Metformin is the first-line drug that can lower blood sugar levels in type 2 diabetes patients. One third of patients do not respond to metformin treatment and 5 per cent experience serious side effects, which is the reason many choose to stop medicating. Researchers have now identified biomarkers that can show in advance how the patient will respond to metformin treatment via a simple blood test.
According to the researchers, the study led by Lund University with the University of Eastern Finland as one of the collaborators, constitutes an important step towards the goal of personalised care for diabetes patients because it can contribute to ensuring that the right person receives the right care as soon as there is a diagnosis.
When diet and exercise are not enough to regulate blood sugar, metformin is the first drug introduced to treat type 2 diabetes, according to international guidelines. If it does not have the intended effect in the form of lowered blood sugar levels, or if the patient experiences serious side effects, patients then go on to trial other drugs.
“If it takes a long time for the patient to receive the correct treatment, there is a risk of complications due to the elevated blood sugar levels. Approximately 30 per cent of all patients with type 2 diabetes do not respond to metformin and should be given another drug right from the start. For this reason, it is important to be able to identify these patients upon diagnosis”, the researchers point out.
One third of patients experience side effects usually in the form of gastrointestinal difficulties such as nausea, stomach pain and diarrhoea. Five per cent stop taking the medicine due to severe side effects.
Although previous studies have identified some genetic variations that have been associated with tolerance and response to metformin, they have been unable to predict how well the patient will respond to treatment.
The present study is the first pharmacoepigenetic study in diabetes. In other words, the researchers studied how epigenetic factors, such as DNA methylation (see fact box), can be used as biomarkers to predict the effect of a drug. To a certain extent, pharmacoepigenetics has been used within cancer care to predict how a person will respond to a treatment, however, it has never been done in diabetes care before.
The researchers looked at epigenetic modifications, so-called DNA methylations, in blood from individuals diagnosed with diabetes before they started taking metformin. In a follow-up a year later, the researchers could see which patients had benefited from the treatment - with resulting lowered blood sugar levels - and whether or not they had suffered from side effects.
By compiling the responses, they found biomarkers that can identify already at diagnosis of diabetes which patients will benefit from and tolerate metformin, which will advance personalised therapy in type 2 diabetes.
The study was conducted on 363 participants from three different patient cohorts (All New Diabetics in Skåne, All New Diabetics in Uppsala and Optimed from Latvia). As a next step, the researchers are planning for a new clinical study in which they will repeatthe study with a larger patient group – 1000 patients will be invited to participate from all around the world.
Facts about epigenetics
Our genetic material, or DNA, containing genes, is found in the body’s cells. We inherit these genes and they cannot be changed. On the genes are the so-called methyl groups that regulate the gene expression, whether it is on or off. The methyl groups can be affected in different ways, by exercise, diet and lifestyle in a process called DNA methylation. By measuring DNA methylation in a specific cell type, it is possible to obtain an epigenetic pattern that can be used to study how we are affected by different environmental factors.
Jussi Pihlajamäki, professor of clinical nutrition at the University of Eastern Finland
jussi.pihlajamaki (a) uef.fi, +358 50 344 0187
Charlotte Ling, professor of epigenetics at the Lund University Diabetes Centre
charlotte.ling (a) med.lu.se, telephone: +46 706-145146
Sonia García Calzón, associate professor at University of Navarra, Spain
sgcalzon (a) unav.es, telephone: +46 722677424 / +34 650588674
The article was published in Science Translational Medicine.
Sonia García-Calzón, Alexander Perfilyev, Mats Martinell, Monta Ustinova, Sebastian Kalamajski, Paul W Franks, Karl Bacos, Ilze Elbere, Jussi Pihlajamäki, Petr Volkov, Allan Vaag, Leif Groop, Marlena Maziarz, Janis Klovins, Emma Ahlqvist and Charlotte Ling. Epigenetic markers associated with metformin response and intolerance in drug-naïve type 2 diabetes patients. Sci. Transl. Med.12, eaaz1803 (2020).
The study was financed with support from the Novo Nordisk Foundation, the Swedish Research Council, Region Skåne (ALF), H2020-Marie Skłodowska-Curie grant agreement no. 706081(EpiHope), ERC Consolidator Grant, the Swedish Heart-Lung Foundation, EFSD, EXODIAB, the Swedish Foundation for Strategic Research, the Swedish Diabetes Foundation and the Albert Påhlsson Foundation.