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

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 multisource 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 2 reviewers. Out of 1814 articles identified, 52 studies were selected, comprising 21 randomized 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 the FAERS database showed no increased LT3 safety signals. A meta-analysis of RCTs (n = 2128) showed a similar AEs risk for combination vs monotherapy [relative risk (RR) 1.22, 95% confidence interval (CI) 0.66-2.25]. A 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). 

Conclusion: Our findings are reassuring that regulated LT3 use is not associated with the risk of death or serious AEs. More studies are needed to supplement existing data.