Beware the Cardiovascular Risks Associated with Thyroid Hormone Replacement Therapy
By Austin Ulrich, PharmD, BCACP
Consultant Pharmacist, Ulrich Medical Writing LLC, Greensboro, NC
SYNOPSIS: Thyroid levels outside the euthyroid range have been associated with higher cardiovascular risk in patients taking thyroid hormone to treat hypothyroidism. In this study, a higher cardiovascular mortality rate was associated with exogenous hyperthyroidism and exogenous hypothyroidism.
SOURCE: Evron JM, Hummel SL, Reyes-Gastelum D, et al. Association of thyroid hormone treatment intensity with cardiovascular mortality among US veterans. JAMA Netw Open 2022;5:e2211863.
Synthetic levothyroxine for thyroid hormone replacement therapy is one of the most common prescriptions globally and in the United States.1 While thyroid replacement therapy is an essential treatment for many patients with hypothyroidism, it is not without risk. Cardiovascular risks, such as development of arrhythmias, are known side effects of thyroid hormone supplementation.2 Additionally, imbalances in thyroid hormone status (both exogenous hyperthyroidism and hypothyroidism) demonstrate elevated cardiovascular risk and all-cause mortality in patients taking thyroid hormone treatment for hypothyroidism.3,4 However, the association between cardiovascular mortality and the intensity of thyroid hormone treatment has not been fully explored. Evron et al conducted a population-based cohort study of U.S. veterans receiving thyroid hormone replacement therapy to determine whether treatment intensity affects cardiovascular mortality.
The authors used data from the Veterans Health Administration for patients who had initiated thyroid hormone treatment between Jan. 1, 2004, and Dec. 31, 2017. Patients were age 18 years or older and had undergone at least two serum thyrotropin measurements in an outpatient setting. Individuals with a history of thyroid cancer or concurrent treatment with lithium or amiodarone were excluded. Outcomes for cardiovascular mortality were adjusted for prespecified covariates, including sex, age, race, ethnicity, smoking status, and presence of comorbid conditions (e.g., history of cardiovascular disease or arrhythmias, diabetes, hypertension, and hyperlipidemia). Cardiovascular mortality after initiation of thyroid hormone treatment was ascertained with a median follow-up time of four years.
In total, 705,307 patients (median age was 67 years) received thyroid hormone treatment. Most patients were men, white, non-Hispanic, had hypertension or hyperlipidemia, and were current or former smokers. After adjusting for covariates, patients with exogenous hyperthyroidism (thyrotropin < 0.1 mIU/L or free T4 levels greater than 1.9 ng/dL) were at a higher risk of cardiovascular mortality vs. individuals with euthyroidism (adjusted HR, 1.39; 95% CI, 1.32-1.47 for thyrotropin; adjusted HR, 1.29; 95% CI, 1.20-1.40 for free T4). Additionally, patients with exogenous hypothyroidism (thyrotropin > 20 mIU/L or free T4 levels less than 0.7 ng/dL) were at a higher risk of cardiovascular mortality vs. those with euthyroidism (adjusted HR, 2.67; 95% CI, 2.55-2.80 for thyrotropin; adjusted HR, 1.56; 95% CI, 1.50-1.63 for free T4). As the degree of hyperthyroidism or hypothyroidism increased, a corresponding increase in cardiovascular risk was observed compared to patients with euthyroidism. Additionally, when stratified by age, patients age 85 years and older were at the highest cardiovascular risk resulting from dysthyroidism.
This large study of the effects of thyroid hormone replacement therapy intensity on cardiovascular mortality was well-conducted; the authors adjusted for many pertinent covariates. The results can help guide clinical practice for mitigating excess cardiovascular risk for patients treated with thyroid hormone supplementation. Although variance in thyrotropin and free T4 levels are inevitable for most patients, clinicians should continue applying best practices to keep thyroid levels in the euthyroid range. Limitations of this study include the observational nature of the data, which limits the ability to control for other confounders, such as body mass index, alcohol use, or whether co-morbid conditions were managed appropriately, since these data were unavailable. Also, women and racial and ethnic minorities were underrepresented, limiting generalizability.
Primary care practitioners (PCPs) often prescribe thyroid hormone supplementation to correct deficiencies in thyroid hormone levels. The findings of Evron et al highlight the importance of monitoring serum thyrotropin and free T4, where applicable, to identify patients who are not euthyroid. Notably, the hazard ratios reported in this study suggest there may be a greater risk of cardiovascular mortality from exogenous hypothyroidism vs. exogenous hyperthyroidism. Thus, PCPs should consider adjusting thyroid hormone treatment to avoid a hypothyroid state in their patients as part of mitigating cardiovascular risk. For patients who are excessively hyperthyroid or hypothyroid, adjustments to thyroid hormone dosing and close follow-up are essential because of the elevated risk with increasing degrees of dysthyroidism.
- Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocrine Reviews 2014;35:433-512.
- Cappola AR, Desai AS, Medici M, et al. Thyroid and cardiovascular disease: Research agenda for enhancing knowledge, prevention, and treatment. Circulation 2019;139:2892-2909.
- Sohn SY, Seo GH, Chung JH. Risk of all-cause mortality in levothyroxine-treated hypothyroid patients: A nationwide Korean cohort study. Front Endocrinol (Lausanne) 2021;12:680647.
- Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, et al. Over- and under-treatment of hypothyroidism is associated with excess mortality: A register-based cohort study. Thyroid 2018;28:566-574.
Thyroid levels outside the euthyroid range have been associated with higher cardiovascular risk in patients taking thyroid hormone to treat hypothyroidism. In this study, a higher cardiovascular mortality rate was associated with exogenous hyperthyroidism and exogenous hypothyroidism.
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