Introduction
Cardiovascular disease remains the leading cause of death worldwide, with ischaemic heart disease and stroke accounting for 8.9 million and 6.1 million deaths in 2019, respectively [
1]. The United Kingdom (UK) population is increasing, and in 2018, it was predicted that by 2043, the number of people aged over 85 years will have nearly doubled to 3 million [
2]. Each year, 160,000 deaths in the UK are attributed to cardiovascular events, accounting for approximately 23.9% of all deaths in the UK [
3]. Several studies have found no association between subclinical hypothyroidism (SCH) and coronary heart disease, cerebrovascular, and peripheral arterial disease in the older population [
4‐
8]. On the contrary, an association has been found between subclinical hyperthyroidism and cardiovascular risk [
9,
10]. Moreover, several studies have explored the association between SCH and bone health outcomes in the ageing population, yielding inconsistent results [
11‐
13].
Thyroid hormones are responsible for the metabolism in all tissues, including the heart, liver, brain, muscles, and bones, and thyroid hormone imbalance can lead to metabolic dysfunction [
14]. The overall prevalence of hypothyroidism is approximately 5–10% in the general population in the UK, diagnosed when a person has elevated thyroid-stimulating hormone (TSH) levels [
15]. SCH refers to TSH levels being higher than the accepted reference range, while free thyroxine levels remain within range [
14].
Approximately 3.5% of the UK population is prescribed thyroid hormone replacement, and the number of prescriptions for levothyroxine (LT4) is increasing yearly [
16,
17]. The goal of prescribing LT4 is to return the TSH level within the normal range and improve symptoms related to hypothyroidism. Since hypothyroidism is a chronic, irreversible condition, participants prescribed LT4 usually require long-term thyroid hormone treatment. The National Health and Nutrition Examination Survey (NHANES) study [
18] and the Thyroid Epidemiology, Audit, and Research Study (TEARS) [
19] found that serum TSH levels increase with age. The TEARS study indicated that the normal range for serum TSH could be 0.4–5.9 mU/L for participants aged 90 and over, rather than the 0.4–4.0 mU/L range currently used across all age groups in the UK [
20]. The National Institute for Health and Care Excellence has recognised that TSH levels between 4.0 and 7.0 mU/L could be typical with ageing [
21]. A review of cross-sectional studies estimated that nearly half the participants prescribed LT4 are either over or under-treated [
22]. Both under- and over-treatment with thyroid hormones can be associated with adverse effects, particularly in older individuals, at higher risk of thyroid hormone toxicity [
23].
This systematic review and meta-analysis aimed to combine the current literature on cardiovascular and bone health outcomes in SCH participants aged over 50 years to assess whether older individuals with SCH have worse cardiovascular and bone health outcomes when prescribed LT4. More specifically, this review compared the results of participants prescribed LT4 versus those untreated. This review was registered on PROSPERO, an international database of prospectively registered systematic reviews in health and social care (registration number CRD42022308006). No protocol was prepared for this review.
Methods
Search strategy
The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were employed in this review (Additional file 1) [
24]. Two reviewers, MH and MSF, independently searched the Web of Science, Cochrane Library, MEDLINE, and EMBASE databases from inception until March 13, 2023. Any conflicts were resolved by a third reviewer, SW. Five terms were included in the search strategy based on disease, treatment, outcome event, age of participants, and study type (Additional file 2). Two reviewers, MH and MSF, removed the duplicates, and then the title and abstract of each article were screened against the inclusion criteria. The remaining articles had their full text filtered against the eligibility criteria, and their reference lists were checked for any additional qualifying studies.
Eligibility criteria
Studies with participants aged 50 years or older diagnosed with SCH were eligible. An intervention group of participants taking LT4 and a control group of participants taking a placebo or no medication were required. Only full-text articles published in English with the study type randomised control trial (RCT), cohort study, case–control study, cross-sectional study, or longitudinal study design were considered.
Articles that included participants diagnosed with thyroid cancer, pituitary disease, secondary hypothyroidism, overt hypothyroidism, tertiary hypothyroidism, or hyperthyroidism were excluded. Also, articles including participants receiving a different form of thyroid replacement therapy to LT4 were excluded from this review. Studies examining participants exclusively with a history of cardiovascular disease or studies on pregnant females were also excluded.
