Risk of death and adverse effects in patients on Liothyronine: a multi-source systematic review and meta-analysis

Bahl, Suhani ORCID: https://orcid.org/0009-0002-3216-896X, Taylor, Peter N. ORCID: https://orcid.org/0000-0002-3436-422X, Premawardhana, Lakdasa D., Stedman, Mike, Heald, Adrian, Dayan, Colin M. ORCID: https://orcid.org/0000-0002-6557-3462 and Okosieme, Onyebuchi E. 2025. Risk of death and adverse effects in patients on Liothyronine: a multi-source systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism , dgaf449. 10.1210/clinem/dgaf449

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Abstract

Context Although some patients with hypothyroidism prefer combination therapy with Liothyronine (LT3) and Levothyroxine (LT4), the safety of LT3 remains unresolved. Objective We undertook a multi-source systematic-review and meta-analysis of LT3 safety. Data sources We searched PubMed for articles relating to death, adverse events (AEs), and cardiovascular outcomes in LT3 users. We also searched AEs data in the UK yellow-card scheme and US Food and Drug Administration Adverse Reporting System (FAERS). Data extraction Data was extracted independently by two reviewers. Out of 1814 articles identified, 52 studies were selected, comprising 21 randomised controlled trials (RCTs), 4 cohort-studies, and 27 case-reports. Meta-analyses were conducted for adverse outcomes in RCTs and cohort studies of combination vs. monotherapy. Data synthesis LT3-related AEs were only reported with unregulated LT3 use or pharmacy compounding errors. LT3 and LT4 showed similar adverse severity profiles in the yellow-card scheme. Disproportionality analysis in FAERS database showed no increased LT3 safety signals. Meta-analysis of RCTs (n=2128) showed similar AEs risk for combination vs. monotherapy (Relative risk [RR] 1.22, 95% Confidence Interval [95%CI] 0.66–2.25). Cohort study meta-analysis (LT3 vs. LT4-only users, n=630,254) showed no increased risk of atrial fibrillation (RR 1.10 95%CI, 0.74–1.63), heart failure (RR 1.54, 95%CI 0.95–2.47), or strokes (RR 0.86, 95%CI 0.11–6.75), but reduced mortality risk was observed for LT3 (RR 0.70, 95%CI 0.62–0.78). Conclusions Our findings are reassuring that regulated LT3 use is not associated with risk of death or serious adverse outcomes. More studies are needed to supplement existing data.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher:	Oxford University Press (OUP)
ISSN:	0021-972X
Date of First Compliant Deposit:	13 August 2025
Date of Acceptance:	7 August 2025
Last Modified:	13 Aug 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/180404

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