Parma, April 10, 2026 - Imagine that different people take the same medicine, with the same diagnosis. For some that medicine works in its entirety, while for others it almost doesn't work. That's what happens with some GLP-1-based drugs, and the cause may be written in the DNA.
The GLP-1 drugs (the family that includes semaglutide, liraglutide, and exenatide) have become some of the most prescribed and discussed drugs in the world in just a few years, both for type 2 diabetes and for weight loss. But it has long been known that they are not equally effective in all people, and until now it was not known exactly why. An international group of male and female researchers, coordinated among others by University of Parma professor Elisa Araldi together with colleagues from the University of Oxford, ETH Zurich, University of Adelaide and Stanford, has found a surprising answer in a study just published in "Genome Pharmacy": a variant in a single gene, called PAM, can halve the effectiveness of these drugs.
"We think of the PAM gene as an internal post office in the body. Its job - explains Elisa Araldi, professor of Biochemistry at the University of Parma - is to "stamp" certain hormones before they can be delivered and work. Without that stamp, the hormone arrives at its destination but is not recognized. Those who have a defective variant of PAM have, in fact, a poorly functioning post office, and one of the hormones that suffers the most is GLP-1."
The PAM gene produces the only enzyme in the human body capable of performing a chemical process called amidation: a final modification that makes many hormones, including GLP-1, active. Without this modification, many hormones do not function properly.
The study found that two genetic variants in the PAM gene, called p.S539W (present in about 1 in 50 people) and p.D563G (in about 1 in 10), greatly reduce the activity of this enzyme.
These variants are small "oversights" in the DNA text, present from birth, that alter the functioning of the PAM enzyme. By themselves they do not cause disease, but they can affect how the body responds to certain drugs. They are inherited from the parents like any other genetic trait.
If a GLP-1 receptor agonist (GLP-1RA) drug, such as semaglutide or exenatide, is prescribed to a person who carries these variants, the person gets about half the benefit compared to someone who does not carry them, without knowing it. The therapy seems to work poorly, but it is not known why. The person may be unnecessarily switched from drug to drug, when the cause is instead genetic.
If confirmed by further studies, these findings pave the way for a simple genetic test to be done before prescribing a GLP-1RA. A person carrying the PAM variants could be directed to equally effective alternative drugs right away, avoiding months of insufficient therapy.
The study analyzed mainly patients of European origin. Results are less clear for newer, more potent drugs such as tirzepatide, which were not included in the meta-analysis. Further testing is needed on more diverse populations and on this new generation of drugs.
"Genetics may explain why the same drug works well for some people and almost not at all for others. About one in ten people with type 2 diabetes carries a variant in their DNA that halves the effectiveness of GLP-1RA drugs. If we had a test to identify them - concludes Prof. Araldi - we could choose the right therapy right away, saving time, money and health."
