Genetic Variants May Reduce Response to GLP-1 Drugs

More than a quarter of people with Type 2 diabetes take GLP-1 receptor agonists, but a new study suggests these drugs may work less well in people who carry certain genetic variants. The variants are present in about 10% of the general population and are linked to a phenomenon the researchers call GLP-1 resistance, where GLP-1 levels are higher but have less biological effect.

The study, published in Genome Medicine, focused on blood sugar regulation and combined human experiments, mouse studies and diabetes drug trial data. In some clinical trials, participants with the variants were less able to lower blood glucose after six months of treatment, according to senior author Anna Gloyn from Stanford Medicine. She said that knowing in advance who is likely to respond could help patients move more quickly to the right treatment and support more precise care.

The researchers centered their work on two variants that affect PAM, an enzyme that helps activate several hormones, including GLP-1. They first tested adults with and without the p.S539W variant by giving them a sugary drink and measuring blood samples over four hours. They expected to see lower GLP-1 levels in people with the variant, but instead found higher circulating GLP-1 with no corresponding increase in biological activity. In other words, more GLP-1 was required to achieve the same effect on blood sugar.

To confirm the finding, the team studied mice lacking the PAM gene. Those animals also showed elevated GLP-1 levels that did not improve blood sugar control. They had faster gastric emptying, and GLP-1 receptor agonist treatment did not slow that process. The mice also showed reduced response to GLP-1 in the pancreas and gut, but GLP-1 receptor expression in those tissues was unchanged. Additional work showed that the PAM defect did not affect GLP-1 receptor binding or signaling, suggesting the resistance occurs further downstream.

The team then examined clinical trial data from people with diabetes. In a meta-analysis of three trials with 1,119 participants, carriers of PAM variants responded less well to GLP-1 receptor agonists and were less likely to reach the recommended HbA1c target after six months. The variants did not affect responses to sulfonylureas, metformin or DPP-4 inhibitors, which suggests the effect is specific to GLP-1-based drugs. Two other trials using longer-acting GLP-1 receptor agonists showed similar responses between carriers and non-carriers, which may indicate those drugs help offset the resistance.

The mechanism is still unknown, and the researchers say more work is needed, including on possible effects on weight loss.