Outcome measures
Studies were required to evaluate the number of participants who experienced a cardiovascular event (ischemic heart disease, peripheral vascular disease, cerebrovascular disease, coronary angioplasty, or cardiovascular death) or experienced a bone health outcome (osteoporosis or a fragility fracture) since LT4 treatment was commenced. These two outcomes were grouped separately for synthesis. The following covariates were also considered to enable subgroup analyses: age, sex, LT4 dose, and TSH levels.
Two independent reviewers, MH and MSF, screened the relevant articles against the eligibility criteria. A third reviewer (SW) resolved any conflicts. Data extraction of each study was completed, including the following details where possible:
i.
Authors, title, and publication year
ii.
Study period, study design, and number of participants
iii.
Population demographics, e.g. age and sex
iv.
LT4 dosage, frequency, and length of time prescribed
v.
The number of participants experiencing a cardiovascular or bone health outcome
Any missing data were assumed to have not been collected.
The quality of studies was assessed using the Cochrane risk of bias tool for RCTs [
25,
26] and the Newcastle–Ottawa scale for non-randomised trials [
27]. The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines [
28,
29]. The assessment of both the quality of studies and the quality of evidence was independently carried out by two reviewers, MH and MSF.
Data analysis
Statistical analysis was conducted using R, implementing the ‘metafor’ package. Heterogeneity was assessed through the
I2 statistic such that if
I2 = 0%, there was no heterogeneity; if
I2 < 50%, there was moderate heterogeneity; if
I2 > 50%, there was substantial heterogeneity [
30]. Studies were pooled depending on their outcome measures—cardiovascular and bone health. The principal analysis was based on a random-effects model, pooling all suitable studies using hazard ratios (HR).
Sensitivity analysis
A sensitivity analysis was conducted to ensure the integrity of the data. We checked for any potential duplication of participants in the studies, ensuring that each participant was counted only once.
Discussion
Main findings
The cardiovascular and bone health-related outcomes for participants over 65 years and prescribed LT4 remain inconclusive. There was a paucity of studies looking at the bone health and cardiovascular outcomes of LT4 in older SCH subjects. In particular, no studies were found on participants between 50 and 65 years old. The meta-analysis showed no association between adverse cardiovascular outcomes and LT4 use or not, in SCH participants over 65 years, and identified a gap in the literature for LT4 outcomes in participants with SCH between the ages of 50 and 65 years.
Strengths and limitations
This is the largest systematic review and meta-analysis to date. The main limitation of this systematic review was the lack of suitable studies with large sample sizes and adequate power, particularly looking at bone health outcomes. This review could not find any articles about participants aged 50 to 65 years, and it identified just one article regarding osteoporosis outcomes. Only two studies had a follow-up period over 3 years, limiting the assessment of the long-term effects of LT4. Most studies included in the review had few participants or poor recruitment uptake, as demonstrated in the TRUST RCT [
62]. Furthermore, this systematic review was constrained by the small number of events in all the studies considered, except Razvi et al. [
60] and Andersen et al. [
58] as well as insufficient raw data on the IEMO80 + trial. The results of the IEMO80 + trial were shared in a publication that included combined findings from the TRUST study, both with participants aged 65 years and over and with participants aged 80 years and over. This limited the meta-analysis as no adjusted risk estimate could be calculated individually for the IEMO80 + study. Nonetheless, the findings of all included studies are similar regardless of individual and pooled results.
Comparison with literature
The broader literature concludes that patients prescribed LT4 who have TSH levels above 10 mIU/L and are middle-aged or young adults have better cardiovascular outcomes [
65]. Clinical practice guidelines for LT4 prescribing remain unchanged, indicating LT4 for adults when they have two TSH readings above 10 mIU/L at least 3 months apart [
65]. The TRUST study identified challenges in conducting an RCT to provide guidance for LT4 prescribing for this group of patients, and a large epidemiological database study may provide further evidence.
Implications for clinical practice
This study represents the largest systematic review and meta-analysis to date and demonstrates no difference in cardiovascular health for older people with SCH whether LT4 treatment was initiated or not. The available data identified in this systematic review and meta-analysis lacks the power to give any new recommendations on prescribing LT4 for participants over 65 years with SCH. Prescribing for elderly patients with SCH will likely remain in equipoise with patient symptoms driving clinical practice.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.