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Cardiovascular outcomes and rates of fractures and falls among patients with brand-name versus generic L-thyroxine use

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To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use.


Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control.


195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58–1.60), myocardial infarction (HR 0.66, 0.39–1.14), congestive heart failure (HR 1.30, 0.78–2.16), stroke (0.72, 0.49–1.06), spine (HR 0.87, 0.38–1.99) and hip fractures (HR 0.86, 0.26–2.82), or fall outcomes (HR 1.02, 0.14–7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61–1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups.


We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine.

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All data generated or analyzed during this study are included in this published article.


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Author contributions

J.P.B., J.S.R., L.S., N.D.S., and K.J.L. contributed to the study concept and design. J.P.B., J.S.R., Y.D., L.S., D.J.G., Y.Q., Z.W., X.Y., L.Z., N.D.S., and K.J.L. contributed to the development of the study protocol. Y.D. and L.S. were responsible for conducting the data analysis for this study. All authors contributed to the data interpretation. All authors critically reviewed the manuscript.


This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [Center of Excellence in Regulatory Science and Innovation grant to Yale University and Mayo Clinic, U01FD005938]. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

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Correspondence to Juan P. Brito.

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Conflict of interest

J.S.R. has received research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International and to establish the Collaboration for Research Integrity and Transparency (CRIT) at Yale. N.D.S. has received research support through Mayo Clinic from the Centers of Medicare and Medicaid Innovation, from the Agency for Healthcare Research and Quality (R01HS025164; R01HS025402; R03HS025517; U19HS024075), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R56HL130496; R01HL131535), National Science Foundation, and from the Patient Centered Outcomes Research Institute (PCORI). K.J.L. receives support from the Centers of Medicare and Medicaid Services (CMS) and the National Institute on Aging and the American Federation of Aging Research through the Paul Beeson Career Development Award (K23AG048359). R.C.S. receives support from the Alfred D. and Audrey M. Petersen Professorship in Cancer Research. D.J.G., Y.Q., Z.W., and L.Z. are employed by the US Food and Drug Administration. The remaining authors have nothing to disclose.

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Appendix Table 1

Appendix Table 1

Clinically relevant medications that may affect thyroid function

• Antithyroid Medications (PTU, Propylthiouracil, 6-N Propylthiouracil, Methimazole, Felimazole, Northyx, Tapazole, Thiamazole, Carbimazole, Benzylthiouracil, Methylthiouracil)

• Lithium carbonate

• Amiodarone hydrochloride

• Phenytoin

• Interferon alfa

• Interleukin 2

• Gefitinib

• Erlotinib

• Sorafenib

• Sunitinib

• Dasatinib

• Lenvatinib

• Imatinib

• Cabozantinib

• Vandetanib

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Brito, J.P., Ross, J.S., Deng, Y. et al. Cardiovascular outcomes and rates of fractures and falls among patients with brand-name versus generic L-thyroxine use. Endocrine 74, 592–602 (2021).

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