PERMIT is a 30-month NIHR-funded project aiming to determine the relative effectiveness of alternative oral drug regimens for first stage treatment intensification for people with Type 2 Diabetes Mellitus, and provide the evidence required to target treatments for individual patients.
PERMIT will use an instrumental variable design and a microsimulation model to investigate the relative effectiveness of second line antidiabetic treatment in different groups of patients. We will use UK data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES).
The PERMIT study aims to determine the relative effectiveness of treatments for people with Type 2 Diabetes and provide the evidence required to target treatments for individual patients.
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 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 characteristics such as age or weight.
However, NICE (The National Institute for Health & Care Excellence, who recommends 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.
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 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), a large ongoing general practice database of anonymised UK medical records.
This section provides more detailed information about the study design for researchers. More information, including the study protocol, is available on the NIHR website.
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?
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.
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.
The objectives are:
- To assess short-term relative effectiveness according to individual risk factor profiles.
- To calibrate and extend a microsimulation model developed in the US, for patients with T2DM in the UK (RAPIDS-UK).
- 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.
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.
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).
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.
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.
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.
PERMIT is led by a team of health economists at the London School of Hygiene and Tropical Medicine in collaboration with clinicians and other experts. An Advisory Group, with an independent chair, oversees the study. PPI and Clinical Panels provide specialist guidance to the study.
What is PPI?
PPI means ‘Patient and Public Involvement’ and is a core component of our research. It helps us to ensure that our researchers are asking the right questions and using the right methods, so that our studies will provide answers that will make a real difference to people’s lives.
If you would like to know more about PPI, this video explains more about the value of involving patients and the public in research. It is made by our funders, National Institute for Health Research (NIHR). You can read more about patient and public involvement in research on the NIHR/INVOLVE website.
PPI in the PERMIT study
PPI in the PERMIT study is managed by our PPI co-applicants, Paul Charlton and Bill Huston.
We will provide more details here, as we shape the PPI component of the PERMIT study.
This study is funded by the National Institute for Health Research Health Services and Delivery Research (project number NIHR128490).
You can find out more information about the study on the NIHR website:
Please note: the views and opinions expressed on this website are those of the research team and do not necessarily reflect those of the Health Services and Delivery Research Programme, NIHR, NHS or the Department of Health.
LSHTM handles any data used in the ESORT study in accordance with data protection laws and its own internal policies and procedures. Read LSHTM’s data protection policy.
The main way in which the PERMIT study uses data is by receiving information from Clinical Practice Research Datalink. These data are pseudonymised, meaning any personally identifiable information (e.g. NHS number, exact birth date) is removed before our research team receives the data. All study data are stored on secure LSHTM servers in line with the existing multi-study license between LSHTM and CPRD.
Additionally, we will receive information about people who participate in the Patient and Public aspect of our study. Their information is governed by LSHTM’s Research Participant Privacy notice.
The PERMIT study was approved by the Independent Scientific Advisory Committee (ISAC) of the Medicines and Healthcare Products Regulatory Agency (protocol no. 20_064) and the LSHTM Observational/Interventions Research Ethics Committee (reference no. 21395) in March 2020.
Read more information on ethics at LSHTM.
Find out further information on CPRD.