Type 2 diabetes affects millions of people worldwide and now a new international study, jointly led by Adelaide University, University of Oxford, ETH Zurich, and Stanford University, has found one in ten people may not be benefiting from common medications used to treat the condition.
The collaborative study discovered genetic variations present in ten percent of the population could prevent GLP-1 receptor medications, such as Ozempic, from working effectively.
The results highlight the need for more personalized approaches to prescribing these widely used medications, which are also used for weight-loss.
“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,” said lead author Dr Mahesh Umapathysivam from Adelaide University’s Centre of Research Excellence: Translating Nutritional Science to Good Health.
“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 the journal Genome Medicine, were the result of multiple human and animal trials investigating why two specific gene variants in the PAM gene increased the risk of type two diabetes.
It builds on previous studies which have shown the PAM 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 this most recent study, researchers demonstrated that genetic variants of the PAM gene made the enzyme less effective, elevated natural GLP-1 levels while blocking the beneficial effects of the hormone on blood sugar levels. This suggests that people with PAM variants had some resistance to GLP-1.
Researchers then looked at how this affected the body’s response to GLP-1 medications. In people with the PAM genetic variants, the glucose lowering properties of the medications was reduced by up to 44 percent at six months of use.
Only 11 percent 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 percent 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."
Dr. Mahesh Umapathysivam, Study Lead Author, Centre of Research Excellence: Translating Nutritional Science to Good Health, Adelaide University
“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.”
GLP-1-based medications like Ozempic are often injectable therapies that manage blood sugar levels by encouraging the pancreas to produce more insulin and control appetite.
“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,” said Dr 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.”
Ongoing work into the study is being carried out with funding support from Diabetes Australia.
“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, maximizing the chance of good diabetes care and minimizing the risk of adverse outcomes,” said Dr Umapathysivam.
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