LT4 Plus T3 Therapy Reduces Dementia, Mortality Risks in Hypothyroidism

Hypothyroidism is associated with increased risks for dementia and mortality despite standard levothyroxine (LT4) therapy, according to study findings published in The Journal of Clinical Endocrinology & Metabolism.

Investigators combined a systematic review, meta-analysis, and meta-regression analysis with a retrospective cohort study to assess whether hormone replacement therapy in hypothyroidism is associated with heightened dementia risk. TriNetX data comprised 1.25 million patients with hypothyroidism aged at least 18 years treated with LT4, LT4 plus liothyronine (T3), or desiccated thyroid extract (DTE) with 3.32 million control individuals. Follow-up was from January 2004 through December 2023.

The systematic review and meta-analysis included case-control and observational cohort studies with participants aged at least 18 years and diagnosed with overt hypothyroidism and an outcome of dementia.

Covariates for sex, age, and comorbidities were balanced with propensity score matching (PSM). Dementia risk in hypothyroidism was assessed in a parallel systematic review and meta-analysis of 12 studies.

A composite dementia diagnosis occurring at least 1-year post-index encounter was the primary outcome. Participants with outcomes before 1 year were excluded from analysis. All-cause mortality was the secondary outcome, evaluated to help account for possible survival bias.

Compared with the control individuals, patients with hypothyroidism were more likely to be older, White, and female with a greater prevalence of smoking and higher burdens of thyroid-stimulating hormone (TSH), body mass index (BMI), HbA_1c levels, and comorbidities.

Patients with vs without hypothyroidism had a 1.4-fold higher risk for dementia and more than a 2.0-fold increased risk of death, even for those with normal TSH. Among patients with off-target TSH levels, these risks were greater. In a parallel meta-analysis, the investigators found a 1.4-fold higher risk for dementia.

PSM comparing LT4 monotherapy vs combination therapy showed relative risk (RR) of 27% lower dementia risks and 31% lower mortality risks with the combination therapy. The investigators identified dementia and mortality risk reductions of 16% and 25%, respectively, for patients treated with combination therapy in adjusted Cox models.

Study limitations include limited generalizability to other world populations due to the preponderance of American healthcare organizations representing the TriNetX network, potential misclassification bias, and residual confounding. Additionally, the meta-analysis exhibited significant between-study heterogeneity (I²=97.3%).

“Despite standard LT4 therapy, hypothyroidism remains associated with heightened risks of dementia and mortality,” the investigators concluded. “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.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Endocrinology Advisor