Genetic variants linked to reduced efficacy of GLP-1 diabetes drugs

Research shows variants affecting the PAM enzyme may blunt the glucose-lowering effects of GLP-1 receptor agonists with implications for precision treatment in type 2 diabetes

More than a quarter of individuals with type 2 diabetes (T2DM) have received glucagon-like peptide-1 (GLP-1) receptor agonists, yet a substantial subset may derive reduced benefit due to an underlying genetic variation, according to a study led by researchers at Stanford Medicine, California, USA. The findings have identified a previously underexplored biological phenomenon termed GLP-1 resistance, in which circulating levels of the hormone remain elevated but fail to produce the expected physiological response.

The genetic variants – present in roughly 10 per cent of the general population – affect the function of peptidyl-glycine alpha-amidating monooxygenase, an enzyme central to the post-translational modification of peptide hormones. The study focused on glucose regulation and has drawn on evidence from human metabolic studies, mouse models and meta-analysis of clinical trial data.

“In some of the trials, we saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment,” said Dr. Anna Gloyn, professor of paediatrics and genetics and one of the senior authors. 

“At that point, a doctor would likely change the patient’s drug regimen. Knowing ahead of time who is likely to respond would help patients get on the right drugs faster – [in] a step toward precision medicine,” she said.

GLP-1 plays a central role in metabolic homeostasis, particularly in the postprandial state. It enhances insulin secretion, delays gastric emptying and suppresses appetite. Drugs such as semaglutide – marketed as Ozempic and Wegovy – exploit this pathway and have become widely prescribed both for glycaemic control and – at higher doses – for obesity management. However, the extent to which genetic variation modulates therapeutic response has remained uncertain.

To interrogate this question, the researchers examined two variants in the gene encoding peptidyl-glycine alpha-amidating monooxygenase. This enzyme catalyses amidation, a chemical modification that extends peptide half-life and enhances biological potency. Previous work has established that such variants impair insulin secretion, prompting investigation into their effect on GLP-1 signalling.

In controlled metabolic studies, adult participants without diabetes, stratified by variant status, consumed a glucose-rich solution, after which blood samples were collected at five-minute intervals for four hours. Contrary to the initial hypothesis, individuals carrying the variant exhibited higher circulating concentrations of GLP-1.

“What we actually saw was they had increased levels of GLP-1. This was the opposite of what we imagined we would find,” said Gloyn.

Despite this elevation, there was no corresponding improvement in glucose clearance. Instead, the data suggested a functional resistance, whereby greater hormone concentrations were required to achieve equivalent biological effects.

“Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity,” said Gloyn.

“They were not reducing their blood sugar levels more quickly. More GLP-1 was needed to have the same biological effect, meaning they were resistant to GLP-1,” she added.

The unexpected nature of these findings prompted extensive validation across experimental systems. In mouse models lacking the peptidyl-glycine alpha-amidating monooxygenase gene, researchers observed a parallel phenotype characterised by elevated GLP-1 levels alongside impaired glycaemic regulation. Notably, these mice also displayed accelerated gastric emptying, a process normally slowed by GLP-1 signalling. Administration of receptor agonists failed to restore this physiological response, reinforcing the concept of downstream resistance.

Further mechanistic work – in collaboration with researchers in Copenhagen – has demonstrated that the defect does not arise from impaired receptor binding or signalling at the receptor level. Instead, the resistance appears to emerge at a point further along the signalling cascade, although the precise mechanism remains unresolved.

To assess clinical relevance, the team conducted a meta-analysis of three trials comprising 1,119 participants with T2DM treated with GLP-1 receptor agonists. The analysis revealed a diminished therapeutic response among carriers of the variants. After six months of treatment, approximately 25% of non-carriers achieved recommended glycated haemoglobin targets, compared with 11.5% of individuals with the p.S539W variant and 18.5% with the p.D563G variant.

Importantly, the effect appeared specific to GLP-1-based therapies. Carriers of the variants responded comparably to other commonly prescribed antidiabetic agents, including metformin, sulfonylureas and dipeptidyl peptidase-4 inhibitors.

“What was really striking was that we saw no effect from whether you have a variant on your response to other types of diabetes medications,” said Gloyn. 

“We can see very clearly that this is specific to medications that are working through GLP-1 receptor pharmacology,” she said.

Additional clinical trial data, not included in the meta-analysis due to methodological differences, suggested that longer-acting GLP-1 receptor agonists may partially overcome this resistance, although further investigation will be required to confirm this effect.

The implications for obesity treatment remain uncertain. Limited data from two trials indicated no significant difference in weight loss between carriers and non-carriers, although the dataset was insufficient to draw firm conclusions. Given the widespread clinical adoption of these agents for weight management, further analysis of existing trial datasets may clarify whether genetic stratification can inform treatment selection.

“When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically,” said Dr. Mahesh Umapathysivam, an endocrinologist and co-lead author. 

“This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process,” he said.

The mechanistic basis of GLP-1 resistance remains an open question. Researchers have proposed that the phenomenon may involve complex, multifactorial processes analogous to insulin resistance which itself remains incompletely understood despite decades of study.

“That is the million-dollar question. We have ticked off this enormous list of all the ways in which we thought GLP-1 resistance might come about. No matter what we have done, we have not been able to nail precisely why they are resistant,” Gloyn concluded.

For further reading please visit: 10.1186/s13073-026-01630-0