A large new study suggests that GLP-1 receptor agonists may offer more protection against dementia in patients with type 2 diabetes mellitus than metformin, the long-established first-line treatment.
The findings, published in BMJ Open Diabetes Research & Care, represent the first direct comparison between GLP-1s and metformin. The researchers analyzed electronic health record data from more than 98 healthcare organizations, covering nearly two decades of treatment patterns. They focused on adults with type 2 diabetes who had started either GLP-1 receptor agonists or metformin as their initial diabetes therapy.
Commenting on the study, 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.”
After applying matching methods to control for confounding factors, the study included over 174,000 patients, evenly divided between the two treatment groups. All patients had a minimum of two years of follow-up, and those with prior cognitive disorders or mixed treatment histories were excluded to strengthen the comparison.
The headline result was a modest but statistically significant reduction in the risk of developing dementia among those who began treatment with GLP-1 receptor agonists. These patients had a 10% lower risk of all-cause dementia compared to those on metformin, with particularly notable reductions in Alzheimer’s disease and other non-vascular dementias. No meaningful difference was observed for vascular dementia.
The researchers also found that the benefits of GLP-1 therapy were especially pronounced in older adults, women, and certain racial subgroups. Additionally, the study reported lower all-cause mortality among GLP-1 users, which, while encouraging, complicates interpretation of the dementia findings – patients who live longer may simply have more time to develop cognitive symptoms.
Mechanistically, GLP-1s are thought to cross the blood-brain barrier and act directly on the brain, potentially reducing neuroinflammation, improving insulin signaling, and altering amyloid and tau pathology. Metformin, by contrast, exerts its effects largely through systemic metabolic pathways.
“Both medications demonstrate neuroprotective properties, such as reducing neuroinflammation and oxidative stress, improving insulin sensitivity, and enhancing cerebrovascular health, which likely contribute to their benefits in overall dementia,” explain the researchers.
The authors stop short of calling for immediate changes to treatment guidelines, but argue that the findings should inform future clinical research and policy decisions. They conclude: “Given the severe societal, familial, and economic burden of diabetes-related dementia, these findings raise important considerations about the role of GLP-1 [receptor agonists] as first-line therapies in [type 2 diabetes] management.
While further long-term studies are warranted to validate these results, integrating GLP- as primary therapeutic agents may represent a paradigm shift in preventing the cognitive complications of diabetes.”
A number of other researchers have come forward to comment on the study.
Patrick Kehoe, Gestetner Professor of Translational Dementia Research and Director of the Elizabeth Blackwell Institute for Health Research at the UK’s University of Bristol, said: “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.”
Martin Whyte, an associate professor at the University of Surrey also added, “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.”
The full study is available here.
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