Pharmacoepigenetics for precision medicine in type 2 diabetes

Project Information

Proceed

Grant agreement ID: 101113278

DOI

10.3030/101113278

Project closed

EC signature date 25 April 2023

Start date 1 October 2023

End date 31 March 2025

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

LUNDS UNIVERSITET
Sweden

Periodic Reporting for period 1 - Proceed (Pharmacoepigenetics for precision medicine in type 2 diabetes)

Reporting period: 2023-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

The prevalence of diabetes will rise to ~592 million in 2035. Type 2 diabetes (T2D) is a leading cause of death through its vascular complications. High glucose increases the risk for complications, and thereby suffering for patients and costs for society. It is important that patients with T2D receive an optimal therapy that lowers blood glucose. Metformin is first-line T2D therapy. However, ~30% of patients do not respond to metformin. Currently, there are no biomarkers that predict the response to metformin.

Within PAINTBOX we discovered blood-based epigenetic markers that could discriminate between responders/non-responders to metformin in drug-naïve patients with T2D. This epigenetic tool may be further developed to help patients with T2D receive an optimal therapy. The aim of PROCEED is therefore to develop and commercialize our pharmacoepigenetic tool. We expect this biomarker tool to aid clinical decision-making in T2D therapy.

The specific goals of this project was to create a pharmacoepigenetic tool by i) testing if we could validate and optimize our previous findings, where we found that DNA methylation in blood could predict glycemic response and intolerance to metformin in newly diagnosed people with type 2 diabetes, and then ii) testing the validated epigenetic markers in a randomized control trial, SMARTEST, and iii) Finally, developing the blood-based epigenetic biomarker tool that predict glycemic response to metformin into a diagnostic tool, that can be easily used in the clinic.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To achieve the three specific goals described above, the following specific activities have been performed within PROCEED, and we made the following main achievements.

i) Within PROCEED, we have been working on validating and optimizing blood-based epigenetic markers that predict glycemic response to metformin in newly diagnosed people with type 2 diabetes, using larger cohorts than in our discovery study. We have also been developing a pharmacoepigenetic tool for clinical use.
To achieve this goal we have selected 960 DNA samples from blood from newly diagnosed individuals with diabetes, which have clinical follow up data regarding glycemia (HbA1c), BMI and medication (metformin). Based on the clinical data we could select responders and non-responders to metformin. DNA samples from these 960 people have been pipetted to the correct format for DNA methylation for analysis using Infinium EPICv2 chips from Illumina. Within proceed, we have also developed the bioinformatic pipeline to analyze the methylation data from the recently developed Infinium EPICv2 chips. Within this project, we have also applied for and received permits to analyze the blood samples and to receive and analyze all the clinical data needed for this project. We have performed a procurement process for the company to analyze the samples which is finished.

ii) Within PROCEED, we have finished the randomized clinical trial, SMARTEST, where patients with type 2 diabetes were randomized to treatment with either metformin or SGLT2-inhibitors, and blood samples and clinical data were collected at baseline and during follow-up of the study. All the blood samples for DNA methylation analyses and the clinical data for 500 participants within SMARTEST are available and are compared with the DNA methylation results in aim 1.

iii) To develop the diagnostic tool, we have set up the method to analyze our key DNA methylation data from the EPIVv2 arrays using pyrosequencing (Qiagen, available in our lab). Thereby making it possible to easily analyze the optimized biomarkers in a clinical setting.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The PROCEED study and its collected cohort are unique in its kind and constitute our largest effort in the field, so far. The results beyond state of the art and the overview of our results include finishing parts of the biomarker validation in independent DNA samples from newly diagnosed people with type 2 diabetes, and collecting all samples for the randomized clinical trial SMARTEST, as well as finishing setting up the analyses of pyrosequencing for the final diagnostic kit. Although we have done research into all of the parts described above, further work is needed regarding IP, access to the market, commercialization, and regulatory frameworks. This work will continue after PROCEED has finished, to get a final diagnostic tool to the clinic and the market.