L-thyroxine therapy in subclinical hypothyroidism : effect on cardiovascular risk factors, endothelial function and patient-reported outcomes

Context: It is controversial whether the treatment of subclinical hypothyroidism (SCH) with L-thyroxine improves cardiovascular (CV) risk factors and quality of life (QoL). Objective: To determine whether CV risk factors, endothelial function and patient-reported outcomes improve in people with SCH with L-thyroxine treatment. Design: Randomised double blind, cross-over study. Setting: Patients from primary care practices identified from laboratory database. Patients: One hundred patients (81 females) with mild SCH, and no existing thyroid or vascular disease, mean (SD) age 53.8 (12) years, thyrotropin (TSH) of 6.6 (1.3) mIU/L. One patient withdrew due to perceived side-effects. Intervention: Oral 100 meg of L-thyroxine or matching placebo daily for twelve weeks each. Main outcome measures: Powered to detect significant improvements in two primary parameters: total cholesterol (TQ levels and endothelial function (brachial artery flow mediated dilatation-FMD), the earliest marker of atherosclerosis. Results: L-thyroxine treatment reduced (mean difference, 95% Q TSH (5.64 mIU/L, 4.11 to 7.17), increased FT4 and FT3 levels (6.98 pmol/L, 5.97 to 7.98 and 0.6 pmol/L, 0.37 to 0.82, respectively), FMD improved (1.65%, 1.2 to 2.1) and TC levels reduced (435 mmol/L, -0.52 to -0.16). Increase in FT4 levels was the only significant determinant of the improvement in TC and FMD. Sexlife and overall QoL were less negatively impacted by SCH during L-thyroxine treatment. Symptom bother scores did not benefit by L-thyroxine but there was a significant improvement in the frequency of tiredness - from 89% to 78%, p<0.05. Health status and treatment satisfaction did not show any significant change. Conclusion: SCH treated by L-thyroxine leads to a significant improvement in CV risk factors and some patient-reported outcomes. The benefit of CV risk reduction is related to the increased level of achieved FT-4 concentration.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Trends, determinants, and associations of treated hypothyroidism in the United Kingdom, 2005-2014

Background: Recent reports suggest that prescriptions for thyroid hormones have increased. Recent trends in and determinants of the prevalence of treated hypothyroidism across the United Kingdom were therefore analyzed. Methods: Data covering the whole of the United Kingdom held by the National Health Service and the Office of National Statistics were examined. The main outcome measured was trends in the prevalence of treated hypothyroidism between 2005 and 2014. In addition, linear trend forecasting was performed to estimate projected trends in the prevalence of treated hypothyroidism up to the year 2025. Furthermore, determinants of variation of treated hypothyroidism prevalence across each of the 237 health areas in the United Kingdom in 2014 and its association with other health conditions were explored by multivariate linear regression analyses. Results: The prevalence of treated hypothyroidism increased from 2.3% (1.4 million) to 3.5% (2.2 million) of the total British population between the years 2005 and 2014 and is projected to rise further to 4.2% (2.9 million) by 2025. There was large geographical variation of treated hypothyroidism across the United Kingdom, with London having the lowest (1.4%) and the Western Isles of Scotland having the highest (6.3%) prevalence. This variation was attenuated, but did not completely disappear, after some potential determinants were accounted for. The prevalence of treated hypothyroidism was independently related to health areas, with a higher proportion of individuals who were female, white, and obese, and negatively associated with prevalent cigarette smoking. The prevalence of treated hypothyroidism was significantly associated with the frequency of prevalent atrial fibrillation but not with other major health conditions, including ischemic heart disease and osteoporosis. Conclusions: Between 2005 and 2014, the prevalence of treated hypothyroidism increased across the United Kingdom, has wide geographical variation, and is likely to increase further for the foreseeable future. Clinical effects and cost-effectiveness of the trend in increasing treatment of hypothyroidism remains to be evaluated

Older patients’ experience of primary hypothyroidism: A qualitative study

Background - Primary hypothyroidism is a common endocrine disorder, more so in an increasing UK ageing population. There is no qualitative research examining the older patient perspective of symptoms, treatment and self‐management of hypothyroidism. Objective - In this study we explored the experience of hypothyroidism in older people and examined how this may influence their understanding and acceptance of diagnosis, treatment with Levothyroxine and the monitoring process. Design - We conducted semi‐structured interviews with 18 participants aged between 80 and 93 years. Interview transcripts were analysed using a thematic approach. Results - The themes involved older individuals’ knowledge about symptoms, confidence in diagnosis and understanding of clinical management regimen to understand hypothyroidism. Interpretation of the themes was informed by the Health Belief Model. Conclusion - Our findings can help to inform the development of interventions by treating clinicians and support staff to engage older patients in the long‐term management of this chronic condition

