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Proposal 1843

Title of the Proposed Research

The genetics of glycaemic response to GLP-1 receptor agonists in Type 2 diabetes

Lead Researcher

Ewan Pearson

Affiliation

University of Dundee
Dundee
DD1 9SY

Funding Source

EU FP7 Innovative medicines Initiative. IMI-DIRECT (http://www.direct-diabetes.org)

Potential Conflicts of Interest

Summary for all Researchers and Statistician
Honoraria from Lily, Novo Nordisk, Sanofi, AZ, BI. Paid industry consultancy with AstraZeneca, Grifols, Takeda, Sanofi and Roche.

Data Sharing Agreement Date

16 August 2017

Lay Summary

Approximately 387 million people between the ages of 20 and 79 live with diabetes worldwide, increasing to 642 million by 2040. Following initial lifestyle changes, there is a progressive need to add additional treatment to maintain the blood sugar as close to normal as possible. This usually involves initial treatment with tablets before moving on to injectable treatments such as insulin or a class of drugs called ‘GLP-1 Receptor agonists’ or GLP-1RA.

Clinically, glycaemic response to GLP-1RAs is highly variable with some patients benefitting from marked response (assessed by HbA1c reduction and/or weight reduction) while others have disappointing lack of benefit. This is highlighted in the UK ABCD audit of exenatide and liraglutide, where nearly 30% of patients had weight loss (suggesting they were using the drug) but no HbA1c reduction with GLP-1RA treatment. The mechanism for this variability in response is poorly understood. There is a need to understand this variation to better target this effective treatment to the right patients.

How the research will add to medical science or improve patient care?

By understanding the mechanisms underlying this variation we will gain insight into the biological mechanism of action of GLP-1RAs or in biological differences in people’s diabetes. Importantly, we will also potentially be able to identify subpopulations who, due to their genetics, are likely to respond well to GLP1-RA and thus should potentially be given these treatments early, or who will respond badly and who therefore should not be given these treatments as the harm is likely to outweigh the risks.

Given the high, and increasing, prevalence of T2DM and increasing use of expensive treatments such as GLP-1RAs if we can find a way to better target these treatments to those who will benefit the most, this will have major impact to patients, to payers and to society.

The aims and objectives of the research?

The overarching aim of this project is to identify clinical and genetic determinants of variation in therapeutic response to GLP-1RAs. Our objectives are:

1. To replicate an initial finding on genetic variants in the GLP-1 receptor
2. To undertake a combined analysis between our existing cohorts and the GSK trial data across all captured variants in the genome (Genome wide association study)
3. To undertake a gene-based rare variant analysis in relation to GLP-1RA response.

How will the research be conducted?

We will use the available clinical trial data on treatment with Albiglutide (GLP-1RA) to define response based upon the HbA1c reduction and weight at 6 months after initiation of treatment. We will explore how clinical parameters impact on this response (e.g. weight, age, sex) and then investigate how an individual’s genetics impacts on this treatment response.

Interpretation and communication to patients/public

Results will be published and communicated to patients via patient organisations.

Study Data Provided

GSK-GLP114179: A Randomized, Open-Label, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide as Compared With Liraglutide in Subjects With Type 2 Diabetes Mellitus
GSK-GLP114130: A Randomized, Double-Blind, Active-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide as Compared With Sitagliptin in Subjects With Type 2 Diabetes Mellitus With Renal Impairment
GSK-GLP112753: A Randomized, Double-Blind, Placebo and Active-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide When Used in Combination With Metformin Compared With Metformin Plus Sitagliptin, Metformin Plus Glimepiride, and Metformin Plus Placebo in Subjects With Type 2 Diabetes Mellitus
GSK-GLP112754: A randomized, open-label, parallel-group, multicenter study to determine the efficacy and long-term safety of albiglutide compared with insulin in subjects with type 2 diabetes mellitus.
GSK-GLP112757: A Randomized, Double-blind, Placebo and Active-Controlled, Parallel-group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide Administered in Combination With Metformin and Glimepiride Compared With Metformin Plus Glimepiride and Placebo and with Metformin plus Glimepiride and Pioglitazone in Subjects With Type 2 Diabetes Mellitus
GSK-GLP112755: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide When Used in Combination With Pioglitazone With or Without Metformin in Subjects with Type 2 Diabetes Mellitus
GSK-GLP112756: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Two Dose Levels of Albiglutide Compared With Placebo in Subjects With Type 2 Diabetes Mellitus

Statistical Analysis Plan

Publication Citation

The publication citation will be added after the research is published.

Summary Results

Results summary or link will be posted when available.