A new international study has raised new questions about how effectively some patients respond to GLP-1 medications, with researchers finding that genetic variations may reduce the benefits of drugs such as Ozempic in around 1 in 10 people.
The research, jointly led by Adelaide University, the University of Oxford, ETH Zurich, and Stanford University, found that variants in the PAM gene could significantly reduce the glucose-lowering effects of GLP-1 receptor medications commonly prescribed for type 2 diabetes and weight management.
Published in the journal Genome Medicine, the study examined why 2 specific PAM gene variants increase the risk of type 2 diabetes and how they influence treatment response.
The study is said to build on previous studies, which have shown the PAMÂ gene increases the risk of type 2 diabetes by reducing the amount of insulin released from the pancreas and altering the structure of hormones, including the GLP-1 hormone which regulates blood sugar.
“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,” says lead author Dr Mahesh Umapathysivam from Adelaide University’s Centre of Research Excellence: Translating Nutritional Science to Good Health.
“However, not all patients respond well to these treatments.
“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.”
In this most recent study, researchers demonstrated that genetic variants in the PAM gene made the enzyme less effective, elevated natural GLP-1 levels, and blocked the hormone’s beneficial effects on blood sugar levels.
“This suggests that people with PAM variants had some resistance to GLP-1,” says Adelaide University in a recent statement.
The researchers then examined how this affected the body’s response to GLP-1 medications.
Adelaide University says, “In people with the PAM genetic variants, the glucose-lowering properties of the medications were reduced by up to 44% at 6 months of use.
“Only 11% of carriers of the more damaging PAM variant were able to achieve recommended glucose levels while on this type of medication, compared to approximately 25% of people who didn’t have the gene 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,” says 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.
“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.”
Adelaide University says the results highlight the “need for more personalised approaches to prescribing these widely used medications, which are also used for weight loss”.
