Researchers from the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, investigating the effect of a Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans, have reported that increased markers are not a sign of pancreatitis, but that GLP‐1RAs is creating a new normal state, a so-called new steady state, in the patients.
The researchers believe the study, ‘No effects of a six‐week intervention with glucagon‐like peptide‐1 receptor analogue on pancreatic volume and edema in obese men without diabetes’, published in Diabetes, Obesity and Metabolism, will contribute to the safety of GLP-1-based medicines worldwide.
"The increased biomarkers should not be interpreted as a sign of disease. Our study shows that GLP-1 treatment makes the pancreatic cells 'work' a bit more than they usually do,” said Resident Medical Doctor and Assistant Professor Nicolai Albrechtsen from the Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Protein Research at the Faculty of Health and Medical Sciences and Rigshospitalet. “Instead of running around the soccer field once, they do it twice. And that in itself is not dangerous. It is something you also see in other contexts.”
Precisely because GLP-1-based treatment is a very frequently used treatment for diabetes and obesity, there has been international focus on detecting and understanding dangerous side effects and thereby also on the increased markers of pancreatitis.
Since 2012, in collaboration with Rigshospitalet and Hvidovre Hospital, the researchers have conducted cell and animal studies and now also a human trial, supporting that GLP-1-based treatment does not increase pancreatitis, but rather increases the activity of the cells.
"We have recruited 17 overweight people who are suitable for receiving the maximum dose of GLP-1. Simultaneously with the treatment, we have monitored their possible development of pancreatitis by means of a particularly advanced imaging technique undertaken by Professor Andreas Kjær from the Department of Biomedical Sciences and Rigshospitalet. The patients did not develop inflammation, but their level of pancreatic enzymes, the biomarker of pancreatitis, increased. At the same time, we could see that the cell activity rose to a new normal level," explained Albrechtsen.
In the study, the participants (age 38 ± 11 years, BMI32 ± 4) were examined by means of blood samples and positron emission tomography (PET) - magnetic resonance imaging (MRI) before, during and after treatment with GLP-1. The primary endpoint was pancreatic volume determined by magnetic resonance imaging (MRI). Secondary endpoints included pancreatic oedema and cellularity, PET based [18F] fluorothymidine (FLT)‐uptake (DNA synthesis) and plasma pancreatic enzymes. The PET-MR technology provides a special tracer that can show those cells in the body that are in a so-called active cell cycle. At the same time, inflammation in and around the cells can be seen.
The outcomes revealed that plasma amylase (+7 U/L [95% confidence intervals (CI) 3–11] p<0.01) and lipase (+19 U/L [7–30] p<0.01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm3 [−8–8] p=0.96]) and no change in pancreatic cellular infiltration was found (p=0.22). During titration of liraglutide, FLT‐uptake in pancreatic tissue increased numerically (+0.08 [0.00–0.17], p=0.0507).
The researchers summarised that six weeks treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes and is the first time that the potential mechanism between GLP-1-based treatment and increased level of pancreatic enzyme has been shown in humans.