Levothyroxine Use in the United States, 2008-2018

Levothyroxine is one of the most commonly prescribed drugs in the US, with approximately 7% of the population estimated to have an active prescription.^1,2 For nonpregnant adults with subclinical hypothyroidism (thyrotropin level elevated but ≤10 mIU/L and normal free thyroxine [FT₄] levels), evidence consistently demonstrates no clinically relevant benefits of levothyroxine replacement for quality of life or thyroid-related symptoms.^3,4 To better understand the use of levothyroxine in the US over time, we analyzed national data for commercially insured and Medicare Advantage enrollees.

We conducted a retrospective analysis of deidentified administrative claims data linked with laboratory results from OptumLabs Data Warehouse, which includes commercially insured and Medicare Advantage enrollees throughout the US.⁵ The study was deemed not to require Mayo Clinic Institutional Review Board review owing to the use of deidentified data in accordance with the Code of Federal Regulations, 45 CFR 46.102. The cohort included adults (≥18 years of age) who newly filled levothyroxine prescriptions between January 1, 2008, and December 31, 2018, and who had a thyrotropin level measured within 3 months prior to levothyroxine initiation. We excluded people with a history of thyroid surgery, thyroid cancer, or central hypothyroidism and pregnant women. We used descriptive statistics to characterize trends in thyrotropin levels and categories of thyroid function measured prior to levothyroxine initiation. In a subsample with thyrotropin and thyroxine levels available, thyroid function was defined as overt hypothyroidism (elevated thyrotropin and low free or total thyroxine [FT₄ or T₄] levels), subclinical hypothyroidism (elevated thyrotropin and normal FT₄ or T₄ levels), and normal thyroid function (normal thyrotropin and FT₄ or T₄ levels).⁶ We also separately examined mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT₄ or T₄), moderate subclinical hypothyroidism (thyrotropin level of 10-19.9 mIU/L), and severe subclinical hypothyroidism (thyrotropin level > 19.9 mIU/L). Pearson correlation test (2-tailed approach; level of significance of .05) was conducted to test the linear associations between thyrotropin and year, and if the proportion of patients in different categories of thyroid function has changed over time. Microsoft Excel 2010 (Microsoft Corp) and SAS, version 9.4 (SAS Institute Inc) were used to conduct the analyses. Data analysis was performed June through March 2021.

Between 2008 and 2018, 110 842 patients newly initiated levothyroxine treatment (Table). The median thyrotropin level at treatment initiation did not significantly change: 5.8 mIU/L in 2008 to 5.3 mIU/L in 2018 (P = .79). In a subset of 58 706 patients with thyrotropin and FT₄ or T₄ levels available, levothyroxine was initiated for overt hypothyroidism (4948 [8.4%]), subclinical hypothyroidism (35 814 [61.0%]), and normal thyroid levels (17 944 [30.5%]). From 2008 to 2018, the proportion of adults with overt hypothyroidism increased (7.6% to 8.4%; P = .02); the proportion with subclinical hypothyroidism did not change (59.3% to 65.7%; P = .36); and the proportion with normal thyroid function did not change (32.9% to 26.2%; P = .84). Among patients with subclinical hypothyroidism, the proportion with mild subclinical hypothyroidism (48.2% to 57.9%; P = .73) and moderate subclinical hypothyroidism (8.5% to 6.4%; P = .16) did not change significantly, and the proportion with severe subclinical hypothyroidism decreased (2.5% to 1.3%; P = .02) (Figure).

We found that levothyroxine treatment was commonly initiated for mildly increased thyrotropin levels, and this did not change significantly over time. Among patients for whom full thyroid function test results were available, 60% initiated levothyroxine for treatment of subclinical hypothyroidism (mostly for mild subclinical hypothyroidism) and 30% for normal thyroid function, without significant change in these patterns over time. Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function.^3,4

Our study has some limitations. The study included commercially insured patients, who may be more likely to use levothyroxine, and thus findings may not generalize to other populations. We could not assess symptoms or other potential compelling reasons for levothyroxine initiation.

In conclusion, these results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care.

Accepted for Publication: March 19, 2021.

Published Online: June 21, 2021. doi:10.1001/jamainternmed.2021.2686

Corresponding Author: Juan P. Brito, MD, MSc, Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism, & Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (brito.juan@mayo.edu).

Author Contributions: Drs Brito and Deng had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Brito, Ross, Maraka, Lipska.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Brito, El Kawkgi, Deng.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Deng.

Obtained funding: Brito.

Administrative, technical, or material support: Brito, Maraka, Shah.

Supervision: Brito.

Conflict of Interest Disclosures: Dr Ross reported grants from the US Food and Drug Administration, Johnson & Johnson, Medical Device Innovation Consortium, Agency for Healthcare Research and Quality (R01HS022882), National Institutes of Health/National Heart, Lung, and Blood Institute (R01HS025164), and the Laura and John Arnold Foundation outside the submitted work. Dr Shah reported receiving research support through Mayo Clinic from the US Food and Drug Administration to establish Yale University–Mayo Clinic Center of Excellence in Regulatory Science and Innovation program (U01FD005938); the Center for Medicare & Medicaid Innovation under the Transforming Clinical Practice Initiative; the Agency for Healthcare Research and Quality (R01HS025164; R01HS025402; R03HS025517; K12HS026379); the National Heart, Lung and Blood Institute of the National Institutes of Health (R56HL130496; R01HL131535; R01HL151662); the National Science Foundation; the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology; and the Patient-Centered Outcomes Research Institute to develop a Clinical Data Research Network (LHSNet). Dr Lipska reported grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Patient-Centered Outcomes Research Institute and support to develop and evaluate publicly reported quality measures from Centers for Medicare & Medicaid Services outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: We would like to thank Naykky Singh Ospina, MD, at Division of Endocrinology, University of Florida, Gainesville, and Rene Rodriguez-Gutierrez, MD, at Department of Internal Medicine, University Hospital Dr Jose E. Gonzalez, Monterrey, Mexico, for providing edits and comments to the manuscript. They did not receive compensation for their contributions.