For most patients with type 2 diabetes, the most common medication used is Metformin, which lowers glucose production in the liver and increases the body’s sensitivity to insulin.
However, should that medication be ineffective, a class of drugs called GLP-1 agonists are recommended in north America and Europe as a second or third-line of treatment. These agonists interact with the GLP-1 protein found in pancreatic beta cells, which then encourages them to produce more insulin.
GLP-1 agonist drugs have proven to be a popular ‘backup’ to Metformin because they also help patients lose weight while not damaging their heart. However, their efficacy varies dramatically from person to person. This is partly down to researchers not understanding exactly when it will interact well with the beta cells.
In a recent paper published in The Lancet Diabetes & Endocrinology, medical researchers at Sanofi and the University of Dundee were able to find which groups of people are most likely to benefit from GLP-1 agonist drugs based on their genetic phenotype. The research is part of the wider Innovative Medicines Initiative (IMI) DIRECT project, which analysed data from diabetic and pre-diabetic people to help find better drug treatments.
“Clinically we see very variable responses, with some people having amazing weight loss, some having great diabetes improvement, and some people having no benefit,” says Ewan Pearson, Professor of Diabetic Medicine at the University of Dundee and one of the authors of the paper. “They seemed ripe to investigate this treatment response heterogeneity – some of which we reasoned must be genetic.”
To conduct their study, they first gathered available clinical and genetic information of over 4 500 adults with type 2 diabetes who consented to their information being used for research. This information was gathered from the DIRECT project, three other diabetes studies, and two randomised clinical trials that acted as a control for their data.
They first evaluated which previously reported variations in the GLP-1 gene were likely to coincide with a poor response to GLP-1 agonist drugs (i.e. the drugs did not lower a person’s glucose levels). After finding variants that fit this result, they then surveyed the genomes of all the adults in their study to see if their data confirmed this correlation.
Their results showed that two genetic variations acting together in 4 % of their study population had a 30 % greater reduction in their glucose levels over three months when treated with GLP-1 agonists. Finding this correlation means that these drugs can be better tailored to those with the two genetic variations, where it is most effective.
Project lives on
Although the DIRECT project ended in 2019, Prof. Pearson says that the project led to many other papers to be written based on the research beyond its formal funding period. In fact, the project has motivated them to continue their research in this area. “We are particularly interested in the genetics of weight loss with these drugs, and whether we can find any genetic variants that alter the cardiovascular benefit,” he said.
Prof. Pearson says that data gathered during the project has led to tens of thousands of samples to be biobanked for later use, which they can then research for the next decade.
The project created a strong network of researchers who are enthusiastic about working together in the future. “We’ve had ongoing industry support to keep the consortium together and most critically to keep the database together,” says Prof. Pearson. “We’re just in the process of renewing our consortium legal agreement again as we feel strongly that there is still a huge amount that can be delivered from the data we collected during the project.”
DIRECT was supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.