Thyroid Hormone Replacement for Subclinical Hypothyroidism

Summary

Subclinical hypothyroidism (SCH) is a common condition among older men and women. Although by definition SCH comprises biochemically mild thyroid hormone deficiency without overt symptoms, it is a possible contributor to multiple problems in older age. Thyroid hormone has effects on numerous physiological systems, including the vascular tree, heart, skeletal muscle and brain. Therefore, thyroxine substitution to overcome thyroid hormone deficiency has the potential to give multisystem benefits to older people with SCH. Small studies have reported reduced atherosclerosis and improved heart function with thyroxine replacement, but no large clinical trials have been performed. Therefore the available evidence is limited, leading to major variations in guidelines and clinical practice, with uncertainty regarding the indications for screening and treatment. The investigators propose a multicentre randomised placebo controlled trial to assess the impact of thyroxine replacement in a minimum of 540 older adults (maximum 750) with persisting SCH (excluding those in whom it is a temporary phenomenon who are unlikely to benefit). The investigators will include older men and women with a wide age range and of varying health status. Outcomes include health related quality of life, muscle strength, executive cognitive function and cardiovascular events, with a minimum of 1 year of follow up. Blood and urine samples will be stored in a biobank, to allow future research on causes of ill health in older people with SCH. The investigators have the support of patient advocacy groups and a consortium with the wide range of expertise and experience required to conduct large scale multicentre clinical trials. The proposal explores the multisystem and quality of life benefits to older people of a tailored approach to management of SCH. This clinical trial should definitively clarify whether thyroxine treatment for SCH provides benefits that are relevant for patients. This trial will provide strong evidence with the potential to improve clinical practice, reduce health care costs and promote healthy ageing of older adults.

Timeline

Start

2014-05

Primary completion

2016-11-18

Completion

2016-11-18

Publications

• van der Spoel E, van Vliet NA, Poortvliet RKE, Du Puy RS, den Elzen WPJ, Quinn TJ, Stott DJ, Sattar N, Kearney PM, Blum MR, Alwan H, Rodondi N, Collet TH, Westendorp RGJ, Ballieux BE, Jukema JW, Dekkers OM, Gussekloo J, Mooijaart SP, van Heemst D. Incidence and Determinants of Spontaneous Normalization of Subclinical Hypothyroidism in Older Adults. J Clin Endocrinol Metab. 2024 Feb 20;109(3):e1167-e1174. doi: 10.1210/clinem/dgad623.
• Netzer S, Chocano-Bedoya P, Feller M, Janett-Pellegri C, Wildisen L, Buchi AE, Moutzouri E, Gonzalez Rodriguez E, Collet TH, Poortvliet RKE, Mc Carthy VJC, Aeberli D, Aujesky D, Westendorp R, Quinn TJ, Gussekloo J, Kearney PM, Mooijaart S, Bauer DC, Rodondi N. The effect of thyroid hormone therapy on muscle function, strength and mass in older adults with subclinical hypothyroidism-an ancillary study within two randomized placebo controlled trials. Age Ageing. 2023 Jan 8;52(1):afac326. doi: 10.1093/ageing/afac326.
• Buchi AE, Feller M, Netzer S, Blum MR, Gonzalez Rodriguez E, Collet TH, Del Giovane C, van Heemst D, Quinn T, Kearney PM, Westendorp RGJ, Gussekloo J, Mooijaart SP, Hans D, Bauer DC, Rodondi N, Aeberli D. Bone geometry in older adults with subclinical hypothyroidism upon levothyroxine therapy: A nested study within a randomized placebo controlled trial. Bone. 2022 Aug;161:116404. doi: 10.1016/j.bone.2022.116404. Epub 2022 Apr 2.
• Du Puy RS, Poortvliet RKE, Mooijaart SP, Stott DJ, Quinn T, Sattar N, Westendorp RGJ, Kearney PM, McCarthy VJC, Byrne S, Rodondi N, Baretella O, Collet TH, van Heemst D, Dekkers OM, Jukema JW, Smit JWA, Gussekloo J, den Elzen WPJ. No Effect of Levothyroxine on Hemoglobin in Older Adults With Subclinical Hypothyroidism: Pooled Results From 2 Randomized Controlled Trials. J Clin Endocrinol Metab. 2022 May 17;107(6):e2339-e2347. doi: 10.1210/clinem/dgac106.
• Zijlstra LE, Jukema JW, Westendorp RGJ, Du Puy RS, Poortvliet RKE, Kearney PM, O'Keeffe L, Dekkers OM, Blum MR, Rodondi N, Collet TH, Quinn TJ, Sattar N, Stott DJ, Trompet S, den Elzen WPJ, Gussekloo J, Mooijaart SP. Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials. Front Endocrinol (Lausanne). 2021 May 20;12:674841. doi: 10.3389/fendo.2021.674841. eCollection 2021.
• de Montmollin M, Feller M, Beglinger S, McConnachie A, Aujesky D, Collet TH, Ford I, Gussekloo J, Kearney PM, McCarthy VJC, Mooijaart S, Poortvliet RKE, Quinn T, Stott DJ, Watt T, Westendorp R, Rodondi N, Bauer DC. L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial. Ann Intern Med. 2020 Jun 2;172(11):709-716. doi: 10.7326/M19-3193. Epub 2020 May 5.
• Gonzalez Rodriguez E, Stuber M, Del Giovane C, Feller M, Collet TH, Lowe AL, Blum MR, van Vliet NA, van Heemst D, Kearney PM, Gussekloo J, Mooijaart S, Westendorp RGJ, Stott DJ, Aeberli D, Bauer DC, Hans D, Rodondi N. Skeletal Effects of Levothyroxine for Subclinical Hypothyroidism in Older Adults: A TRUST Randomized Trial Nested Study. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz058. doi: 10.1210/clinem/dgz058.
• Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RGJ, den Elzen WPJ, Postmus I, Poortvliet RKE, van Heemst D, van Munster BC, Peeters RP, Ford I, Kean S, Messow CM, Blum MR, Collet TH, Watt T, Dekkers OM, Jukema JW, Smit JWA, Langhorne P, Gussekloo J. Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. JAMA. 2019 Nov 26;322(20):1977-1986. doi: 10.1001/jama.2019.17274.
• Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, 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 RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland HA, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J; TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3.
• Stott DJ, Gussekloo J, Kearney PM, Rodondi N, Westendorp RG, Mooijaart S, Kean S, Quinn TJ, Sattar N, Hendry K, Du Puy R, Den Elzen WP, Poortvliet RK, Smit JW, Jukema JW, Dekkers OM, Blum M, Collet TH, McCarthy V, Hurley C, Byrne S, Browne J, Watt T, Bauer D, Ford I. Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST). BMC Endocr Disord. 2017 Feb 3;17(1):6. doi: 10.1186/s12902-017-0156-8.

Drugs

Indications