Treatment of Hypothyroidism That Contains Liothyronine is Associated With Reduced Risk of Dementia and Mortality

Introduction Standard levothyroxine (LT4) therapy may not fully address all risks associated with hypothyroidism—especially cognitive decline, dementia, and mortality—even when TSH levels are normalized. Observational studies link hypothyroidism to higher dementia rates; the role of LT4 plus T3 therapies remains uncertain. Methods This retrospective cohort study analyzed TriNetX data, comparing 1.26 million patients with hypothyroidism (on LT4, LT4 + T3, or desiccated thyroid extract) to 3.32 million controls. Outcomes included dementia, atrial fibrillation, and mortality over 20 years of follow-up. Propensity score matching was used to balance covariates for age, sex, and comorbidities. Adjusted hazard ratios were obtained via Cox proportional hazard modeling. A parallel systematic review and meta-analysis of 12 studies evaluated dementia risk in hypothyroidism. Results Patients with hypothyroidism showed a ∼1.4-fold higher risk of dementia and a >2.0-fold increase in mortality—even with normal TSH—and these risks were most pronounced when TSH levels were off-target. A parallel meta-analysis indicated a 1.4-fold heightened dementia risk. In cohorts formed by propensity score matching comparing LT4 monotherapy vs combination therapy, relative risk analysis indicated 27% and 31% lower dementia and mortality risks, respectively, with combination therapy. The adjusted Cox model (hazard ratio) showed 16% and 25% reductions in these outcomes for combination therapy patients. Conclusion Despite standard LT4 therapy, hypothyroidism remains associated with heightened risks of dementia and mortality. Adding T3 may more effectively mitigate these risks than LT4 alone, but further studies are needed to confirm the cognitive and survival benefits of T3-containing regimens.