Risk of Death and Adverse Effects in Patients on Liothyronine: A Multisource Systematic Review and Meta-analysis

Area of Science:

• Endocrinology
• Pharmacology
• Clinical Medicine

Background:

• Patient preference exists for combination therapy using Liothyronine (LT3) and Levothyroxine (LT4) for hypothyroidism.
• The safety profile of LT3, particularly in combination therapy, requires thorough investigation.

Purpose of the Study:

• To conduct a comprehensive systematic review and meta-analysis evaluating the safety of LT3.
• To assess adverse events, cardiovascular outcomes, and mortality associated with LT3 use.

Main Methods:

• Systematic literature search of PubMed, UK yellow-card scheme, and US FDA Adverse Reporting System (FAERS).
• Inclusion of 52 studies: 21 randomized controlled trials (RCTs), 4 cohort studies, and 27 case reports.
• Meta-analyses performed on adverse outcomes from RCTs and cohort studies comparing combination LT3/LT4 therapy with LT4 monotherapy.

Main Results:

• LT3-related adverse events (AEs) were primarily linked to unregulated use or compounding errors.
• Analysis of FAERS and the yellow-card scheme revealed no increased LT3 safety signals or significant differences in AE severity compared to LT4.
• Meta-analysis of RCTs showed similar AE risks between combination and monotherapy (RR 1.22).
• Cohort meta-analysis (n=630,254) indicated no increased risk for atrial fibrillation, heart failure, or stroke, but a reduced mortality risk with LT3 (RR 0.70).

Conclusions:

• Regulated use of LT3 is not associated with increased risks of death or serious adverse outcomes.
• Findings support the safety of LT3 in combination therapy for hypothyroidism.
• Additional research is warranted to further corroborate these safety data.