Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials

Christina Lyko; Manuel R. Blum; Nazanin Abolhassani; Mirah J. Stuber; Cinzia del Giovane; Martin Feller; Elisavet Moutzouri; Jolanda Oberle; Katharina T. Jungo; Tinh-Hai Collet; Wendy P. J. den Elzen; Rosalinde K. E. Poortvliet; Robert S. du Puy; Olaf M. Dekkers; Stella Trompet; J. Wouter Jukema; Drahomir Aujesky; Terry Quinn; Rudi Westendorp; Patricia M. Kearney; Jacobijn Gussekloo; Diana van Heemst; Simon P. Mooijaart; Douglas C. Bauer; Nicolas Rodondi

doi:https://doi.org/10.1111/joim.13544

Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials

Christina Lyko, Manuel R. Blum, Nazanin Abolhassani, Mirah J. Stuber, Cinzia del Giovane, Martin Feller, Elisavet Moutzouri, Jolanda Oberle, Katharina T. Jungo, Tinh-Hai Collet, Wendy P. J. den Elzen, Rosalinde K. E. Poortvliet, Robert S. du Puy, Olaf M. Dekkers, Stella Trompet, J. Wouter Jukema, Drahomir Aujesky, Terry Quinn, Rudi Westendorp, Patricia M. KearneyJacobijn Gussekloo, Diana van Heemst, Simon P. Mooijaart, Douglas C. Bauer, Nicolas Rodondi

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

Abstract

Background: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between-group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

Original language	English
Pages (from-to)	892-903
Number of pages	12
Journal	Journal of Internal Medicine
Volume	292
Issue number	6
Early online date	2022
DOIs	https://doi.org/10.1111/joim.13544
Publication status	Published - Dec 2022

Keywords

autoimmune thyroid disease
levothyroxine treatment
subclinical hypothyroidism

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https://doi.org/10.1111/joim.13544

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Lyko, C., Blum, M. R., Abolhassani, N., Stuber, M. J., del Giovane, C., Feller, M., Moutzouri, E., Oberle, J., Jungo, K. T., Collet, T.-H., den Elzen, W. P. J., Poortvliet, R. K. E., du Puy, R. S., Dekkers, O. M., Trompet, S., Jukema, J. W., Aujesky, D., Quinn, T., Westendorp, R., ... Rodondi, N. (2022). Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials. Journal of Internal Medicine, 292(6), 892-903. https://doi.org/10.1111/joim.13544

@article{e263c131266b4481a8448841b7557377,

title = "Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials",

abstract = "Background: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between-group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.",

keywords = "autoimmune thyroid disease, levothyroxine treatment, subclinical hypothyroidism",

author = "Christina Lyko and Blum, {Manuel R.} and Nazanin Abolhassani and Stuber, {Mirah J.} and {del Giovane}, Cinzia and Martin Feller and Elisavet Moutzouri and Jolanda Oberle and Jungo, {Katharina T.} and Tinh-Hai Collet and {den Elzen}, {Wendy P. J.} and Poortvliet, {Rosalinde K. E.} and {du Puy}, {Robert S.} and Dekkers, {Olaf M.} and Stella Trompet and Jukema, {J. Wouter} and Drahomir Aujesky and Terry Quinn and Rudi Westendorp and Kearney, {Patricia M.} and Jacobijn Gussekloo and {van Heemst}, Diana and Mooijaart, {Simon P.} and Bauer, {Douglas C.} and Nicolas Rodondi",

