Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement

\ua9 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.Persistent symptoms in patients treated for hypothyroidism are common. Despite more than 20 years of debate, the use of liothyronine for this indication remains controversial, as numerous randomised trials have failed to show a benefit of treatment regimens that combine liothyronine (T3) with levothyroxine over levothyroxine monotherapy. This consensus statement attempts to provide practical guidance to clinicians faced with patients who have persistent symptoms during thyroid hormone replacement therapy. It applies to non-pregnant adults and is focussed on care delivered within the UK National Health Service, although it may be relevant in other healthcare environments. The statement emphasises several key clinical practice points for patients dissatisfied with treatment for hypothyroidism. Firstly, it is important to establish a diagnosis of overt hypothyroidism; patients with persistent symptoms during thyroid hormone replacement but with no clear biochemical evidence of overt hypothyroidism should first have a trial without thyroid hormone replacement. In those with established overt hypothyroidism, levothyroxine doses should be optimised aiming for a TSH in the 0.3–2.0 mU/L range for 3 to 6 months before a therapeutic response can be assessed. In some patients, it may be acceptable to have serum TSH below reference range (e.g. 0.1–0.3 mU/L), but not fully suppressed in the long term. We suggest that for some patients with confirmed overt hypothyroidism and persistent symptoms who have had adequate treatment with levothyroxine and in whom other comorbidities have been excluded, a trial of liothyronine/levothyroxine combined therapy may be warranted. The decision to start treatment with liothyronine should be a shared decision between patient and clinician. However, individual clinicians should not feel obliged to start liothyronine or to continue liothyronine medication provided by other health care practitioners or accessed without medical advice, if they judge this not to be in the patient\u27s best interest

Clinical, behavioural and pharmacogenomic factors influencing the response to levothyroxine therapy in patients with diagnosed primary hypothyroidism

Background Suboptimal thyroid hormone therapy including under-replacement and over-replacement is common amongst patients with hypothyroidism. This is a significant health concern as affected patients are at risk of adverse cardiovascular or metabolic consequences. Despite a growing body of evidence on the effects of various factors on thyroid hormone replacement, a systematic appraisal of the evidence is lacking. This review aims to appraise and quantify the extent to which clinical, behavioural and pharmacogenomic factors affect levothyroxine therapy in patients with primary hypothyroidism. Methods/Design The databases Web of Science, Cochrane Library, EMBASE, and PubMed will be searched. Patients must be adults over the age of 18 years, suffering from primary hypothyroidism including overt and subclinical hypothyroidism, and receiving levothyroxine treatment. Studies in children, pregnant women, and patients with secondary or tertiary hypothyroidism will not be included. We will also exclude studies focused on forms of thyroid hormone replacement therapy other than levothyroxine. The primary outcome is to quantify the effect of clinical, behavioural and pharmacogenomic factors on thyroid stimulating hormone (TSH) levels. Secondary outcomes are the effect these factors have on Thyroxine (T4) and Triiodothyronine (T3) levels, mortality, morbidity, quality of life, treatment complications, adverse effects, physical and social functioning. Studies will be screened through reading the title, abstract, and then full text. Two reviewers will independently extract the data and select articles, and a third reviewer will be consulted if there is any disagreement. We will undertake a meta-analysis of studies in which there is a defined intervention or exposure, patients are receiving levothyroxine for hypothyroidism, there is an appropriate control group of levothyroxine treated patients that are not exposed to the intervention, and the primary outcome is determined by serum TSH levels. Studies will comprise of randomised controlled trials as well as observational data. Eligible studies will be assessed for bias using the risk of bias tool available in the Cochrane Handbook 2011, and the quality of evidence will be judged according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. A flow diagram describing the data search will be created according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis: The PRISMA Statement. A narrative synthesis will be undertaken in the description of the data, and summary tables will be created of the results. Discussion This review will be the first systematic review of this nature. The evidence synthesised will be useful to general practitioners in their management of hypothyroidism. Findings will be disseminated at conferences and in professional and peer-reviewed journals

Designing a combined Liothyronine (LT3), L-thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 – the importance of patient selection, choice of LT3 and trial design

Approximately 10%–15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection—(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 μg/day or 100 μg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication

Can Admission and Fasting Glucose Reliably Identify Undiagnosed Diabetes in Patients With Acute Coronary Syndrome?

OBJECTIVE—Our objectives were to determine the prevalence of previously undiagnosed abnormal glucose tolerance, i.e., diabetes and impaired glucose tolerance (IGT) in patients with acute coronary syndrome and to assess the utility of admission and fasting glucose in identifying diabetes in these patients

Liothyronine (LT3) prescribing in England: Are cost constraints inhibiting guideline implementation?

Background: Primary hypothyroidism affects about 3% of the general population in Europe. In most cases people with hypothyroidism are treated with levothyroxine. In the context of the 2023 British Thyroid Association guidance and the 2020 Competitions and Marketing Authority (CMA) ruling, we examined prescribing data for levothyroxine, Natural desiccated thyroid (NDT) and liothyronine by dose, regarding changes over the years 2016–2022. Design: Monthly primary care prescribing data for each British National Formulary code were analysed for levothyroxine, liothyronine and NDT. Patients and Measurements: The rolling 12‐month total/average of cost or prescribing volume was used to identify the moment of change. Results included number of prescriptions, the actual costs, and the cost/prescription/mcg of drug. Results: Liothyronine: In 2016 94% of the total 74,500 prescriptions were of the 20 mcg dose. In 2020 the percentage prescribed in the 5 mcg and 10 mcg doses started to increase so that by 2022 each reached nearly 27% of total liothyronine prescribing. The average cost/prescription in 2016 of 20 mcg was £404/prescription and this fell by 80% to £101 in 2022; while the 10 mcg cost of £348/prescription fell by only 35% to £255 and the 5 mcg cost of £355/prescription fell by 38% to £242/prescription. The total prescriptions of liothyronine in 2016 were 74,605, falling by 30% up to 2019 when they started to grow again ‐ most recently at 60,990−15% lower than the 2016 figure, with the result that total costs fell by 70% to £9 m/year. Conclusions: Liothyronine costs fell after the CMA ruling but remain orders of magnitude higher than for levothyroxine. The remaining 0.2% of patients with liothyronine treated hypothyroidism are still absorbing 16% of medication costs. The lower liothyronine 5cmg and 10 mcg doses as recommended by BTA are 240% the costs of the 20 mcg dose. Thus, following latest BTA guidance which recommends the lower liothyronine doses still incurs substantial additional costs vs the prescribing liothyronine in the no longer recommended treatment regime. High drug price continues to impact clinical decisions, potentially limiting liothyronine therapy availability to a considerable number of patients who could benefit from this treatment

Trace elements in glucometabolic disorders: an update

Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed