Title: Heart failure in type 2 diabetes: improving diagnosis and management in a multi-ethnic population.
Funder: Department of Health and Social Care

Abstract: Research question: Can we improve the detection, prevention and treatment of heart failure (HF) in type 2 diabetes (T2D)?Background: In 2015/16, one third of hospital admissions for HF were in people with diabetes (>115,000) despite representing only 6% of the population. The epidemic of obesity in children and T2D in younger adults, who have the highest lifetime risk, represents a potential time-bomb of patients who will develop HF. Early HF (before symptoms develop) can be detected with cardiac imaging, providing a potential therapeutic target but the causes and treatment are not well understood, especially in ethnic minorities and females.Aims: to improve the management of HF in T2D. Specific objectives in the work packages (WP) are to determine in T2D: WP1- How common early HF is (imaging) in a multi-ethnic population and to devise a clinical risk score to identify those with HF. WP2 Develop a blood test(s) that can accurately diagnose patients with early HF. WP3- Whether treatment with an SGLT2i or intensive blood pressure lowering can reverse early HF in younger adults ( WP4- Whether a low-calorie diet is a feasible treatment in a multi-ethnic cohort of obese patients with HFpEF.Methods: In all WP, patients will be extensively phenotyped with glcyometabolic profiling, 24 hour blood pressure, echocardiography and cardiac MRI.WP1: cross sectional study of 600 adults with T2D and no established cardiovascular disease from a multi-ethnic population in Leicestershire. Independent risk factors for early HF will be determined and a clinical risk score will be devised.WP2- using detailed proteomic analyses in 50 patients from WP1 we will develop a panel of blood biomarkers that accurately identifies early HF (discovery set). This will be internally validated in the remaining cohort and externally validated in a subset of the UK Biobank population.WP3- prospective, randomised, open label, multicentre, blinded endpoint trial in 825 adults (WP4 is a feasibility study of a 12 week low-calorie meal replacement diet aiming to recruit 20 obese adults with T2D and HF with preserved ejection fraction, which has no proven treatments. Outcomes: recruitment, compliance, symptoms, cardiac imaging.Timelines for delivery- Start November 2018. Completion: WP1 and 2: 2022; WP4 2019 and if successful further funding will be sought (2020). Funding for WP3 will be applied for aiming to start in 2019 and complete in 2023.Anticipated impact and dissemination: The results will impact on the management of HF in T2D globally. Dissemination will be through traditional scientific conferences, journal articles and conventional and new media with support from patient representatives, NIHR communications team and charities.

Lay abstract: Aims: to improve the detection, prevention and management of heart failure in a multi-ethnic population with type 2 diabetes.Background: There has been a dramatic increase in the number of patients with type 2 diabetes which is closely linked to obesity. People from minority ethnic groups such as Asians and blacks are more prone to developing type 2 diabetes and adolescents and young adults are increasingly affected.Patients with diabetes, despite representing only 6% of the population, account for one third of all patients admitted to hospital with heart failure. Almost 50% die within five years and heart failure is a major cause of reduced quality of life in type 2 diabetes. How best to prevent and treat heart failure in patients with diabetes, particularly in women and ethnic minorities, is poorly understood. Design and methods: we will conduct 4 studies in patients with type 2 diabetes.1. We will recruit 600 adults from a mixed ethnic population in Leicestershire who do not have heart symptoms. Each patient will have detailed scans (ultrasound, MRI and CT) to look at the structure and function of the heart. This study will tell us what proportion of patients of different sex and ethnic backgrounds have early signs of heart failure. This will aid health care professionals identify which patients with diabetes are at highest risk of developing heart failure.2. We will aim to develop a blood test than can reliably identify those patients in study 1 who have early signs of heart failure. Using sophisticated analysis techniques, we will measure hundreds of small proteins in blood samples from 50 patients. The best combination of proteins will then be tested to see if they can accurately identify those of the remaining 550 patients who have early signs of heart failure. We will validate the results in a completely different population, from the UK Biobank study. 3. We will test whether i) a new diabetes drug or ii) lowering blood pressure from 140 to 130 compared to iii) standard care can reverse the early signs of heart failure. Eight hundred and twenty- five adult patients without symptoms from 8 UK centres will be randomly allocated to one of the 3 treatment arms and the effect on heart function will be studied after 1 year. This study will tell us whether the new drug or intense blood pressure lowering are likely to prevent patients developing symptomatic heart failure. 4. In patients with symptomatic heart failure we will test whether a low-calorie meal replacement diet (810 calories per day) for 12 weeks may improve symptoms, quality of life and heart function. The low-calorie diet can completely reverse diabetes and improves high blood pressure. This will be a small study in 20 patients with heart failure to test that they can complete the treatment. If successful we will aim to conduct a further study to confirm the results in a larger population.Patient and public involvement: we have developed these ideas with a representative group of patients in the Leicestershire community who have diabetes. We have undertaken focus groups, where patients have sampled the low-calorie diet. Patient representatives will continue to be involved in the studies throughout their duration, helping to shape the research and make it more meaningful to potential participants. Dissemination: the results of the studies will be of keen interest to the general public, media and the medical community. We will work with patient groups, the NIHR communications office and other stakeholders to ensure that the results are disseminated as widely as possible so that patient care can be improved.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE;CARDIOVASCULAR