note = "Funding Information: This project is funded by grants from the Swiss National Science Foundation (320030‐172676 and 32003B_200606 to Nicolas Rodondi). A research grant from the European Union FP7‐ HEALTH‐2011 program (grant agreement number 278148) financed the TRUST trial. Other financial support was supplied by grants from the Swiss Heart Foundation (to Nicolas Rodondi), and an investigator‐driven grant from Velux Stiftung (974a to Nicolas Rodondi). IEMO 80+ trial was funded by Netherlands Organisation for Health Research and Development (ZonMw, grant number 627001001). The anti‐TPO measurements were funded by the European Commission‐funded project THYRAGE (Diana van Heemst, Horizon 2020 research and innovation programme under grant agreement 666869). Levothyroxine and matching placebo were furnished free of charge by the healthcare business of Merck KGaA, Darmstadt, Germany. The IEMO 80+ thyroid trial has been peer‐reviewed and approved for funding under the ZonMw programme Evidence‐based Medicine in Old Age, ZonMW programme number: 627001001. Tinh‐Hai Collet's research is supported by grants from the Swiss National Science Foundation (PZ00P3‐167826), the Leenaards Foundation, the Vontobel Foundation, the Swiss Society of Endocrinology and Diabetes, and the Swiss Multiple Sclerosis Society. Funding Information: This project is funded by grants from the Swiss National Science Foundation (320030-172676 and 32003B_200606 to Nicolas Rodondi). A research grant from the European Union FP7- HEALTH-2011 program (grant agreement number 278148) financed the TRUST trial. Other financial support was supplied by grants from the Swiss Heart Foundation (to Nicolas Rodondi), and an investigator-driven grant from Velux Stiftung (974a to Nicolas Rodondi). IEMO 80+ trial was funded by Netherlands Organisation for Health Research and Development (ZonMw, grant number 627001001). The anti-TPO measurements were funded by the European Commission-funded project THYRAGE (Diana van Heemst, Horizon 2020 research and innovation programme under grant agreement 666869). Levothyroxine and matching placebo were furnished free of charge by the healthcare business of Merck KGaA, Darmstadt, Germany. The IEMO 80+ thyroid trial has been peer-reviewed and approved for funding under the ZonMw programme Evidence-based Medicine in Old Age, ZonMW programme number: 627001001. Tinh-Hai Collet's research is supported by grants from the Swiss National Science Foundation (PZ00P3-167826), the Leenaards Foundation, the Vontobel Foundation, the Swiss Society of Endocrinology and Diabetes, and the Swiss Multiple Sclerosis Society. The funders, the trial sponsors (NHS Greater Glasgow and Clyde Health Board and the University of Glasgow, UK; University College Cork, Ireland; Leiden University Medical Center, the Netherlands; University of Bern and Bern University Hospital, Switzerland), and the healthcare business of Merck KGaA, Darmstadt, Germany had no role in the design, analysis, or reporting of the results of the trial. The authors vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the trial to the protocol. The authors thank all the participants in the TRUST and IEMO trials: the medical staff, general practitioners, nurses, laboratories, and secretarial staff; members of the TRUST/IEMO Biobank committee (Patricia M. Kearney, MD, PhD, University College Cork, Ireland; Wendy P. J. den Elzen, PhD, Atalmedial Diagnostics Centre, Amsterdam and Department of Clinical Chemistry, Amsterdam UMC, The Netherlands; and Stella Trompet, PhD, Leiden University Medical Center, the Netherlands); Mawdsley-Brooks & Co. (UK) for the organization of handling and distributing the study medication; and the healthcare business of Merck KGaA, Darmstadt, Germany for giving the levothyroxine and matching placebo for free; they did not receive or provide financial contributions. Open access funding provided by Universitat Bern. Publisher Copyright: {\textcopyright} 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.",

year = "2022",

month = dec,

doi = "https://doi.org/10.1111/joim.13544",

language = "English",

volume = "292",

pages = "892--903",

journal = "Journal of Internal Medicine",

issn = "0954-6820",

publisher = "Wiley-Blackwell",

number = "6",

}

Lyko, C, Blum, MR, Abolhassani, N, Stuber, MJ, del Giovane, C, Feller, M, Moutzouri, E, Oberle, J, Jungo, KT, Collet, T-H, den Elzen, WPJ, Poortvliet, RKE, du Puy, RS, Dekkers, OM, Trompet, S, Jukema, JW, Aujesky, D, Quinn, T, Westendorp, R, Kearney, PM, Gussekloo, J, van Heemst, D, Mooijaart, SP, Bauer, DC & Rodondi, N 2022, 'Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials', Journal of Internal Medicine, vol. 292, no. 6, pp. 892-903. https://doi.org/10.1111/joim.13544

TY - JOUR

T1 - Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism

T2 - A pooled analysis of two randomized controlled trials

AU - Lyko, Christina

AU - Blum, Manuel R.

AU - Abolhassani, Nazanin

AU - Stuber, Mirah J.

AU - del Giovane, Cinzia

AU - Feller, Martin

AU - Moutzouri, Elisavet

AU - Oberle, Jolanda

AU - Jungo, Katharina T.

AU - Collet, Tinh-Hai

AU - den Elzen, Wendy P. J.

AU - Poortvliet, Rosalinde K. E.

AU - du Puy, Robert S.

AU - Dekkers, Olaf M.

AU - Trompet, Stella

AU - Jukema, J. Wouter

AU - Aujesky, Drahomir

AU - Quinn, Terry

AU - Westendorp, Rudi

AU - Kearney, Patricia M.

AU - Gussekloo, Jacobijn

AU - van Heemst, Diana

AU - Mooijaart, Simon P.

AU - Bauer, Douglas C.

