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Cited by 75Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryHormonal and reproductive studies

Association of thyroid hormone treatment intensity with cardiovascular mortality among US veterans.

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Evron, Josh M., Hummel, Scott L., Reyes-Gastelum, David, Haymart, Megan R., Banerjee, Mousumi, Papaleontiou, Maria·2022·JAMA Network Open
DOI 10.1001/jamanetworkopen.2022.11863PMC PMC9099430
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Abstract

Importance: Cardiovascular disease is the leading cause of death in the United States. Synthetic thyroid hormones are among the 3 most commonly prescribed medications, yet studies evaluating the association between the intensity of thyroid hormone treatment and cardiovascular mortality are scarce. Objective: To evaluate the association between thyroid hormone treatment intensity and cardiovascular mortality. Design, Setting, and Participants: This retrospective cohort study used data on 705 307 adults who received thyroid hormone treatment from the Veterans Health Administration Corporate Data Warehouse between January 1, 2004, and December 31, 2017, with a median follow-up of 4 years (IQR, 2-9 years). Two cohorts were studied: 701 929 adults aged 18 years or older who initiated thyroid hormone treatment with at least 2 thyrotropin measurements between treatment initiation and either death or the end of the study period, and, separately, 373 981 patients with at least 2 free thyroxine (FT4) measurements. Data were merged with the National Death Index for mortality ascertainment and cause of death, and analysis was conducted from March 25 to September 2, 2020. Exposures: Time-varying serum thyrotropin and FT4 levels (euthyroidism: thyrotropin level, 0.5-5.5 mIU/L; FT4 level, 0.7-1.9 ng/dL; exogenous hyperthyroidism: thyrotropin level, <0.5 mIU/L; FT4 level, >1.9 ng/dL; exogenous hypothyroidism: thyrotropin level, >5.5 mIU/L; FT4 level, <0.7 ng/dL). Main Outcomes and Measures: Cardiovascular mortality (ie, death from cardiovascular causes, including myocardial infarction, heart failure, or stroke). Survival analyses were performed using Cox proportional hazards regression models using serum thyrotropin and FT4 levels as time-varying covariates. Results: Of the 705 307 patients in the study, 625 444 (88.7%) were men, and the median age was 67 years (IQR, 57-78 years; range, 18-110 years). Overall, 75 963 patients (10.8%) died of cardiovascular causes. After adjusting for age, sex, traditional cardiovascular risk factors (eg, hypertension, smoking, and previous cardiovascular disease or arrhythmia), patients with exogenous hyperthyroidism (eg, thyrotropin levels, <0.1 mIU/L: adjusted hazard ratio [AHR], 1.39; 95% CI, 1.32-1.47; FT4 levels, >1.9 ng/dL: AHR, 1.29; 95% CI, 1.20-1.40) and patients with exogenous hypothyroidism (eg, thyrotropin levels, >20 mIU/L: AHR, 2.67; 95% CI, 2.55-2.80; FT4 levels, <0.7 ng/dL: AHR, 1.56; 95% CI, 1.50-1.63) had increased risk of cardiovascular mortality compared with individuals with euthyroidism. Conclusions and Relevance: This study suggests that both exogenous hyperthyroidism and exogenous hypothyroidism were associated with increased risk of cardiovascular mortality. These findings emphasize the importance of maintaining euthyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

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  • These risks were particularly more pronounced in those with serum TSH levels consistently at extremes (<0.1 or >10.0 mU/L).

    “These risks were particularly more pronounced in those with serum TSH levels that are consistently at the extremes (<0.1 or >10.0 mU/L).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [73]

    The Results report higher cardiovascular mortality at TSH <0.1 mIU/L and at 10–20 mIU/L, with risk rising further above 20 mIU/L. The Methods treat TSH as a time-varying measure, so the paper does not establish that these patients were consistently at those extremes; the Discussion identifies <0.1 and >20 mIU/L as the levels with the highest increased risk, rather than <0.1 and >10. (LLM, conf=0.86)

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  • Analyses of real-world data from patient registries have demonstrated that serum TSH levels outside reference intervals in LT4-treated hypothyroidism are associated with adverse health outcomes, including ischemic heart disease events, cardiac dysrhythmias, fractures, and heart failure.

    “Analyses of real-world data from patient registries have demonstrated that the levels of serum TSH outside the reference intervals, in patients with LT4-treated hypothyroidism, are associated with adverse health outcomes, including ischemic heart disease events, cardiac dysrhythmias, fractures, and heart failure (5, 72, 73).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [73]

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  • There is some evidence that in older individuals (median age 67 years), even slight levothyroxine over-replacement is associated with adverse outcomes with regard to cardiovascular mortality, potentially indicating a lower thyroid-status setpoint in these individuals.

    “There is some evidence that in older individuals (median age 67 years), even slight levothyroxine over-replacement is associated with adverse outcomes with regard to cardiovascular mortality,162 potentially indicating a lower thyroid-status setpoint in these individuals.”

    From Hypothyroidism (2024) · cites this paper as [162]

  • Serum thyrotropin levels below or above the reference range while taking levothyroxine have been associated with increased risk of adverse cardiovascular events.

    “Serum thyrotropin levels below or above the reference range while taking levothyroxine have been associated with increased risk of adverse cardiovascular events. 72-75”

    From Hypothyroidism: A Review (2025) · cites this paper as [74]

  • A recent study found that cardiovascular mortality risk increased progressively with higher TSH, especially in older adults.

    “Furthermore, a recent study found that the cardiovascular mortality risk increased progressively with higher TSH, especially in the older adults [14].”

    From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [14]

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Research works printed but not linked: 2

  1. [5]IMS Institute for Healthcare Informatics. Medicine Use and Shifting Costs of Healthcare. IMS Health; 2014: 46.
  2. [7]IQVIA. Medicine use and spending in the U.S.: a review of 2018 and outlook to 2023. Accessed July 1, 2021. https://www.iqvia.com/insights/the-iqvia-institute/reports/medicine-use-and-spending-in-the-us-a-review-of-2018-and-outlook-to-2023

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Authors
Evron, J. M., Hummel, S. L., Reyes-Gastelum, D., Haymart, M. R., Banerjee, M., & Papaleontiou, M.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • University of Michigan (US)
  • Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor
Corresponding author
Papaleontiou, Maria
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2022-05-12
Volume
5
Issue
5
Pages
e2211863
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2022.11863
PMC
PMC9099430
OpenAlex
W4280515411
Cited by
75
References
21
Citations by year
2026: 11 · 2025: 23 · 2024: 16 · 2023: 15 · 2022: 10
FWCI
11.85
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Network Open (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Michigan Institute for Clinical and Health Research
  • National Institute on Aging (K08AG049684)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
thyroid hormone replacement, cardiovascular mortality, thyroid-stimulating hormone, free thyroxine, hyperthyroidism, hypothyroidism, euthyroidism, veterans, thyroid dysfunction, cardiovascular risk factors, heart failure, myocardial infarction, stroke, mortality risk stratification, treatment intensity, veterans' health care utilization, adverse drug reactions
MeSH terms
Adult, Aged, Cardiovascular Diseases, Female, Humans, Hyperthyroidism, Hypothyroidism, Male, Retrospective Studies, Thyroid Hormones, Thyrotropin, Thyroxine, United States, Veterans

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