Too Much or Too Little of a Good Thing: Thyroid Treatment and Cardiovascular Risk

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Dr. Gregory Weiss breaks down a recent JAMA study that provides estimates of the impact over- and under-treatment with thyroid hormone treatment on cardiovascular disease risk in a cohort of US Veterans.

It has long been known that thyroid hormone levels are linked to cardiovascular (CV) regulation and that hyper- and hypo-thyroid states are detrimental to CV health. What is less clearly understood is how the intensity of thyroid hormone therapy affects CV risk and mortality.

The authors of this study sought to evaluate the association between thyroid replacement intensity and cardiovascular mortality by examining a large pool of data from the Veterans Health Administration database.

Josh Evron, MD, and colleagues looked at 705,307 adults who received thyroid replacement therapy.3 They found that 10.8% of those patients died of cardiovascular causes.3 Thyrotropin and Free T4 levels were gathered for all patients in the study to determine if therapy led to exogenous hypo-, euthyroid, or hyper-thyroid conditions. The authors used regression modeling to produce survival analyses with cardiovascular mortality from myocardial infarction, heart failure, or stroke representing the primary outcomes studied.

The results clearly showed that patients with exogenous hyperthyroidism (thyrotropin levels <0.1 mIU/L) and those with exogenous hypothyroidism (thyrotropin levels >-20mIU/L) had increased risk of cardiovascular mortality when compared to patients who remained euthyroid.3 The association between exogenous hypo- and hyper-thyroid states and mortality increase with higher or lower thyrotropin levels in the hypo- and hyper-thyroid ranges.3

This study provides a unique perspective looking at cardiovascular risk based on a very common treatment, thyroid replacement therapy. When prescribing a replacement therapy, the goal of treatment is to achieve a normal level in vivo of whatever hormone you are replacing. This is not as easy as it seems.

Arriving at the appropriate dose takes time and requires frequent measurements of thyrotropin and free thyroxine levels. Even during stable therapy patient factors may change the response, absorption, and metabolism of thyroid hormone. Thus, the intensity of treatment the authors are talking about is a constantly moving target.

The results of this study highlight the importance of regular testing and a willingness among clinicians to put in the work. The authors found that allowing thyroid replacement therapy to fall short or overshoot has real consequences in the form of increased cardiovascular mortality.3

This means lives are at stake. This is the essence of a modifiable risk factor. Only, in this case, the modification is not a behavior the patient exhibits but one the clinician is responsible for. The authors state that variability in free T4 levels and thyroid hormone dosage adjustment are inevitable and thus agree with my assertion that regular monitoring and small targeted adjustments are essential parts of not only good thyroid care but also cardiovascular risk mitigation.3

These results and conclusions are underscored by the fact that cardiovascular disease is the leading cause of death in the United States. Even though this was an observational study, the results are robust.

An important feature of these results was the linear relationship up and down between the extent of hypo- or hyperthyroid intensity and CV risk. This gives clinicians some room to work while at the same time placing guard rails and warning signs on the limits of acceptability where over and undertreating are concerned.

More work is needed. While the authors have identified an area where we as clinicians can improve, they have also brought up a few new questions. It needs to be determined if there are sex differences in this effect. Further, the degree to which comorbidities were managed was not examined in this study. It is clear however, that tighter observation, monitoring, and intervention are in order with regards to thyroid replacement therapy.


  1. Centers for Disease Control and Prevention. Heart disease. Accessed July 29, 2021.
  2. Benjamin EJ, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi:10.1161/CIR.0000000000000659