A major new study led by researchers at the University of Texas Medical Branch suggests that standard treatment for hypothyroidism may not fully protect patients from long-term risks such as dementia and premature death—even when thyroid-stimulating hormone (TSH) levels are within the normal range. The findings, published in The Journal of Clinical Endocrinology & Metabolism, highlight potential benefits of combination therapy that includes both levothyroxine (T4) and liothyronine (T3).
Hypothyroidism is a common endocrine disorder in which the thyroid gland does not produce sufficient thyroid hormone, leading to symptoms such as fatigue, weight gain, slowed cognition, and cold intolerance. Approximately 20 million Americans are affected by thyroid disease, with up to 5% of adults experiencing hypothyroidism—most of whom are treated with levothyroxine (LT4), the current standard therapy.
The UTMB study, a large-scale retrospective cohort analysis, leveraged data from TriNetX, a federated health research network providing anonymized, real-time electronic health records from 126 healthcare organizations across 17 countries, representing approximately 145 million individuals. Researchers analyzed outcomes from over 4.5 million patients, comparing 1.26 million patients with hypothyroidism (on LT4, LT4 + T3, or desiccated thyroid extract [DTE]) to 3.32 million controls.
Over a 20-year follow-up period, hypothyroid patients had a 1.4-fold higher risk of dementia and more than a twofold increase in mortality, even when TSH levels were in the normal range. These risks were most pronounced in individuals whose TSH was not well controlled.
Propensity score–matched comparisons showed that patients receiving combination therapy (LT4 + T3 or DTE) had a 27% lower risk of dementia and a 31% lower risk of mortality compared to those receiving LT4 alone. Adjusted Cox proportional hazard models confirmed a 16% reduction in dementia risk and a 25% reduction in mortality for patients on combination therapy.
The study was further supported by a systematic review and meta-analysis of 12 independent studies, which found a consistent 1.4-fold increased risk of dementia in individuals with hypothyroidism.
“These results challenge the long-held assumption that TSH normalization alone is sufficient to ensure optimal outcomes in hypothyroidism,” said study author Dr. Antonio Bianco, Interim Dean of the John Sealy School of Medicine and Chief Research Officer at UTMB. “The observed reductions in dementia risk are significant, but the findings on mortality are particularly impactful. They suggest that current standard treatment may not adequately protect all patients—and that combination therapy could offer important benefits for long-term survival.”
This research contributes to a growing body of evidence supporting more personalized approaches to thyroid hormone therapy, particularly for patients who do not experience full symptom relief with LT4 alone.
Other contributing authors include Giulia Carvalhal from the Federal University of Campina Grande; Bruna Albino Rafael Matos Andrade, Fabyan Esberard de Lima Beltrão and Danielle Albino Rafael Matos from the Federal University of Paraíba; Daniele Carvalhal de Almeida Beltrão from University Centre of João Pessoa; Helton Estrela Ramos from the Federal University of Bahia; Miriam O Ribeiro from the Mackenzie Presbyterian University; Matthew D Ettleson from the University of Chicago; and Vandrize Meneghini and George Golovko from UTMB.