Efficacy of Levothyroxine (LT4) and Liothyronine (T3) Combination Therapy vs. LT4 Monotherapy for Hypothyroidism: A Meta-Analysis
DOI:
https://doi.org/10.71341/bmwj.v3i1.56Keywords:
Hypothyroidism, Levothyroxine, Liothyronine, Meta-analysisAbstract
Background: Levothyroxine (LT4) monotherapy is the standard treatment for hypothyroidism, using serum thyroid-stimulating hormone (TSH) as the primary indicator of therapeutic adequacy. However, many patients remain symptomatic despite achieving normal TSH levels.
Objectives: This meta-analysis evaluates the biochemical and metabolic efficacy of adding liothyronine (T3) to LT4 compared to standard monotherapy.
Method: A systematic search was conducted to identify randomized controlled trials (RCTs) comparing LT4+T3 combination therapy with LT4 monotherapy in adults. TSH was the primary outcome, while secondary outcomes included free T4 (fT4), total T3, lipid profiles, and body weight.
Results: Seven RCTs involving 355 participants were analyzed. Biochemical outcomes showed no significant difference in TSH suppression (P=0.40) or total T3 levels (P=0.38) between groups. Notably, LT4 monotherapy resulted in significantly higher fT4 levels (MD=0.27; 95%CI: 0.13, 0.40; P=0.0001). Regarding metabolic outcomes, combination therapy significantly improved LDL cholesterol (MD=4.79; 95%CI: 1.63, 7.96; P=0.003) with zero heterogeneity (I2=0%). A borderline significant trend toward weight reduction was also observed in the combination group (MD=-2.26; 95%CI: -4.52, 0.01; P=0.05).
Conclusion: Compared to monotherapy, LT4+T3 combination therapy provides significant metabolic advantages, particularly in LDL reduction, while maintaining biochemical euthyroidism.
References
Azizi, F., Moeini, A. S., Mehran, L., Masoumi, S., Abdi, H., Foroutan, S. M., et al. (2025). Treatment of hypothyroidism with the combination of levothyroxine and slow-release triiodothyronine: A randomized clinical trial. Journal of Clinical and Translational Endocrinology, 40, Article 100395.
Brigante, G., Santi, D., Boselli, G., Margiotta, G., Corleto, R., Monzani, M. L., et al. (2024). Randomized double-blind placebo-controlled trial on levothyroxine and liothyronine combination therapy in totally thyroidectomized subjects: The LEVOLIO study. European Journal of Endocrinology, 190(1), 12–22.
Hajtalebi, F., Alaei-Shahmiri, F., Golgiri, F., Shahini, N., Akbari, H., Assadian, K., et al. (2025). Early effects of LT3 + LT4 combination therapy on quality of life in hypothyroid patients: A randomized, double-blind, parallel-group comparison trial. BMC Endocrine Disorders, 25, Article 22.
Kaminski, J., Miasaki, F. Y., Paz-Filho, G., Graf, H., & de Carvalho, G. A. (2016). Treatment of hypothyroidism with levothyroxine plus liothyronine: A randomized, double-blind, crossover study. Archives of Endocrinology and Metabolism, 60(6), 562–571.
Mehran, L., Amouzegar, A., Foroutan, S. M., Masoumi, S., Tohidi, M., Abdi, H., et al. (2023). Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained-release liothyronine: A randomized controlled clinical trial. BMC Endocrine Disorders, 23, Article 182.
Phan, G. Q., Yavuz, S., Stamatouli, A. M., Madan, R., Chen, S., Grover, A. C., et al. (2025). A feasibility double-blind trial of levothyroxine vs. levothyroxine-liothyronine in postsurgical hypothyroidism. Frontiers in Endocrinology, 16, Article 1522753.
Shakir, M. K. M., Brooks, D. I., McAninch, E. A., Fonseca, T. L., Mai, V. Q., Bianco, A. C., et al. (2021). Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in hypothyroidism. The Journal of Clinical Endocrinology & Metabolism, 106(11), e4400–e4413.
Antonelli, A., Wartofsky, L., & Miccoli, P. (2021). Editorial: Levothyroxine therapy in patients with hypothyroidism. Frontiers in Endocrinology, 12, Article 734895.
