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new international study has found that a proportion of people with type 2 diabetes may not respond as well to widely used GLP-1 receptor medications, including treatments such as Ozempic, due to genetic differences.
The research, led jointly by the University of Adelaide, University of Oxford, ETH Zurich and Stanford University, suggests that around one in ten people carry genetic variants that can reduce the effectiveness of these medicines, which are commonly prescribed for both blood sugar control and weight management.
The study focused on variations in the PAM gene and found that these changes can interfere with how the body responds to GLP-1 hormones. These hormones play a key role in regulating blood sugar by stimulating insulin release from the pancreas.
Researchers discovered that people with certain PAM gene variants had a reduced response to GLP-1-based medications, with glucose-lowering effects cut by up to 44 per cent after six months of treatment. Only 11 per cent of carriers of a more impactful variant reached recommended blood glucose targets, compared with about 25 per cent of those without the variants.
Lead author Dr Mahesh Umapathysivam from the University of Adelaide said the findings highlight clear differences in how patients respond to the same treatment.
“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, like Ozempic. However, not all patients respond well to these treatments”
“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, like Ozempic. However, not all patients respond well to these treatments,” he said.
“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.”
The findings, published in Genome Medicine, build on earlier research linking the PAM gene to an increased risk of type 2 diabetes. That earlier work showed the gene can affect insulin release and alter hormone structure, including GLP-1 activity.
In the latest study, researchers found that the PAM variants made an enzyme less effective, which led to higher natural GLP-1 levels but also reduced the hormone’s ability to regulate blood sugar effectively. This created what researchers described as a form of resistance to GLP-1 activity.
GLP-1 receptor medications work by helping the pancreas produce more insulin and by reducing appetite, and have become widely used in recent years for both diabetes management and weight loss support.
Dr Umapathysivam said that despite advances in treatment options, many people still struggle to reach recommended blood glucose levels.
“Type 2 diabetes 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,” he said.
“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.”
The research team, supported by Diabetes Australia, is now exploring how additional genetic markers could be combined to better predict how individuals respond to different diabetes treatments.
Dr Umapathysivam said future work could support the development of genetic testing tools to guide prescribing decisions.
“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,” he said.
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