Gene variants may reduce response to Ozempic-style GLP-1 diabetes drugs

International research has found that variants in the PAM gene may reduce the glucose-lowering effect of glucagon-like peptide-1 receptor medicines, strengthening the case for personalised prescribing in type 2 diabetes

An international study has found that genetic variants present in about one in ten people may reduce the effectiveness of common glucagon-like peptide-1 (GLP-1) receptor medicines used to treat type 2 diabetes (T2DM).

The collaborative research, jointly led by Adelaide University in Australia, the University of Oxford in the UK, the Eidgenössische Technische Hochschule Zürich in Switzerland and Stanford University, USA, has suggested that variants in the PAM gene could prevent GLP-1 receptor medicines – including Ozempic – from working as effectively in some patients.

The findings highlight the need for more personalised approaches to prescribe medicines that have become central to the treatment of T2DM and obesity. GLP-1 receptor medicines help to regulate blood glucose by stimulating insulin release from the pancreas and can also affect appetite control. Many are given by injection and have become widely used in clinical care.

“In recent years there have been major improvements in the treatment of diabetes and obesity, driven by the widespread use of GLP-1-based medications … however, not all patients respond well to these treatments,” said lead author Dr Mahesh Umapathysivam, from Adelaide University’s Centre of Research Excellence.

“Understanding why and how to predict who will respond well or poorly will allow us to have the best chance to get the right medication to the right patient,” he said.

The study examined why two specific variants in the PAM gene increased the risk of T2DM. Previous research has shown that the PAM gene can influence diabetes risk by reducing insulin release from the pancreas and by altering the structure of hormones, including GLP-1 which helps to regulate blood glucose.

In the latest study, researchers used human and animal research to show that variants in the PAM gene made the associated enzyme less effective. The variants elevated natural GLP-1 levels but also appeared to block the hormone’s beneficial effects on blood glucose control. The results suggested that people with these variants had a degree of resistance to GLP-1.

The researchers then assessed how this altered the body’s response to GLP-1 receptor medicines. In people with PAM gene variants, the glucose-lowering effect of these medicines was reduced by as much as 44 per cent after six months of use. Only 11 per cent of carriers of the more damaging PAM variant achieved recommended glucose levels while they used this class of medicine, compared with about 25 per cent of people who did not have the variants.

“Our study is one of the first to provide in-depth, clinical evidence to show how people who carry specific gene variants are at greater risk of developing diabetes and also have a reduced response to GLP-1 receptor medication,” said Dr Umapathysivam.

“A likely development of this research is that, as other genetic variants that predict response to diabetes medication are found, we can combine this information to determine which diabetes medication will have the greatest chance of improving blood sugar levels and diabetes care for a patient,” he said.

T2DM remains a major cause of illness and death worldwide. Although several glucose-lowering medicines are available, many patients still do not meet recommended blood glucose targets. The study’s authors said this gap in care underlined the need to match patients more precisely with the medicines most likely to benefit them.

“T2DM is a leading cause of morbidity and mortality worldwide. Despite the availability of multiple glucose-lowering agents, only half of individuals with diabetes achieve the recommended blood glucose targets,” said Umapathysivam.

“This indicates that although there have been major improvements in treatments, we still need to improve the care we offer patients and there is potential to achieve this with more personalised approaches to prescribing these widely used medications,” he added.

Ongoing work related to the study has received funding support from Diabetes Australia. The researchers said the findings could help to guide future development of genetic testing panels intended to predict which diabetes medicines are most likely to work for individual patients.

“Our hope is that this research will serve as a blueprint for future studies looking at genetic variants, eventually leading to the development of a genetic testing panel to identify the best medication for the patient, maximising the chance of good diabetes care and minimising the risk of adverse outcomes,” Umapathysivam concluded.

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