Assessing the cardiovascular effects of levothyroxine use in an ageing United Kingdom population (ACEL-UK) protocol: a cohort and target trial emulation study

Background Subclinical hypothyroidism is diagnosed when serum thyroid stimulating hormone levels are higher whilst free thyroxine levels remain within their respective reference ranges. These reference ranges are uniformly applied in all adults, despite serum thyroid stimulating hormone levels naturally increasing with age. Research has found that mildly elevated thyroid stimulating hormone levels may be associated with some benefits in ageing patients, including reduced mortality and better cardiorespiratory fitness. Levothyroxine is typically prescribed to patients with hypothyroidism, but no conclusive evidence exists on whether levothyroxine therapy is beneficial or detrimental in older subclinical hypothyroid patients. Despite this, prescriptions for levothyroxine are increasing yearon-year. This study aims to determine if receiving levothyroxine affects the cardiovascular and bone health outcomes of subclinical patients in primary care aged 50 years and over. Methods This project includes a retrospective cohort analysis and a target trial emulation study using electronic patient records collected between 2006 and 2021 and recorded in The Health Improvement Network database. The primary outcome of this study is to compare the cardiovascular outcomes of subclinical hypothyroid patients aged over 50 years treated with levothyroxine compared to those untreated. Secondary outcomes are bone health and allcause mortality outcomes. Descriptive and inferential statistics will both be employed to analyse the data. Secondary analysis will explore confounding factors, including age, sex, smoking status, body mass index, co-morbidities, and levothyroxine dosage. Discussion There needs to be a greater understanding of the potential risks of the current treatment for older patients with subclinical hypothyroidism in a primary care setting. We will investigate the clinical importance of this issue and whether older subclinical hypothyroid patients have poorer outcomes when treated. Clarifying this concern may help address the healthcare resource implications of ageing patients being misclassified as having mild hypothyroidism, as these patients are more likely to repeat their blood tests. This could reduce prescription wastage and improve patient outcomes and quality of life in the ageing population

Association of diabetes with atrial fibrillation types: a systematic review and meta-analysis

Background: Atrial fibrillation (AF) is a common arrhythmia classified as paroxysmal and non-paroxysmal. Non-paroxysmal AF is associated with an increased risk of complications. Diabetes contributes to AF initiation, yet its role in AF maintenance is unclear. We conducted a systematic review and meta-analysis to summarize the evidence regarding the association of diabetes with AF types. Methods: We searched 5 databases for observational studies investigating the association of diabetes with the likelihood of an AF type (vs another type) in humans. Study quality was evaluated using the Newcastle-Ottawa Scale. Studies classifying AF types as paroxysmal (reference) and non-paroxysmal were pooled in a meta-analysis using random effects models. Results: Of 1997 articles we identified, 20 were included in our systematic review. The population sample size ranged from 64 to 9816 participants with mean age ranging from 40 to 75 years and percentage of women from 24.8 to 100%. The quality of studies varied from poor (60%) to fair (5%) to good (35%). In the systematic review, 8 studies among patients with AF investigated the cross-sectional association of diabetes with non-paroxysmal AF (vs paroxysmal) of which 6 showed a positive association and 2 showed no association. Fourteen studies investigated the longitudinal association of diabetes with "more sustained" AF types (vs "less sustained") of which 2 showed a positive association and 12 showed no association. In the meta-analysis of cross-sectional studies, patients with AF and diabetes were 1.31-times more likely to have non-paroxysmal AF than those without diabetes [8 studies; pooled OR (95% CI), 1.31 (1.13-1.51), I2 = 82.6%]. The meta-analysis of longitudinal studies showed that for patients with paroxysmal AF, diabetes is associated with 1.32-times increased likelihood of progression to non-paroxysmal AF [five studies; pooled OR (95% CI), 1.32 (1.07-1.62); I2 = 0%]. Conclusions: Our findings suggest that diabetes is associated with an increased likelihood of non-paroxysmal AF rather than paroxysmal AF. However, further high quality studies are needed to replicate these findings, adjust for potential confounders, elucidate mechanisms linking diabetes to non-paroxysmal AF, and assess the impact of antidiabetic medications on AF types. These strategies could eventually help decrease the risk of non-paroxysmal AF among patients with diabetes

Multinational survey of treatment practices of clinicians managing subclinical hypothyroidism in older people in 2019

