	48 037
9.	Or/5-8	127 431
Study types: systematic reviews and meta-analysis
10.	TITLE-ABS-KEY ( ( systematic W/2 review ) OR "meta analy" OR& metaanaly ) AND (EXCLUDE (DOCTYPE, “le”) OR EXCLUDE (DOCTYPE, “ed”) OR EXCLUDE (DOCTYPE, “ch”) OR EXCLUDE (DOCTYPE, “cp”))	743 999
Combined sets:
11.	4 AND 9 AND 10	254
Final result
12.	4 AND 9 AND 10	254

Page published February 4, 2025

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