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An observational study published in BMJ Open Diabetes Research & Care looks at GLP-1 drugs vs metformin and the risk of dementia in people with type 2 diabetes.
Dr Richard Oakley, Associate Director of Research and Innovation, Alzheimer’s Society, said:
“Dementia is the UK’s biggest killer and one in three people born today will go onto to develop the condition. So, it’s exciting to see more research which shows how drugs currently being used for diabetes and weight loss – which are relatively cheap and easy to use – may also reduce the risk of dementia.
“This study found that GLP1RAs may significantly reduce some people’s risk of developing Alzheimer’s disease, and more so than those taking a second diabetes drug called metformin.
“However, they’re not a silver bullet in the fight against dementia and this study had several limitations that mean we mustn’t rush to conclusions about the effectiveness of these drugs – clinical trials will tell us more.
“These treatments didn’t reduce people’s risk of developing other types of dementia, such as vascular dementia, and there was a significant difference in risk reduction depending on patients’ ethnicity, with White patients much more likely to have a reduced risk than other racial groups.
“The study was retrospective, meaning we don’t know participants’ long-term outcomes and how many went on to develop dementia beyond the lifespan of the study. We need more dedicated research to understand whether these drugs could be used to tackle dementia while also finding therapies that benefit people from all backgrounds.
“We’re not at the finish line by any means, but we’re heading in the right direction.”
Dr Sheona Scales, Director of Research, Alzheimer’s Research UK, said:
“Research shows that nearly half (45 %) of dementia cases are linked to 14 risk factors, including type 2 diabetes. Recent studies suggest that some commonly prescribed diabetes medicines could help reduce the risk of dementia, but it’s still unclear which treatments are most effective. This new study adds to a growing body of evidence that GLP-1 medicines may play a role in lowering dementia risk.
“This is the first major study to compare the effect of two common diabetes treatments — GLP-1 medicines and metformin — on dementia risk, using health records from more than 174,000 people. The findings suggest that people with type 2 diabetes taking GLP-1 medicines had a lower risk of developing dementia than those taking metformin.
“Using real health records helps us understand how these medicines might work in everyday life — not just in clinical trials. And the findings suggest a lower dementia risk in those taking GLP-1 medicines, but the study cannot tell us how these medicines affect the underlying biology that causes dementia. People with type 2 diabetes often have other health conditions, like high blood pressure or high cholesterol, which are also linked to dementia — so it’s hard to untangle what role these factors might have had on dementia risk in this study.
“The two-year follow-up period may also be too short to tell what longer-term benefits these medicines may have on the brain. To build on the findings, we will need longer studies and clinical trials to look in detail at how different medicines may affect the brain and risk of developing dementia, in people with and without diabetes.
“Anyone who has concerns or questions about their diabetes medications, brain health or dementia risk should speak to their GP.”
Prof Patrick Kehoe, Gestetner Professor of Translational Dementia Research and Director of the Elizabeth Blackwell Institute for Health Research, University of Bristol, said:
“This retrospective observational study gives more credence to the growing narrative about Alzheimer’s disease, as opposed to Vascular dementias, having a strong insulin resistance component, which happens in ageing but is thought to be more pronounced in Alzheimer’s disease.
“But, as the authors acknowledge, it would need a formal trial to prove. There are some other considerations to note from this study. Most of the GLP-1 drugs studied in this group, of which there are several, remain largely under patent protection. This means they are more expensive and therefore not as widely available in some countries, such as those with public health care systems – compared to insurance-funded healthcare provision. So there is a possibility the favourable findings for this group of drugs may relate to the people who take them having some additional socioeconomic advantages, including diet, greater or more frequent access to exercise, and maybe higher or longer levels of education, that have also offered some other forms of protection.
“A properly designed blinded randomised clinical trial could help address and counter these potential sources of bias, allowing a better head-to-head comparison. Such a trial would also enable the monitoring of drug side effects, which is also important. However, such robust research would be prohibitively costly and time-consuming, particularly when some of the GLP-1 drugs are already off patent or soon to be, making them less attractive to investigate in the commercial sector, and so it would fall to ever-tightening publicly-funded schemes, such as UKRI or Research Charities in the UK to fund them.
“It may be the case that over time, as more GLP-1 drugs fall off patent and become available in cheaper forms, doctors will prescribe more of them because they have more choice and additional evidence might have become available. They are fortunate to have several choices to treat the diabetes which would be the more immediate concern. Further evidence of benefit may emerge in a way similar to what seems to have happened when there was a huge and successful effort to improve the detection and treatment of high blood pressure, in other words hypertension, and so with the increased levels of prescribing those drugs it possibly provided some protection as well as some slowing. Accordingly, reduced rates of dementia were observed, as reported in a similar observational study reported in 2016.
