Title: Interventions to preserve insulin-secreting beta cell function in people newly diagnosed with type 1 diabetes: a systematic review of quantitative and qualitative evidence.
Funder: Department of Health and Social Care

Abstract: Background Type 1 diabetes (T1D) is a devastating chronic illness that reduces life-expectancy by more than 15 years. It is one of the commonest cause of blindness, foot amputation, renal failure, and cardiac disease. The annual financial cost of T1D to the NHS is &pound;2billion. T1D results from loss of insulin-producing pancreatic beta cells. Following diagnosis, T1D is treated with lifelong insulin injection therapy. The destruction of beta cells is incomplete at the time people are diagnosed with T1D, and a small but significant proportion of them continue to function. There are clear clinical benefits to preserving these beta cells. These benefits include better glucose control, less hypoglycaemia, and fewer long-term diabetic complications. Preservation of residual beta cells has therefore been the focus of over 70 clinical trials in T1D for over 3-decades. Whilst some trials have shown promise, not one therapy alone has demonstrated sufficient benefit to be used routinely in clinical practice. Aims Our overarching aim is to identify the most effective interventions for preserving insulin secreting beta-cell function in people newly diagnosed with T1D. This understanding will be used to inform the design of a combinatorial therapy for beta-cell preservation as part of a future intervention trial to preserve beta-cell function in people newly diagnosed with T1D (not the subject of this application). Our specific objectives are to determine which interventions most effectively preserve beta-cell function in people newly diagnosed with T1D using: -outcome measures of circulatory C peptide -other outcome measures related to T1D -adverse events and compliance Plan The proposed objectives will be achieved through a quantitative systematic review. The review will identify the most effective intervention(s) to preserve beta-cell function in people newly diagnosed with T1D when beta-cell function is measured using the recommended outcome measure of stimulated C peptide. It will also identify what other outcome measures of beta-cell function have been used in studies of interventions to preserve beta-cell function and the evidence on modifiers of effects of interventions (e.g. age, gender). The review will include randomised controlled trials of at least 6-months follow-up of newly diagnosed T1D patients (within 2-years of diagnosis) from initiation of any intervention/comparator where beta-cell function is measured. Summary of potential benefits to patients and the NHS There is no previous unbiased systematic analysis of therapies for beta cell preservation in patients newly diagnosed with T1D. This project will provide a clear picture of the therapies that show greatest clinical benefit to patients. We propose that this will inform practice and lead to a feasibility and acceptability trial of a combination of these identified therapies in people newly diagnosed with T1D with the aim of preserving residual beta cell function. A 30% improvement in preserving beta cell function results in a 10%, 1.5% and 6% reduction in severe hypoglycaemia, retinopathy, and overall hypoglycaemia respectively. It is possible that a combination of therapies will be able to achieve this in a way that is acceptable to patients. These improvements are meaningful to clinicians and to patients, and are well worth striving for.

Lay abstract: BACKGROUND AND AIM Diabetes is a common illness which causes the sugar level in a person s blood to be too high. This is due to the body not producing enough of the hormone insulin, or not responding to insulin. In one form of diabetes (type 1 diabetes), the cells that make insulin, called beta-cells, are damaged and stop making insulin. However, not all of these cells are damaged when patients are first diagnosed. This means that patients can still produce a little insulin. Protecting these remaining beta-cells helps control sugar levels, and prevents the development of many diabetes problems, such as blindness and heart attacks. Many studies have been done over the past 35years to protect these beta-cells. The aim of this research is to review all of these previous studies so that we understand which approaches work best for patients with type 1 diabetes. DESIGN We will find these studies by searching through libraries of scientific research. We will look at how well the studies have been done, and then combine the information from them using internationally approved methods. We are experts in these methods and we have previously helped produce national treatment guidelines for diabetes. PATIENT AND PUBLIC INVOLVEMENT We have discussed this study with patients with type 1 diabetes. Three of them (supported by a further group of 10 patients, and parents of children with type 1 diabetes) will be part of the study team. They have helped develop this application. They will provide thoughts on the studies we identify. DISSEMINATION We will publicise these results widely through writing research papers and talks to doctors, researchers, and patients. We will then use the results of this study to develop a combination of therapies to treat patients to protect their beta-cells and improve diabetes control.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: METABOLIC AND ENDOCRINE