Title: Weight changes, cardio-metabolic risks and mortality in patients with hyperthyroidism; all-cohort natural history and comparison of treatment effects in a CPRD-HES linked study
Funder: Department of Health and Social Care

Abstract: Hyperthyroidism is a common condition that affects 3% of women and 0.3% of men in the UK adult population. Most common symptoms include weight loss, heat intolerance, tremor and palpitations. Treatment to achieve euthyroid status improves symptoms and reduces the risk of atrial fibrillation and stroke that contribute to the increased mortality risk in hyperthyroidism. Current treatment options include: antithyroid drugs (ATDs), radioactive iodine (I-131 radioiodine) and thyroidectomy. Weight gain during treatment is commonly seen, though it is unclear whether this simply represents regain of previously lost weight. Whether there are differences in either weight change or the long-term cardio-metabolic risk between the three treatments is unclear. The absence of this information limits fully informed patient treatment choice. The aim of this project is to investigate the risks of developing obesity, of developing cardio-metabolic conditions and of death in a large cohort of patients with hyperthyroidism and to compare the risks of these outcomes between all three modalities used to treat hyperthyroidism. We propose to investigate the data collected in primary care pre- and post-diagnosis as a retrospective cohort study using Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and Office of National Statistics (ONS) Death Registry. CPRD includes records from over 1,100 primary care practices within the UK including data from 35 million patients of whom 10 million are currently registered. CPRD is well-validated for epidemiological research across a range of health outcomes. We will include patients with newly diagnosed hyperthyroidism in primary care between 1st January 1996 and 31st December 2015, allowing for a minimum of 4 years follow-up. The diagnosis will be identified based on the appropriate Read codes; treatment administered will be based on the appropriate code: British National Formulary, Read system, the Office of Population Censuses and Surveys Classification of Interventions and Procedures (OPCS-4), or International Classification of Diseases. From feasibility searches, we anticipate identifying 25,000 patients with newly diagnosed hyperthyroidism eligible for HES linkage whose data meet acceptable quality record criteria. Our study will consist of three work packages: (1) modelling natural history of weight change during the course of hyperthyroidism treatment; (2) comparing post-treatment prevalence of obesity in the hyperthyroid cohort with the background population (Health Survey England); (3) analysing incidence of cardiovascular, metabolic and mortality outcomes between the three treatment arms. Deeming real-life clinical trial not feasible, we are proposing analytical approaches emulating a clinical trial using routinely collected data. We anticipate the results of our study to bring new knowledge on risks of becoming obese following the treatment for hyperthyroidism as well as risks of developing cardio-metabolic morbidity and mortality. Our study has the unique potential to better inform treatment choice, a priority voiced by patients in during our Patients and Public Engagement meeting. The findings from this study will also inform future design of any interventional studies to prevent excessive weight gain and adverse cardio-metabolic outcomes following treatment for hyperthyroidism.

Lay abstract: Patients with an overactive thyroid gland (hyperthyroidism) usually lose a significant amount of weight. Leaving the condition untreated can lead to serious diseases including irregular heartbeat (atrial fibrillation) and stroke. At onset of the disease, patients most commonly lose weight and they gain considerable amounts of weight during the treatment. Whether this weight gain represents simple return to the weight before the illness or whether it continues, thereby resulting in excess weight (weight overshoot), is not clear. These weight changes may put patients at increased risk of becoming overweight or developing obesity which in turn increases the risk of developing diabetes and heart disease. The current treatments for hyperthyroidism include either surgery, radioiodine or medication. Recent studies showed that there are significant differences in mortality between those treatments. However, not much is known about any other risks, despite the common use of all three treatments. We recently held a patient discussion evening and patients told us that weight gain and associated cardio-metabolic risks were important issues as part of decision-making in which treatment to choose. They were disappointed that there was not much information available and that there was no ongoing research in that field. They felt strongly about the need to warn patients of potential risk of excessive weight gain, if such exists, and about the need to prevent the excess weight gain that many of them had experienced when they were treated. In this research proposal, we aim: (i) to establish if patients gain weight during or after the treatment for hyperthyroidism and compare their post-treatment weight to the average sex and age comparable weight in England; (ii) to compare which of the three treatments available is linked to the most weight gain; (iii) to establish if after treatment patients overshoot their weight before onset of hyperthyroidism; (iv) to see which of the three treatments is associated with the biggest risk of a patient getting diabetes, heart disease or death. We will achieve these aims by analysing data from a large national general practise (GP) database called the Clinical Practice Research Datalink (CPRD). The database includes information on over 10% of UK GP practices. We would like to link information on individual patients to their hospital records. We will identify patients who have been treated for hyperthyroidism from this large database and look at the therapy they received. Based on the results of this work we aim to produce high quality information for doctors and patients about the risks of different treatment options. This will mean patients can make more informed choices about their treatment. If our study shows excessive weight gain following treatment for hyperthyroidism, we will develop a plan to prevent this.

Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: METABOLIC AND ENDOCRINE