GLP-1 receptor agonists linked to lower dementia risk in type 2 diabetes

GLP-1 receptor agonists, a class of drug used to treat type 2 diabetes, likely trump the widely prescribed metformin for curbing dementia risk in people with the condition, finds the largest study of its kind, published in the open access journal BMJ Open Diabetes Research & Care.

The findings suggest that future clinical guidelines for the treatment of type 2 diabetes would do well to consider prioritising drugs with both blood glucose and neuroprotective effects, say the researchers. 

Published research suggests that both GLP-1 receptor agonists and metformin, which are widely used to treat type 2 diabetes, protect the brains of people with the disease. But as yet there have been no direct real-world comparisons of the potential impact of these drugs on dementia risk-a risk that is around 70% higher in people with type 2 diabetes.

To explore this further, the researchers drew on anonymised electronic health records from a global health research network (Trinetx) spanning the period 2004 to 2024 to track the development of dementia in patients with type 2 diabetes, treated with either GLP-1 receptor agonists or metformin (87,229 patients in each group; average age 58) for at least 6 consecutive months. 

There was no significant difference in vascular dementia risk between the two types of drug, when used as first line therapy.

But GLP-1 receptor agonist use was associated with a significantly lower cumulative (10%) risk of developing dementia, overall, with an incidence of almost 2.5% (2130 people) compared with an incidence of nearly 5% (4215 people) for metformin. 

And specifically, taking this type of drug was associated with a 12% lower risk of developing Alzheimer's disease, and a 25% lower risk of developing non-vascular dementias than metformin use. 

Further in-depth analyses showed that these positive effects were evident across all age groups, but with the strongest effect among the over 60s, women, and those of White ethnicity. 

Risk of death from any cause was also lower: nearly 5% of those treated with GLP-1 receptor agonists died compared with nearly 9% of those treated with metformin.

"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.

But unlike metformin, whose benefits primarily derive from systemic metabolic effects, GLP-1 receptor agonists exert direct central nervous system effects by crossing the blood-brain barrier, they add.

"However, the multifactorial nature of [vascular dementia], driven by cerebrovascular damage, such as small vessel disease and white matter lesions, poses significant challenges for pharmacological interventions targeting metabolic or neurodegenerative pathways," they continue.

This is an observational study, and as such, no firm conclusions can be drawn about cause and effect. And the researchers point out that the tracking period, while sufficient for observing dementia outcomes, may not fully capture long-term cognitive effects, especially given the progressive nature of Alzheimer's disease.

But they nevertheless 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-1 [receptor agonists] as primary therapeutic agents may represent a paradigm shift in preventing the cognitive complications of diabetes."