Ayasa, Y., Omarion, A., Omarion, Z., Jayouse, B., & Ayesh, H. (2025). Comparative efficacy of levothyroxine monotherapy and levothyroxine/liothyronine combination therapy for hypothyroidism: A systematic review and meta-analysis. Journal of the Endocrine Society, 9(Suppl 1), Article bvaf149.2153.
Beltrão, F. E. L., Carvalhal, G., Beltrão, D. C. A., Beltrão, F. E. L., Ribeiro, M. O., Ettleson, M. D., et al. (2025). Treatment preferences in patients with hypothyroidism. The Journal of Clinical Endocrinology & Metabolism, 110, 887–900.
Benabdelkamel, H., Jaber, M. A., Dahabiyeh, L. A., Masood, A., Almalki, R. H., Abdel Rahman, A. M., et al. (2022). Metabolomic profile of patients on levothyroxine treatment for hypothyroidism. European Thyroid Journal, 12(4), Article e230062.
Bianco, A. C. (2024). Emerging therapies in hypothyroidism. Annual Review of Medicine, 75, 307–319.
Ettleson, M. D., & Papaleontiou, M. (2022). Evaluating health outcomes in the treatment of hypothyroidism. Frontiers in Endocrinology, 13, Article 1026262.
Fischman, A., & Domínguez, J. M. (2018). Combined therapy with levothyroxine and liothyronine for hypothyroidism. Medwave, 18(8), Article e7375.
Hostalek, U. G., & Tayrouz, Y. (2024). A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism. Current Medical Research and Opinion, 40(12), 2109–2116.
Jonklaas, J., Bianco, A. C., Cappola, A. R., Celi, F. S., Fliers, E., Heuer, H., et al. (2021). Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: A consensus document. European Thyroid Journal, 10, 10–38.
Kahaly, G. J., & Gottwald-Hostalek, U. (2022). Use of levothyroxine in the management of hypothyroidism: A historical perspective. Frontiers in Endocrinology, 13, Article 1054983.
McAninch, E. A., Rajan, K. B., Miller, C. H., & Bianco, A. C. (2018). Systemic thyroid hormone status during levothyroxine therapy in hypothyroidism: A systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism, 103(12), 4533–4542.
Peterman, K., Tacata, R. H. N., Cerezo, N., & Casimiro, I. (2025). Combination therapy with levothyroxine and liothyronine in hypothyroid patients with persistent symptoms: A case series. Journal of Clinical and Translational Endocrinology Case Reports, 38, Article 100201.
Premawardhana, L. D., Taylor, P. N., Okosieme, O. E., Adlan, M. A., Obuobie, E. K., & Dayan, C. M. (2023). Designing a combined liothyronine (LT3), L-thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4: The importance of patient selection, choice of LT3 and trial design. Frontiers in Endocrinology, 14, Article 1282608.
Suryantini, N. K. M., Putri, L. L., Salim, B. H., Mawaddah, A., & Trianis, E. (2024). Gangguan hormon tiroid hipotiroidisme: Literature review. Jurnal Kesehatan Malahayati, 11(6), 1226–1233.
Thomas, A. F. (2025). Monotherapy versus combination levothyroxine and liothyronine in the treatment of hypothyroidism. The PA Department Journal of Medical Science. https://digitalcommons.gardner-webb.edu/pa-department-journal-of-medical-science/53
Uricoechea, H. V., & Wartofsky, L. (2024). LT4/LT3 combination therapy vs. monotherapy with LT4 for persistent symptoms of hypothyroidism: A systematic review. International Journal of Molecular Sciences, 25, Article 9218.
Wilson, S. A., Stem, L. A., & Bruehlman, R. D. (2021). Hypothyroidism: Diagnosis and treatment. American Family Physician, 103(10), 605–613.
Zamwar, U. M., & Muneshwar, K. N. (2023). Epidemiology, types, causes, clinical presentation, diagnosis, and treatment of hypothyroidism. Cureus, 15(9), Article e46241.
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Gede Made Cahya Trisna Pratama, Dewi Catur Wulandari
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
License
This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format for any purpose, even commercial purposes.
- Adaptation — mixing, changing, and developing materials for any purpose, even commercial ones.
Under the following terms:
- Attribution — You must give appropriate credit , provide a link to the license, and indicate if changes were made . You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
