Title: PERsonalised Medicine for Intensification of Treatment (PERMIT): the case of type 2 Diabetes Mellitus
Funder: Department of Health and Social Care

Abstract: Background_x000D_ In the UK around 3 million people have been diagnosed with Type 2 diabetes , a condition that causes high levels of sugar (glucose) in the blood, and accounts for about £1 in £10 that the NHS spends. Most people with Type 2 diabetes start treatment with a drug called metformin, but some are later obliged to take additional drugs when the metformin is not effective enough. It is unclear which of the additional drugs is best for which patient, and there is variation across the UK in the choice of drug. Ideally, the choice of the additional drug should be ‘personalised’ according to patient differences such as age or weight. However, NICE who recommend which treatments should be provided in the NHS, say that there is insufficient evidence to decide on the right drug or drug combinations for individual patients with Type 2 diabetes. _x000D_ Diabetes UK surveyed people with Type 2 diabetes, who said research to find out how to prevent long term complications is a high priority. Diabetes UK have requested studies that aim to improve care for the individual and which reduce long-term complications. They fully support this study. This study will address this gap in the evidence base by examining patient data in the Clinical Practice Research Datalink (CPRD; https://www.cprd.com), a large ongoing general practice database of anonymised UK medical records._x000D_ Aim_x000D_ Our study will investigate how metformin and the additional drugs have been used and how different patients have responded in respect of improvements in their health. We shall look at general practitioner records of people using metformin and a number of additional drugs between 2011 and 2019. We shall investigate the effect of these different treatments and provide evidence to help choose the right treatment for individual patients in the future._x000D_ Methods_x000D_ This study will examine the variation in treatment choices across local Clinical Commissioning Groups for patients seen in general practice . We will compare the outcomes experienced by different groups of people with Type 2 diabetes who have taken metformin with the alternative additional drugs. Our study recognises that patients receiving these alternative treatments are different from one other so we will provide accurate estimates of how effective these alternative treatments are for individual patients, according for example to their age or initial weight. We will report the impact of these alternative treatments on short-term outcomes such as cholesterol levels, and long-term outcomes like amputation rates._x000D_ Patient & public involvement (PPI)_x000D_ This application has benefited from the input of co-applicant Paul Charlton, a Patient Research Champion with the National Institute of Health Research, and advisor Bill Huston who was recently diagnosed with Type 2 diabetes. Paul and Bill drafted the plain English summary and also support the plans for two workshops with patient and public representatives, diabetologists, primary care physicians, and practice nurses. They have emphasised the need for the study to inform the public about how this use of patient data can improve health care. Also, they have recommended that the patient and public workshop attendees include people with Type 2 diabetes from a range of ages and ethnic groups, to help the study provide evidence that is ‘personalised’._x000D_ Making a Difference_x000D_ The study will directly communicate findings to key clinical organisations and into clinical guidelines. We will draft lay summaries of the key research findings which will be made widely available through the project website, and as ‘news’ items to forums widely used by patients and the public, such as Diabetes UK. The research will help commissioners and providers better target treatments for individual people with T2DM.

Lay abstract: Research questions: For people with Type 2 Diabetes Mellitus (T2DM), what is the relative effectiveness of alternative drugs for 1st stage intensification (2nd line treatment) according to the individual patient’s baseline risk profile? _x000D_ Background: Clinical guidelines for T2DM require evidence to help personalise treatment choice. For people who require an antidiabetic drug as an ‘add on’ to metformin, there is controversy about whether newer, more costly classes of drug- dipeptidyl peptidase-4 inhibitors (DPP4is) or sodium-glucose cotransporter-2 inhibitor (SGLTis) reduce the risk of long-term complications versus sulfonylureas (SUs). There is widespread variation across NHS Clinical Commissioning Groups (CCGs) in drug choice for first-stage intensification. _x000D_ Aims and objectives: This study aims to evaluate the relative effectiveness of alternative oral drug regimens for 1st stage treatment intensification for people with T2DM, and provide the evidence required to target treatments for individual patients._x000D_ The objectives are:_x000D_ 1. To assess short-term relative effectiveness according to individual risk factor profiles._x000D_ 2. To calibrate and extend a microsimulation model developed in the US, for patients with T2DM in the UK (RAPIDS-UK)._x000D_ 3. To use the findings from objective 1, together with the model developed in objective 2, to estimate long-term effectiveness according to individual risk factor profiles, and project the NHS budget impact of personalising drug choice. _x000D_ Methods: This study will use an advanced Instrumental Variable (IV) method and adapt a microsimulation model to the UK setting to provide unbiased estimates of relative effectiveness according to the individual patients’ risk profile. We will exploit the natural variation in prescription rates for 1st-stage intensification across CCGs. The study will apply this IV design to Clinical Practice Research Datalink (CRPD) linked to Hospital Episode (HES) data from 2011-2019. _x000D_ The target population is people with T2DM, aged over 18 years, prescribed SU, DPP4i or SGLT2i for 1st-stage intensification. This study will access linked CPRD-HES data on baseline characteristics, biomarker levels, concomitant medications, and also on long-term outcomes (micro- and macro- vascular complications, mortality and related hospital admissions). We will estimate the short-term effectiveness of the different drugs on haemoglobin A1c (HbA1c) according to individual patient’s risk profiles (e.g. age, gender, established cardiovascular disease (CVD) and baseline biomarker levels) (Obj 1). _x000D_ We will extend a microsimulation model to calibrate long-term outcomes (follow-up to 9 years) according to those observed in the CPRD (Obj 2). We will predict long-term effectiveness of the treatment alternatives according to individual-level risk profiles (Obj 3), and project the budget impact of ‘personalising’ the choice of 1st-stage intensification therapy. _x000D_ The co-applicants with direct experience of influencing NICE recommendations for technology appraisals (Adler) and clinical guidelines for T2DM (Khunti and Smeeth), have driven the study design to help ensure that the results can directly change practice._x000D_ Anticipated impact and dissemination: Our design workshops with clinical and Public and Patient representatives will help the study provide results of direct NHS relevance. Team members will directly communicate knowledge into clinical guidelines. Research findings will be reported

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE