Click to Enlarge: This figure shows that the risk of incident heart failure was cumulative over time for both thyroid hormone under-replacement and over-replacement, with under-replacement demonstrating a stronger association with incident heart failure. Source: The Journal of Clinical Endocrinology & Metabolism
ANN ARBOR, MI — In adults treated with thyroid hormone, both under-replacement and over-replacement with thyroid hormone are associated with increased incident heart failure, according to a recent veteran study.
In the United States, heart failure affects more than 6 million adults, and the prevalence is increasing. Levothyroxine, the most commonly used synthetic form of thyroid hormone, is also among the most frequently prescribed medications in the U.S. Previous studies have shown a high frequency of over- and under-replacement in thyroid hormone users, with rates exceeding 40%.
Growing evidence indicated that thyroid hormone over- and under-replacement might be associated with increased risk of cardiovascular disease, stroke, cardiovascular mortality and all-cause mortality, according to the retrospective cohort study published in The Journal of Clinical Endocrinology & Metabolism.1
Serum thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels are potentially independent predictors of cardiovascular risk. Data on the association between thyroid hormone over- and under-replacement and incident heart failure are limited, so this study investigated this association, the researchers explained.
Study authors are affiliated with the University of Michigan in Ann Arbor, MI; VA Ann Arbor (MI) Health System; and the University of North Carolina at Chapel Hill, NC.
“Our research team has a particular interest in understanding clinical outcomes from over- and under-replacement with thyroid hormone, including cardiac outcomes such as heart failure,” Maria Papaleontiou, MD, associate professor in the Division of Metabolism, Endocrinology and Diabetes and research associate professor in the Institute of Gerontology at University of Michigan, told U.S. Medicine. “The VA CDW [Corporate Data Warehouse] offers a rich source of demographic, clinical and biochemical data allowing us to study outcomes longitudinally.”
In this study, eligible patients were adults age 18 years and older without a diagnosis of preexisting heart failure, who were initiated on thyroid hormone during the study period. The participants were 641,504 adults who began thyroid hormone treatment between Jan. 1, 2004, and Dec. 31, 2017, at the VA. Two cohorts of adults were separately studied. The first cohort was 638,323 adults with at least two outpatient TSH measurements between the beginning of the study period and incident heart failure or between the beginning and end of the study period.
The second cohort was 338,249 adults with at least two outpatient FT4 measurements, between thyroid hormone initiation and incident heart failure or study conclusion. The researchers analyzed the associations between time-varying TSH and FT4 exposure and incident heart failure as the outcome.
The study excluded patients with a history of thyroid cancer, who might sometimes have a TSH goal below the normal range to reduce recurrence risk (n=18,890), and individuals on medications that might interfere with thyroid function tests, such as amiodarone and lithium (n=94,148), the investigators reported.
“In this observational study, we found that, following adjustment for age, sex and cardiovascular risk factors (e.g., smoking, hypertension), both under-replacement and over-replacement with thyroid hormone were associated with increased incident heart failure compared to euthyroidism,” Papaleontiou explained. “Incident heart failure risk was cumulative over time with both thyroid hormone over- and under-replacement, but association was strongest with under-replacement. Even though we used VA data for our study, these findings may apply more broadly to patients on thyroid hormone therapy and highlight the need to maintain euthyroidism to avoid cardiac adverse outcomes.”
In this analysis, 564,152 (87.9%) patients were men, and the median age was 66 years old. Incident heart failure occurred in 81,286 (12.7%) patients.
The study’s findings suggest that thyroid hormone treatment intensity might be a modifiable risk factor for heart failure. Incident heart failure risk was cumulative over time with both thyroid hormone over- and under-replacement, but researchers found the association was strongest with under-replacement. TSH greater than 5.5 mIU/L was associated with a 5.8-fold increase in incident heart failure over five years, the authors pointed out.
“These findings highlight the importance of proper patient selection for thyroid hormone initiation and appropriate laboratory monitoring to avoid inappropriate treatment in patients taking thyroid hormone,” Papaleontiou suggested. “Given the widespread use of thyroid hormone replacement, it is important that individuals with persistently high or low serum TSH levels while on thyroid hormone replacement therapy are comprehensively evaluated for factors affecting thyroid hormone absorption and availability, proper dosage and administration, adherence with treatment, and concurrent use of medications and comorbid conditions that may result in thyroid function abnormalities.”
Despite the study’s strengths, including being a large, population-based study and using data from a large, integrated healthcare system, the study also had some limitations. Since this is a retrospective observational study, the findings can’t be used to establish a causal relationship between thyroid hormone treatment intensity and incident heart failure. However, the researchers adjusted for a broad list of factors representing downstream effects of obesity, such as hypertension and diabetes, which partly mitigated this limitation. Also, because of reliance on diagnosis codes, they couldn’t assess the degree to which cardiovascular risk factors, such as hypertension, diabetes and hyperlipidemia, were adequately managed.
In addition, the authors noted that, while they excluded individuals taking commonly used medications such as amiodarone and lithium, they recognize that other medications and supplements can interfere with thyroid hormone metabolism and thyroid function tests. They also recognized that FT3 was not included in the analyses because this marker isn’t typically tested in clinically evaluating adequate thyroid hormone replacement in patients. Lastly, studies using VA data under-represent the U.S. population distribution of women and racial and ethnic groups other than white, but this study had a large sample size with more than 70,000 female, 40,000 Black and 30,000 Hispanic patients, according to the study.
- Evron J, Moretti B, Evans R, Burns J, Hummel SL, Esfandiari NH, Hawley ST, Haymart MR, Papaleontiou M. Association between Over- and Under-Replacement with Thyroid Hormone and Incident Heart Failure. J Clin Endocrinol Metab. 2025 Dec 17:dgaf677. doi: 10.1210/clinem/dgaf677. Epub ahead of print. PMID: 41403272; PMCID: PMC12754135.