Many people do not respond well to metformin treatment for type 2 diabetes. New research shows that epigenetic tests can predict who will not benefit from metformin treatment and those who will experience too many side effects.
Metformin is the first-line choice of doctors for managing type 2 diabetes. It has been well tested for 60 years, and millions of people throughout the world take it daily. Nevertheless, about 30% of people with type 2 diabetes do not benefit from metformin treatment, and up to 20–30% experience intolerable side effects. Doctors cannot predict how people will react.
New research shows that a blood test can probably predict who will and will not benefit from metformin and who will develop side effects.
“Up to one third of the people treated with metformin do not get optimal benefits, and the side effects can be quite severe for those who get them. We therefore need to be able to use biomarkers to determine how each individual will respond to the drug. This may save many people from inappropriate treatment,” explains Allan Vaag, a researcher behind the study who is a Chief Physician and Research Manager at Steno Diabetes Center Copenhagen.
The research, which was led by Charlotte Ling, Professor, Department of Clinical Sciences, Lund University, Sweden, has been published in Science Translational Medicine.
Investigated 850,000 sites in DNA
The researchers investigated whether the epigenetic expression in a blood sample can identify who will and will not benefit from metformin treatment.
Allan Vaag explains that many researchers have doubted whether testing for epigenetic markers in blood makes sense at all, since diabetes mainly develops in other tissues, including the pancreas, liver and fat tissue.
Nevertheless, this is exactly what the researchers did.
They used an epigenetic test to analyse DNA methylations in 850,000 sites on the genome.
Methylation is an epigenetic change in the genome in which a methyl group is added to a DNA molecule and makes it either easier or harder for a specific gene to express.
“Methylations generally inhibit the expression of genes, so the more methylated a gene is, the less functional it is,” says Allan Vaag.
Eleven sites on the genome associated with poor response to metformin and four with side effects
The researchers applied the epigenetic test to blood samples from 363 people with type 2 diabetes being treated with metformin. They then investigated how the participants reacted to the treatment to determine whether they could identify patterns in the methylation associated with better or worse treatment outcomes.
The results showed that the degree of methylation at 11 sites on the genome was associated with whether metformin treatment was effective. The more these 11 sites were methylated, the worse the participants responded to the treatment.
In addition, the researchers found that four sites on the genome were associated with an increased risk of experiencing side effects from metformin treatment.
The researchers first identified these 11 and four sites in a cohort of people with type 2 diabetes in Sweden and subsequently verified them in a cohort in Latvia.
“Validating these findings required a lot of work, but this was necessary because we had a hard time believing that we got such conclusive results,” says Allan Vaag.
Identifying the effects of methylated genes
After the researchers had identified the sites on the genome that are associated with the effectiveness of metformin, they closely studied the genes in experiments with liver tissue.
The purpose was to validate that they could replicate the effects they found in the blood in the relevant tissues associated with type 2 diabetes.
In the liver tissue, the researchers silenced the genes found and then investigated how this affected the way that the liver cells metabolize metformin.
They found that one gene produces a transporter protein that transports metformin out of the cell.
According to Allan Vaag, if metformin accumulates within the cells, this may alter the risk of developing side effects.
The researchers found similar effects when some other genes were silenced.
“When we silence some of these genes, it directly alters the liver’s metabolism of proteins that are associated with the effectiveness of metformin,” explains Allan Vaag.
More epigenetic biomarkers for people with type 2 diabetes?
Allan Vaag says that the study has several perspectives.
First, the researchers showed that they can identify epigenetic biomarkers associated with the effectiveness of an anti-diabetes drug in the blood of people with type 2 diabetes.
This is revolutionary, because it means that doctors in the future can look for more such biomarkers that can be used to identify how effective many diabetes drugs are on individuals.
“Is it still justified to doubt the potential of using blood to determine the degree of methylation in fat tissue or in the liver? We clearly showed that epigenetic analysis of a blood sample can provide information about other tissues,” says Allan Vaag.
People with type 2 diabetes can avoid months of ineffective treatment
Second, the study suggests how to determine whether people with type 2 diabetes will respond to metformin treatment.
If doctors can screen for the degree of methylation of these respective 11 and four epigenetic sites on the genome, they can predict how an individual will respond to treatment.
If the person is predicted to not benefit or to have side effects, the doctor may not prescribe metformin and instead prescribe another drug, such as an SGLT2 inhibitor.
“This is almost too good to be true, and if we can further validate the data, this will avoid having many people start treatment that either does not benefit them or that causes many side effects. We can spare them from several months of ineffective treatment by immediately giving them another type of medication if metformin does not suit them,” says Allan Vaag.
“Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes” has been published in Science Translational Medicine. The Novo Nordisk Foundation co-sponsored the research and has awarded grants to Steno Diabetes Center Copenhagen, where Allan Vaag is employed.