Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism
Open accessAbstract
BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).
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Trials do not show a benefit from thyroid hormone replacement in persistent subclinical hypothyroidism.
“or to those with persistent subclinical hypothyroidism, where trials do not show a benefit from thyroid hormone replacement. 12,15,16,44 -46”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [15]
The Participants section (p. 2) confirms that the trial enrolled adults aged 65 or older with persistent subclinical hypothyroidism. The Discussion (p. 10) reports no symptomatic benefit from levothyroxine, but the claim is broader than this trial's population and outcome; the Discussion (p. 9) also says benefit in some subgroups could not be excluded. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNo clear advantages of treating subclinical hypothyroidism in older individuals (>65 years) have been observed in terms of neurocognitive function and quality of life.
“No clear advantages of treating subclinical hypothyroidism in older individuals (>65 years) have been observed in terms of neurocognitive function and quality of life, 146-148”
From Hypothyroidism (2024) · cites this paper as [147]
Large RCTs have shown no improvement in hypothyroid symptoms or quality of life in older patients with subclinical hypothyroidism during treatment with levothyroxine.
“large RCTs have shown no improvement in hypothyroid symptoms or quality of life (QoL) in older patients with subclinical hypothyroidism during treatment with levothyroxine. 15 -17”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [15]
A large placebo-controlled trial among patients with subclinical hypothyroidism at least 65 years of age demonstrated no apparent benefits of LT4 treatment.
“A large placebo-controlled trial among patients with subclinical hypothyroidism at least 65 years of age demonstrated no apparent benefits of LT4 treatment [51].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [51]
The meta-analysis included a significant proportion of elderly participants (mean age > 65 years) with mild TSH elevations which may reflect the aging process rather than intrinsic thyroid disease.
“However, the meta-analysis included a significant proportion of elderly participants (mean age > 65 years) with mild TSH elevations which may reflect the aging process rather than intrinsic thyroid disease [18, 57].”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [18]
Trials of levothyroxine therapy in elderly individuals with mild subclinical hypothyroidism have not shown clinical benefits.
“Likewise, trials of levothyroxine therapy in elderly individuals with mild subclinical hypothyroidism have not shown clinical benefits [18, 57] and it is plausible that TSH elevations in these individuals did not represent intrinsic thyroid failure.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [18]
In TRUST, neither thyroid symptoms nor tiredness scores were changed significantly in the LT4 or placebo groups by 12 months.
“Neither thyroid symptoms nor tiredness scores were changed significantly in the LT4 or placebo groups by 12 months”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [127]
In TRUST, there were no adverse effects of LT4.
“Reassuringly, there were no adverse effects of LT4.”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [127]
In TRUST, although the TSH levels in those on LT4 were reduced impressively, one-quarter of subjects were asymptomatic.
“Although the TSH levels in those on LT4 were reduced impressively, one-quarter of subjects were asymptomatic.”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [127]
Confirmation of the elevated TSH is considered essential in establishing the diagnosis of subclinical hypothyroidism although this is not a guarantee of persistent thyroid failure.
“Confirmation of the elevated TSH is considered essential in establishing the diagnosis of subclinical hypothyroidism although this is not a guarantee of persistent thyroid failure”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [127]
In TRUST, a total of 737 patients aged >65 years were recruited and the primary outcome parameter was QoL (Thyroid-Related Quality of Life Patient Reported Outcome [ThyPro] subscales for hypothyroid symptoms score and tiredness score).
“A total of 737 patients aged >65 years were recruited and the primary outcome parameter was QoL (Thyroid-Related Quality of Life Patient Reported Outcome [ThyPro] subscales for hypothyroid symptoms score and tiredness score).”
From Pharmacodynamic and Therapeutic Actions of Levothyroxine (2021) · cites this paper as [127]
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- Authors
- Stott, D. J., Rodondi, N., Kearney, P. M., Ford, I., Westendorp, R. G. J., Mooijaart, S. P., Sattar, N., Aubert, C. E., Aujesky, D., Bauer, D. C., Baumgartner, C., Blum, M. R., Browne, J. P., Byrne, S., Collet, T.-H., Dekkers, O. M., den Elzen, W. P. J., Du Puy, R. S., Ellis, G., Feller, M., Floriani, C., Hendry, K., Hurley, C., Jukema, J. W., Kean, S., Kelly, M., Krebs, D., Langhorne, P., McCarthy, G., McCarthy, V., McConnachie, A., McDade, M., Messow, M., O’Flynn, A., O’Riordan, D., Poortvliet, R. K. E., Quinn, T. J., Russell, A., Sinnott, C., Smit, J. W. A., Van Dorland, H. A., Walsh, K. A., Walsh, E. K., Watt, T., Wilson, R., & Gussekloo, J.
- Affiliations
- University of Bern (CH)
- ORCID
- Stott, David J.
- Rodondi, Nicolas
- Kearney, Patricia M.
- Ford, Ian
- Westendorp, Rudi G.J.
- Mooijaart, Simon P.
- Sattar, Naveed
- Aubert, Carole E.
- Aujesky, Drahomir
- Bauer, Douglas C.
- Baumgartner, Christine
- Blum, Manuel R.
- Browne, John P.
- Byrne, Stephen
- Collet, Tinh-Hai
- Dekkers, Olaf M.
- Ellis, Graham
- Feller, Martin
- Hurley, Caroline
- Jukema, J. Wouter
- Kean, Sharon
- Langhorne, Peter
- McConnachie, Alex
- Poortvliet, Rosalinde K.E.
- Quinn, Terence J
- Russell, Audrey
- Sinnott, Carol
- Walsh, Kieran A.
- Walsh, Elaine K.
- Watt, Torquil
- Gussekloo, Jacobijn
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-06-29
- Volume
- 376
- Issue
- 26
- Pages
- 2534-2544
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2604882706
- Cited by
- 490
- References
- 25
- Citations by year
- 2026: 42 · 2025: 28 · 2024: 43 · 2023: 47 · 2022: 54 · 2021: 61 · 2020: 62 · 2019: 61 · 2018: 64 · 2017: 27 · 2015: 1
- FWCI
- 46.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- IRIS (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- BORIS (University Library Bern) (submittedVersion, other-oa)
- Cork Open Research Archive (University College Cork, Ireland) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- National Science Foundation
- Velux Stiftung
- University of Bern
- Health Research Board (SPHeRE/2013/1)
- Inselspital, Universitätsspital Bern
- European Commission (278148, FP7‐HEALTH‐2011)
- University of Glasgow
- University College Cork
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (165409, 320 030-150 025, 150025, 278148, 167826, 320030)
- Universiteit Leiden
- Radboud Universiteit
- Gentofte Hospital
- Schweizerische Herzstiftung (278148)
- Leids Universitair Medisch Centrum
- Rigshospitalet
- Radboud Universitair Medisch Centrum
- University of California, San Francisco
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24AR051895)
- FP7 Health
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- subclinical hypothyroidism, levothyroxine, thyroid hormone replacement, older adults, quality of life, fatigue, thyroid-stimulating hormone, dose adjustment, coronary artery disease, body weight, cost-effectiveness, patient-reported outcomes, health-related quality of life
- MeSH terms
- Aged, Aged, 80 and over, Double-Blind Method, Fatigue, Female, Humans, Hypothyroidism, Male, Quality of Life, Thyrotropin, Thyroxine, Treatment Failure, Intention to Treat Analysis
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