Background: International societies have recommended that levothyroxine should not routinely be prescribed in older individuals for the management of mild subclinical hypothyroidism (SCH). However, it is unknown whether clinicians managing people with SCH are either aware of or adhere to these guidelines. Methods: A web-based survey of members of several international thyroid associations and general practitioners in North-East England was conducted. Respondents were presented with a vignette of an 80-year-old gentleman with mild persistent SCH experiencing tiredness. Multivariable logistic regression analyses were performed to evaluate predictors of awareness of guidelines and responses to treatment. Results: The survey response rate was 21.9% (565/2,583). Only 7.6% of clinicians were unaware of guidelines regarding management of SCH in older people. Twenty percent of clinicians stated that they would treat the older patient with mild SCH, whereas 13% were unsure. Clinicians from North America were more likely to treat the older person with mild SCH than clinicians from elsewhere (OR 2.24 [1.25–3.98]). Likewise, non-endocrinologists were also more likely than endocrinologists to treat the older person with mild SCH (OR 3.26 [1.45–6.47]). Conclusion: The majority of clinicians are aware of guidelines regarding management of SCH in older individuals. However, a considerable proportion of clinicians would still treat an older person with non-specific symptoms and mild SCH. These guidelines need to be disseminated more widely and more research is required to understand barriers to adherence to international recommendations

Cardiovascular and bone health outcomes in older people with subclinical hypothyroidism treated with levothyroxine: a systematic review and meta-analysis.

BACKGROUND Thyroid dysfunction is common in older people, with females at higher risk. Evidence suggests that thyroid-stimulating hormone (TSH) levels naturally increase with age. However, as uniform serum TSH reference ranges are applied across the adult lifespan, subclinical hypothyroidism (SCH) diagnosis is more likely in older people, with some individuals also being commenced treatment with levothyroxine (LT4). It is unclear whether LT4 treatment in older people with SCH is associated with adverse cardiovascular or bone health outcomes. METHODS A systematic review and meta-analysis were performed to synthesise previous studies evaluating cardiovascular and bone health outcomes in older people with SCH, comparing LT4 treatment with no treatment. PubMed, Embase, Cochrane Library, MEDLINE, and Web of Science databases were searched from inception until March 13, 2023, and studies that evaluated cardiovascular and bone health events in people with SCH over 50 years old were selected. RESULTS Six articles that recruited 3853 participants were found, ranging from 185 to 1642 participants, with the proportion of females ranging from 45 to 80%. The paucity of data resulted in analysis for those aged over 65 years only. Additionally, a study with 12,212 participants aged 18 years and older was identified; however, only data relevant to patients aged 65 years and older were considered for inclusion in the systematic review. Of these 7 studies, 4 assessed cardiovascular outcomes, 1 assessed bone health outcomes, and 2 assessed both. A meta-analysis of cardiovascular outcomes revealed a pooled hazard ratio of 0.89 (95% CI 0.71-1.12), indicating no significant difference in cardiovascular risk between older individuals with SCH treated with LT4 compared to those without treatment. Due to overlapping sub-studies, meta-analysis for bone health outcomes was not possible. CONCLUSIONS This systematic review and meta-analysis found no significant association between LT4 use and cardiovascular and bone health outcomes in SCH participants over 65 years. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42022308006

Cardiovascular and bone health outcomes in older people with subclinical hypothyroidism treated with levothyroxine: a systematic review and meta-analysis

Background Thyroid dysfunction is common in older people, with females at higher risk. Evidence suggests that thyroid-stimulating hormone (TSH) levels naturally increase with age. However, as uniform serum TSH reference ranges are applied across the adult lifespan, subclinical hypothyroidism (SCH) diagnosis is more likely in older people, with some individuals also being commenced treatment with levothyroxine (LT4). It is unclear whether LT4 treatment in older people with SCH is associated with adverse cardiovascular or bone health outcomes. Methods A systematic review and meta-analysis were performed to synthesise previous studies evaluating cardiovascular and bone health outcomes in older people with SCH, comparing LT4 treatment with no treatment. PubMed, Embase, Cochrane Library, MEDLINE, and Web of Science databases were searched from inception until March 13, 2023, and studies that evaluated cardiovascular and bone health events in people with SCH over 50 years old were selected. Results Six articles that recruited 3853 participants were found, ranging from 185 to 1642 participants, with the proportion of females ranging from 45 to 80%. The paucity of data resulted in analysis for those aged over 65 years only. Additionally, a study with 12,212 participants aged 18 years and older was identified; however, only data relevant to patients aged 65 years and older were considered for inclusion in the systematic review. Of these 7 studies, 4 assessed cardiovascular outcomes, 1 assessed bone health outcomes, and 2 assessed both. A meta-analysis of cardiovascular outcomes revealed a pooled hazard ratio of 0.89 (95% CI 0.71–1.12), indicating no significant difference in cardiovascular risk between older individuals with SCH treated with LT4 compared to those without treatment. Due to overlapping sub-studies, meta-analysis for bone health outcomes was not possible. Conclusions This systematic review and meta-analysis found no significant association between LT4 use and cardiovascular and bone health outcomes in SCH participants over 65 years