AU - Rodondi, Nicolas

N1 - Funding Information: This project is funded by grants from the Swiss National Science Foundation (320030‐172676 and 32003B_200606 to Nicolas Rodondi). A research grant from the European Union FP7‐ HEALTH‐2011 program (grant agreement number 278148) financed the TRUST trial. Other financial support was supplied by grants from the Swiss Heart Foundation (to Nicolas Rodondi), and an investigator‐driven grant from Velux Stiftung (974a to Nicolas Rodondi). IEMO 80+ trial was funded by Netherlands Organisation for Health Research and Development (ZonMw, grant number 627001001). The anti‐TPO measurements were funded by the European Commission‐funded project THYRAGE (Diana van Heemst, Horizon 2020 research and innovation programme under grant agreement 666869). Levothyroxine and matching placebo were furnished free of charge by the healthcare business of Merck KGaA, Darmstadt, Germany. The IEMO 80+ thyroid trial has been peer‐reviewed and approved for funding under the ZonMw programme Evidence‐based Medicine in Old Age, ZonMW programme number: 627001001. Tinh‐Hai Collet's research is supported by grants from the Swiss National Science Foundation (PZ00P3‐167826), the Leenaards Foundation, the Vontobel Foundation, the Swiss Society of Endocrinology and Diabetes, and the Swiss Multiple Sclerosis Society. Funding Information: This project is funded by grants from the Swiss National Science Foundation (320030-172676 and 32003B_200606 to Nicolas Rodondi). A research grant from the European Union FP7- HEALTH-2011 program (grant agreement number 278148) financed the TRUST trial. Other financial support was supplied by grants from the Swiss Heart Foundation (to Nicolas Rodondi), and an investigator-driven grant from Velux Stiftung (974a to Nicolas Rodondi). IEMO 80+ trial was funded by Netherlands Organisation for Health Research and Development (ZonMw, grant number 627001001). The anti-TPO measurements were funded by the European Commission-funded project THYRAGE (Diana van Heemst, Horizon 2020 research and innovation programme under grant agreement 666869). Levothyroxine and matching placebo were furnished free of charge by the healthcare business of Merck KGaA, Darmstadt, Germany. The IEMO 80+ thyroid trial has been peer-reviewed and approved for funding under the ZonMw programme Evidence-based Medicine in Old Age, ZonMW programme number: 627001001. Tinh-Hai Collet's research is supported by grants from the Swiss National Science Foundation (PZ00P3-167826), the Leenaards Foundation, the Vontobel Foundation, the Swiss Society of Endocrinology and Diabetes, and the Swiss Multiple Sclerosis Society. The funders, the trial sponsors (NHS Greater Glasgow and Clyde Health Board and the University of Glasgow, UK; University College Cork, Ireland; Leiden University Medical Center, the Netherlands; University of Bern and Bern University Hospital, Switzerland), and the healthcare business of Merck KGaA, Darmstadt, Germany had no role in the design, analysis, or reporting of the results of the trial. The authors vouch for the accuracy and completeness of the data and analyses reported and for the fidelity of the trial to the protocol. The authors thank all the participants in the TRUST and IEMO trials: the medical staff, general practitioners, nurses, laboratories, and secretarial staff; members of the TRUST/IEMO Biobank committee (Patricia M. Kearney, MD, PhD, University College Cork, Ireland; Wendy P. J. den Elzen, PhD, Atalmedial Diagnostics Centre, Amsterdam and Department of Clinical Chemistry, Amsterdam UMC, The Netherlands; and Stella Trompet, PhD, Leiden University Medical Center, the Netherlands); Mawdsley-Brooks & Co. (UK) for the organization of handling and distributing the study medication; and the healthcare business of Merck KGaA, Darmstadt, Germany for giving the levothyroxine and matching placebo for free; they did not receive or provide financial contributions. Open access funding provided by Universitat Bern. Publisher Copyright: © 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

PY - 2022/12

Y1 - 2022/12

N2 - Background: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between-group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

AB - Background: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti–thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of −2.07 (95% confidence interval: −6.04 to 1.90) for positive antibodies versus 0.89 (−1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores—adjusted between-group difference 1.75 (−3.60 to 7.09) for positive antibodies versus 1.14 (−1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

KW - autoimmune thyroid disease

KW - levothyroxine treatment

KW - subclinical hypothyroidism

UR - http://www.scopus.com/inward/record.url?scp=85134919303&partnerID=8YFLogxK

U2 - https://doi.org/10.1111/joim.13544

DO - https://doi.org/10.1111/joim.13544

M3 - Article

C2 - 35894851

SN - 0954-6820

VL - 292

SP - 892

EP - 903

JO - Journal of Internal Medicine

JF - Journal of Internal Medicine

IS - 6

ER -

Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials

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