MICA: MRC APBI STratification and Extreme Response Mechanism IN Diabetes - MASTERMIND

Context of the research
Over 4% of the population have Type 2 diabetes. It is a major cause of illness and early death accounting for around 10% of the money spent in the NHS. Good control of blood glucose with appropriate life style and medication makes patients feel better and reduces the risks of the development of the complications of diabetes. The MASTERMIND study involves collaboration between academic researchers and industry to help patients with Type 2 diabetes receive the most suitable treatment. At present, the guidelines for treatment of patients with Type 2 diabetes list a large number of drugs without giving clear guidance on which patients should have which drugs. This makes it difficult for patients and their health care professionals to know which drugs are likely to suit them best. We know that patients with Type 2 diabetes vary greatly in how well they respond to different diabetes drugs, and whether they develop side effects to particular medications. Our initial pilot study has helped us to determine the best types of experiment to identify response subgroups and has let us generate preliminary results that we can now test, improve and expand upon.

Aim of the research
The aim of this project is to identify subgroups of patients that respond well or poorly to particular drugs based on particular clinical characteristics such as their weight or blood test results, to enable better targeting of treatment for a particular individual.

Outline of the research
The new project aims to build on the work done in the initial study and involves 2 strands:
1. We will carry out a trial where patients who currently have high blood glucose on metformin and sulphonylurea therapy will receive 3 different diabetes tablets in random order. We will take measurements and blood samples at the start of the study, and then measure the patients' average blood glucose control (HbA1c) at the end of 4 months on each of these drugs. We will also record any side effects and ask the patient which treatment they preferred. These 3 diabetes treatments work in different ways. We will be able to test whether this means different patients have different clinical features (e.g. whether a patient is obese, or whether they have poorer kidney function) that determine whether they respond well to the drugs.
2. We will analyse large publicly-available datasets that have data on thousands of patients with Type 2 diabetes. We will have access to anonymised data from GP practices and data from drug trials run by pharmaceutical companies. We will use statistical analysis to identify which features pick out patients who respond well to the different drugs in the short and long term and also to identify which patients have side effects.

Key outcomes of the research
The key outcomes of this work are:
1. Information on the criteria that can be used to identify which subgroups of patients respond best to which drugs. This evidence will be used to inform new guidelines for prescribing drugs for Type 2 diabetes.
2. Development of methodology for how to identify these subgroups of individuals that will help future studies in this area. These new scientific methods and data analysis techniques can then also be applied to other diseases.
3. A large bioresource of samples from patients with Type 2 diabetes and how they responded to the three different diabetes drugs will be available to both academic groups and pharmaceutical companies. This will be used in future studies where these samples can be analysed to find new blood markers that identify whether an individual is likely to respond well or poorly to a particular drug, and will help drug development by giving insights into why different patients respond differently to the different Type 2 diabetes drugs.

Our vision is that a stratified medicine approach will result in more effective use of glucose-lowering therapy for patients with Type 2 diabetes (T2D). The rationale for this stratified approach is based on:
i)T2D patients showing considerable inter-individual variation in their underlying pathophysiology ii) the increasing number of classes of glucose lowering therapies that work by very different mechanisms of action iii) pilot study evidence that variation in response to therapy is, in part, robustly explained by differences in patients' underlying pathophysiology.

This extension will involve 2 strands: 1. An experimental strand that will involve a 3 way crossover study of third line oral therapy (a thiazolidinedione, DPP4 inhibitor and SGLT2 inhibitor) in patients with inadequate glycaemic control on metformin and sulphonylurea. This work will test specific hypotheses from pilot work with the primary outcome being HbA1c on therapy and secondary outcomes of side effects and patient preference. 2. A data analysis strand that will use routine clinical, academic and commercial trial data to assess how drug response is related to clinical features and routine biochemistry. We will examine short and long term glycaemic response and side effects.

The key outcomes of this work are: 1. Robust evidence to inform guidelines for the most appropriate use of glucose lowering medication for specific subgroups of patients with Type 2 diabetes. This will enable better targeting of old drugs and enable earlier more focussed use of the newer more expensive therapies in patients where old drugs are less effective. 2. Key methodology development for hypothesis generation and subsequent testing/validation of stratification in Type 2 diabetes. This will cover both data analysis and study design. 3. Establishing a large bioresource of individuals with well characterised comparative response to commonly used drugs for biomarker assessment and discovery by industry and academia.

Who will benefit from the MASTERMIND project and how?
a) Patients with type 2 diabetes: It is estimated that only 30-70% of patients respond positively to any given drug (Stratified Medicine in the UK- Vision and Roadmap, TSB, Oct 2011). The greatest beneficiary of the MASTERMIND study will be type 2 diabetes patients. Most second and third line glucose lowering therapies available do not have clear differences in overall effectiveness (NICE management of type 2 diabetes 2015 (draft)). There is therefore considerable uncertainty regarding treatment choice. This study will inform clinical guidelines to facilitate prescription of an agent most likely to be effective. Avoiding less effective medication will improve glycaemic control and reduce side effects.

b) Economic: MASTERMIND will contribute to the UK's shared vision for tackling Stratified Medicine (Stratified Medicine in the UK- Vision and Roadmap, TSB, Oct 2011). This research will complement the vision of supporting world-class research as a solid base for capturing value from the UK's precision medicine research (Precision Medicine Catapult Enhanced Business Case Across the UK, March 2014), with an annual revenue of £44 billion from the pharmaceutical sector and £1.1 billion annual revenue from the diagnostic sector. Healthcare models are facing increased physical and financial pressures in providing for a burgeoning ageing population. Costs are also increasing for the pharmaceutical industry with increased costs for fewer new drugs. The pharmaceutical industry will benefit from this work in the following ways:
- Identified strata with poor response to existing therapies will present an opportunity for the development or positioning of new therapies effective in these strata
- Identification of strata with poor response to older generic therapies but response to more recent therapies will present an opportunity to target therapies appropriately
- Methodology development will assist identification of strata and validation of stratification based pathways within industry and provide a pipeline for confirming strata and health economic impact of stratified interventions
- The development of a bioresource (Strand 1) with well characterised differential response to third line oral therapies and biological sample availability will present an opportunity for industry to identify new biomarkers and strata
- Understanding of pathophysiological mechanisms of altered response may assist the development of newer more effective therapies targeted to non responders

c) National Health Service: Type 2 diabetes now affects 4-5% of adults in the UK and it currently costs the NHS £9.8 billion every year to treat diabetes and related complications (The Cost of Diabetes, Diabetes UK 2014). Clinical guidelines arising from this research will improve diabetes drug prescribing and effectiveness, leading to more targeted use of therapies with greater effect (greater glucose lowering and therefore reduced long term complications) and reduced side effects. This will reduce service utilisation and complications from ineffectively treated hyperglycaemia. This research will also facilitate more effective (and cost effective) use of newer, more expensive, glucose lowering therapies.

d) The Academic Community: MASTERMIND will strengthen stratification research capability across participating centres and the wider academic community by providing the theoretical frame work on which future studies can be performed and access to major resources for further research. In addition this study will strengthen academic collaboration between centres and with industry and provide training, development and experience to increase research capacity in participating centres.