“In the absence of clear findings in relation to these drugs, people still have some choices. Continued efforts to maintain a healthy diet and lifestyle, as well as body weight, will help not only to lessen the effects of diabetes but also improve cardiovascular health, all of which can do no harm to quality of life – and may offer additional protection against dementia.”
Dr Martin Whyte, Associate Professor in Metabolic Medicine, University of Surrey, said:
“Type 2 diabetes (T2D) is known to increase the risk of cognitive impairment and dementia. Two of the most commonly prescribed medications for T2D are metformin and GLP-1 receptor agonists (GLP-1 drugs), which are primarily used to control blood sugar. However, GLP-1 drugs are known to have additional effects beyond glucose lowering, including actions on inflammation and the central nervous system.
“There has been growing interest in whether GLP-1 drugs might help reduce the risk of dementia. The REWIND trial, which tested dulaglutide (a GLP-1 drug) versus placebo in people with T2D, reported a 14% reduction in the risk of significant cognitive decline, although it was not specifically designed to assess dementia risk.
“In a new observational study by Sun and colleagues, based on routinely collected healthcare data, GLP-1 use was associated with a 10% lower risk of developing dementia (of all types) compared to metformin use. Since GLP-1 receptors are present throughout the brain, it is possible that the effect is direct; or it may be indirect—for example, via reductions in systemic inflammation or metabolic risk factors.
“However, this was an observational study, which means it is subject to bias and confounding. Notably, the authors did not provide detailed information about the characteristics of patients in each group, either before or after statistical matching, and treatment duration for either GLP-1 drugs or metformin was not reported. These limitations make it difficult to draw firm conclusions, but the findings add to the growing interest in the potential cognitive benefits of GLP-1 drugs. A number of prospective randomised controlled trials are ongoing, to examine whether GLP-1 drugs can reduce the risk of dementia.”
Dr Craig Beall, Senior Lecturer, University of Exeter, said:
“It is important to note that people with diabetes have a 60% increased risk of dementia. Earlier separate studies using health records have shown that both metformin and GLP-1RAs are associated with reduced dementia risk. This study puts the two drugs head-to-head and shows that GLP-1RAs seem to be associated with a superior risk reduction for dementia.”
“However, whether these drugs only reduce the diabetes related dementia risk is not yet clear. Whether people without diabetes could benefit is still unknown. What we need to determine this are randomised control trials and there are three large randomised control trials currently running. In these trials people without diabetes but with mild cognitive impairment, are given metformin or GLP-1RAs, and metformin in Alzheimer’s disease trial and EVOKE and EVOKE+ trials. Results are not expected until 2026. These studies will give the best evidence of whether these two drugs can slow progression or prevent full blown dementia from becoming established.”
Prof Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, Group Leader in the UK Dementia Research Institute, and Past President of the British Neuroscience Association said:
“This study adds to a series of recent papers indicating GLP-1 receptor agonists likely protect people with diabetes from developing dementia. Lin and colleagues looked at medical records from over 170,000 people with diabetes, half of whom were treated with GLP-1 receptor agonists and half treated with metformin, and the GLP-1 receptor agonist treatment was associated with 10% lower risk of dementia than metformin over a four year follow up time. As the authors point out, this type of study cannot prove that the GLP-1 receptor agonist treatment directly lowered dementia risk. The study also has limitations of relatively short follow up time of 4 years and the types of dementia diagnosed rely on physician diagnosis and were not confirmed with brain scans or other biomarkers, meaning the data on which types of dementia were prevented are not very robust. Overall, this study and many others coming out recently indicate GLP-1 receptor agonists likely lower dementia risk in people with diabetes. Further work is needed including randomised clinical trials to confirm these drugs are protective in people with type 2 diabetes and whether these drugs will be protective in people who do not have type 2 diabetes.”
‘Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes’ by Mingyang Sun et al. was published in BMJ Open Diabetes Research & Care at 23:30 UK time on Tuesday 22nd July.
DOI: doi:10.1136/ bmjdrc-2025-004902
Declared interests
Prof Patrick Kehoe: No interests to declare.
Dr Martin Whyte: “I am a site PI at King’s College Hospital for the FOCUS study which is examining the effect of semaglutide on retinopathy. I am not a grant holder for this.”
Dr Craig Beall: CB has previously collaborated with Rigel Pharmacuticals Inc. (CA, USA) on a JDRF/Breakthrough T1D-funded research project.
CB is currently studying the effects of both drug types brain cells, in the context of diabetes.
Prof Tara Spires-Jones: I have no conflicts with this study but have received payments for consulting, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, and Eisai. I am also Charity trustee for the British Neuroscience Association and the Guarantors of Brain and serve as scientific advisor to several charities and non-profit institutions.
Dr Richard Oakley: None
Dr Sheona Scales: None