A Gene Variant Linked to a Weaker Response to GLP-1 Drugs: What the PAM Study Found

What PAM does

Many hormones only work after a final chemical finishing step called amidation. One enzyme, made from the PAM gene, does that step for GLP-1, the gut hormone that drugs such as semaglutide and liraglutide copy. Two variants of PAM were already known to raise the risk of type 2 diabetes. This study, by groups in Oxford, Zurich, Dundee, Copenhagen and elsewhere, asked whether they also change how people respond to GLP-1.

What was measured

• The enzyme. In adults without diabetes, the rarer variant, p.S539W, cut the enzyme's activity in blood by 52%, and the commoner one, p.D563G, by 20%.
• The hormone. Carriers had more GLP-1 in their blood after a sugary drink, yet carriers of p.S539W got 18% less insulin-boosting effect for each unit of GLP-1. The authors call this GLP-1 resistance.
• Mice. Mice without the gene emptied their stomachs faster, and a GLP-1 drug did not slow them down as it does normal mice.
• The drugs. The team pooled three studies of 1,119 people with type 2 diabetes who started liraglutide, twice-daily exenatide or weekly exenatide, and compared HbA1c, the three-month blood-sugar average, before and after six months.

How big the effect was

Everyone's HbA1c fell. In people without either variant it fell by 1.24 points; in the 26 carriers of p.S539W, by 0.69, which the authors describe as a 44% loss of benefit. The target of an HbA1c below 7% was reached by 25.3% of non-carriers, 18.5% of p.D563G carriers and 11.5% of p.S539W carriers. For p.D563G, the difference was smaller and only borderline statistically. Neither variant changed the response to metformin, sulphonylureas or DPP-4 inhibitors.

What it does not mean

• Not about weight loss, so far. In the two studies that recorded weight, carriers did not lose significantly less, though the numbers were small.
• Not about the newest drugs. Semaglutide and tirzepatide were not studied. In two large drug-company trials of longer-acting weekly drugs, carriers did not respond significantly worse.
• Not a reason to stop. Carriers still improved, just by less on average. Most people carry neither variant, and the participants were mostly of European ancestry.
• No routine test yet. The authors argue PAM genotype could one day help choose a drug, but no guideline recommends testing for it.

Two of the authors list affiliations with Novo Nordisk, which makes semaglutide and liraglutide.

Related on Grey Peptides