Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: a propensity score-matched analysis
Abstract
Background: Combination therapy with liothyronine (LT3) and levothyroxine (LT4) is used in patients with persistent symptoms, despite being administered an adequate dose of LT4. LT3 may also be used in some thyroid cancer patients preparing for radioactive iodine therapy. However, there is a controversy regarding the safety of LT3 use, and there has been no definite evidence of long-term safety of LT3 therapy in Asian populations. The aim of this study was to examine the long-term safety of LT3 therapy using the Common Data Model (CDM). Methods: We conducted a retrospective multicenter study across four hospital databases encoded in the Observational Medical Outcomes Partnership (OMOP) CDM. LT3 users were defined as those who received an LT3 prescription for at least 90 days (with or without LT4), and their safety outcomes were compared with those in LT4-only users after 1:4 propensity score matching. Safety outcomes included the incidences of osteoporosis, cardiovascular disease, cancer, anxiety disorder, and mood disorder. Results: We identified 1434 LT3 users and 3908 LT4-only users. There was a statistically significant difference in the incidence rate of safety outcomes between LT3 users and LT4-only users. The risks of heart failure (incidence rate ratio [IRR] = 1.664, 95% confidence interval [95% CI] 1.002–2.764, p = 0.049) and stroke (IRR = 1.757, CI 1.073–2.877, p = 0.025) were higher in LT3 users than in LT4-only users. When subgroup analysis was performed according to the presence/absence of thyroid cancer history and duration of thyroid hormone replacement, the risk of heart failure was higher in LT3 users with a history of thyroid cancer and those who underwent ≥52 weeks of LT3 therapy. In addition, the risk of stroke was higher in LT3 users without thyroid cancer history and those who underwent ≥52 weeks of LT3 therapy. Conclusions: The use of LT3 was associated with increased incidence of heart failure and stroke in patients with a longer duration of LT3 use and history of thyroid cancer. Therefore, clinicians should consider the risk of heart failure and stroke in thyroid cancer patients with long-term use of LT3. These findings require confirmation in other populations.
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A large cohort study from Korea reported an increased risk of heart failure and strokes among LT3 users compared to LT4 users.
“A large cohort study from Korea reported an increased risk of heart failure and strokes among LT3 users compared to LT4 users (79).”
From Risk of Death and Adverse Effects in Patients on Liothyronine: A Multisource Systematic Review and Meta-analysis (2025) · cites this paper as [79]
The increased risk of stroke and heart failure in the Korean study was most marked in patients with more than a year of liothyronine exposure.
“A larger study of more than 1400 liothyronine users in the Korean population found an increased risk of stroke (incidence rate ratio: 1.8, 95% CI: 1.1 -2.9; p = .025) and heart failure (1.7, 95% CI: 1.0 -2.8; p = .049) compared to those taking levothyroxine alone, that was most marked in patients with more than a year of liothyronine exposure. 70”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [70]
The same Korean study found an increased risk of heart failure compared to those taking levothyroxine alone (incidence rate ratio 1.7, 95% CI 1.0-2.8; p=.049).
“A larger study of more than 1400 liothyronine users in the Korean population found an increased risk of stroke (incidence rate ratio: 1.8, 95% CI: 1.1 -2.9; p = .025) and heart failure (1.7, 95% CI: 1.0 -2.8; p = .049) compared to those taking levothyroxine alone, that was most marked in patients with more than a year of liothyronine exposure. 70”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [70]
Neither the Korean study nor another Swedish study have been able to confirm an association of breast or other cancers, or all-cause mortality with the use of liothyronine.
“Neither this Korean study, nor another Swedish study have been able to confirm an association of breast or other cancers, or all -cause mortality with the use of liothyronine. 70,71”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [70]
A larger study of more than 1400 liothyronine users in the Korean population found an increased risk of stroke compared to those taking levothyroxine alone (incidence rate ratio 1.8, 95% CI 1.1-2.9; p=.025).
“A larger study of more than 1400 liothyronine users in the Korean population found an increased risk of stroke (incidence rate ratio: 1.8, 95% CI: 1.1 -2.9; p = .025) and heart failure (1.7, 95% CI: 1.0 -2.8; p = .049) compared to those taking levothyroxine alone, that was most marked in patients with more than a year of liothyronine exposure. 70”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [70]
The Korean cohort study comprised a high proportion of patients who had been treated for thyroid cancer and would conceivably have been on TSH-suppressive treatment doses.
“This study, however, comprised a high proportion of patients who had been treated for thyroid cancer and would conceivably have been on TSH-suppressive treatment doses.”
From Risk of Death and Adverse Effects in Patients on Liothyronine: A Multisource Systematic Review and Meta-analysis (2025) · cites this paper as [79]
A Korean study of 1,500 patients found an association between the use of LT3 and heart failure and stroke, but the study did not provide LT3 doses, nor serum thyroid hormone or TSH levels.
“Notwithstanding, a Korean study of 1,500 patients did find an association between the use of LT3 and heart failure and stroke, but the study did not provide LT3 doses, nor serum TH or TSH levels (53).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [53]
In a 2022 propensity-matched study involving 5342 patients in Korea, incidences of heart failure and stroke were increased in patients with a longer duration of LT3 use (heart failure incidence rate ratio = 1.664, P = .049; stroke incidence rate ratio = 1.757, P = .025).
“In 2022, a propensity-matched study involving 5342 patients in Korea showed astonishing results (171). The incidences of heart failure and stroke were increased in patients with a longer duration of LT3 use (heart failure incidence rate ratio = 1.664, P = .049, stroke incidence rate ratio = 1.757, P = .025).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [171]
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- Authors
- Yi, W., Kim, B. H., Kim, M., Kim, J., Im, M., Ryang, S., Kim, E. H., Jeon, Y. K., Kim, S. S., & Kim, I. J.
- Affiliations
- Pusan National University Hospital (KR)
- Corresponding author
- Kim, Bo Hyun
- ORCID
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2022-07-01
- Volume
- 32
- Issue
- 7
- Pages
- 764-771
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W4280501309
- Cited by
- 36
- References
- 37
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 5
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- liothyronine, levothyroxine, combination thyroid hormone therapy, heart failure, stroke, thyroid cancer, thyroid hormone replacement, drug safety, cardiovascular risk, osteoporosis, anxiety disorders, mood disorders, cancer risk, Asian populations, propensity score matching
- MeSH terms
- Heart Failure, Humans, Hypothyroidism, Iodine Radioisotopes, Thyroid Neoplasms, Thyrotropin, Thyroxine, Triiodothyronine, Stroke, Propensity Score
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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