Parma, april 10 2026 – Imagine several people taking the same medicine for the same condition. For some, the treatment works perfectly; for others, it barely works at all. This is what happens with certain GLP-1–based drugs, and the reason may be written in DNA.
GLP-1–based drugs (a class that includes semaglutide, liraglutide, and exenatide) have, in just a few years, become among the most prescribed and discussed medications worldwide, both for type 2 diabetes and for weight loss. However, it has long been known that they are not equally effective for everyone—until now, the reasons were unclear.
An international team of researchers, coordinated in part by Elisa Araldi of the University of Parma together with colleagues from the University of Oxford, ETH Zurich, the University of Adelaide, and Stanford University, has found a surprising answer in a study just published in Genome Medicine: a variant in a single gene, called PAM, can halve the effectiveness of these drugs.
“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 become active. Without that stamp, the hormone reaches its destination but is not recognized. Individuals with a defective PAM variant essentially have a malfunctioning post office, and one of the hormones most affected is GLP-1 itself.”
The PAM gene produces the only enzyme in the human body capable of carrying out a chemical process called amidation—a final modification that activates many hormones, including GLP-1. Without this modification, many hormones do not function properly.
The study found that two genetic variants in the PAM gene, known as p.S539W (present in about 1 in 50 people) and p.D563G (in about 1 in 10), significantly reduce the activity of this enzyme.
These variants are small “typos” in the DNA sequence, present from birth, that alter the function of the PAM enzyme. On their own, they do not cause disease, but they can influence how the body responds to certain medications. Like any other genetic trait, they are inherited from one’s parents.
If a GLP-1 receptor agonist (GLP-1RA), such as semaglutide or exenatide, is prescribed to someone carrying these variants, that person may experience only about half the benefit compared to non-carriers—without knowing why. The treatment may appear ineffective, leading patients to switch from one drug to another unnecessarily, when the underlying cause is genetic.
If confirmed by further studies, these findings could pave the way for a simple genetic test to be performed before prescribing a GLP-1RA. Individuals carrying PAM variants could be directed from the outset toward alternative treatments that are equally effective, avoiding months of suboptimal therapy.
The study primarily analyzed patients of European ancestry. The results are less clear for newer and more powerful drugs, such as tirzepatide, which were not included in the meta-analysis. Further research is needed in more diverse populations and on this new generation of therapies.
“Genetics can explain why the same drug works well for some people and hardly at all for others. About one in ten people with type 2 diabetes carries a DNA variant 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 from the start, saving time, money, and health.”
