Could Weight Loss Drugs Be Repurposed as Dementia Treatments?
Studies add further evidence that diabetes drugs could help reduce dementia risk, but further trials are still needed.
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Blood glucose-lowering drugs, traditionally used in the management of Type 2 diabetes, have gained significant attention in recent months due to their additional cardiovascular, kidney and weight loss benefits.
Recent findings suggest that popular diabetes and weight-loss drugs may also lower the risk of developing Alzheimer's disease and related dementias. Two papers, published in JAMA Neurology, have added to this growing body of evidence.
While the findings suggest that these substances may have a neuroprotective effect in patients with Type 2 diabetes, experts warn that robust, randomized trial data are needed before any conclusions can be drawn.
Repurposing diabetes drugs for dementia
Drug repurposing – the strategy of finding new applications for existing drugs – presents an attractive approach to expedite the discovery of new treatments for dementia. Newer blood glucose-lowering drugs such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown potential beneficial effects in treating dementia. These drugs are already approved for the treatment of Type 2 diabetes and obesity, and their safety and tolerability profiles are well-established in these populations.
To provide more definitive evidence that these drugs may help mitigate Alzheimer’s disease and related dementia, researchers at the University of Florida conducted a target trial emulation study using electronic health record data from over 90,000 people with diabetes.
Patients included in the analysis were 50 years or older with Type 2 diabetes and no prior diagnosis of Alzheimer’s disease or antidementia treatment. The patients were split into three cohorts: GLP-1RA vs another glucose-lowering drug, SGLT2i vs another glucose-lowering drug and GLP-1RA vs SGLT2i.
The researchers found that GLP-1RA and SGLT2i use was associated with a 33% and 43% lower risk of Alzheimer’s disease, respectively, compared with other glucose-lowering drugs. However, when directly compared, there was no significant difference in risk between GLP-1RA and SGLT2i users.
These results highlight GLP-1RAs and SGLT2is as potential candidates for dementia prevention strategies. However, the researchers note that the findings should be taken with caution given the relatively short mean duration of follow-up (1.95-3.76 years), with the development of Alzheimer's disease and related dementias often taking several years.
In addition, being an observational study, it’s not possible to rule out the possibility that the differences found in dementia risk are caused by something other than the drugs being taken. “In other words, it may be that the type of person receiving these agents was different from the type of person prescribed other glucose-lowering therapies,” said Dr. Mark Evans, professor of diabetic medicine at the University of Cambridge. “As an example, one obvious potential confounder from their paper was that the groups receiving GLP 1 agonist or SGLT inhibitor therapy were younger than the comparison groups.”
GLP-1, but not SGLT2, linked to a significant reduction in dementia risk
A second study led by researchers from the University of Galway found that GLP1-RAs, but not SGLT2is, were associated with a statistically significant reduction in dementia or cognitive impairment.
A review and meta-analysis of 26 randomized clinical trials was performed comparing cardioprotective blood glucose-lowering therapy with controls that reported dementia or change in cognitive scores. Of the trials, 23 reported the incidence of dementia or cognitive impairment, including 12 trials evaluating SGLT2is, 10 evaluating GLP-1RAs and 1 evaluating pioglitazone.
While a significant reduction in dementia or cognitive impairment was not reported when all drug classes were considered, GP-1RAs were associated with a significantly lower risk of dementia or cognitive impairment when compared with controls. These findings suggest that GLP-1Ras may outperform SGLT-2is in clinical trial settings.
“Diabetes is a known risk factor for dementia, but whether glucose-lowering therapies can help prevent cognitive decline has remained unclear. Our findings suggest that GLP-1 receptor agonists, in particular, may have a protective effect on brain health,” Dr. Catriona Reddin, senior author and researcher at the University of Galway, said in a press release.
Again, this study isn’t without its limitations. Most clinical trials included in the analysis did not systematically evaluate participants for dementia. “Overall, the absolute rates of dementia reported in the studies contributing to their analysis were relatively low, which thus reduces the ability for this type of analysis to identify differences,” explained Evans.
Semaglutide’s effect on the brain
Although the underlying mechanisms of how GLP-1RAs affect the development of dementia remain a mystery, several mechanisms have been proposed.
Preclinical studies have suggested that the potential effects of GLP-1RAs in Alzheimer’s disease may include neuroinflammatory pathways, vascular and blood–brain barrier integrity, reduced synaptic loss and neuroprotection.
“There is optimism GLP-1RAs (and related medicines) may lower future dementia risk, however, given they favorably impact multiple diseases (cardiovascular, hypertension, kidney and diabetes) known to increase dementia risk, it might be that it is having a lower risk of stroke, heart disease and diabetes that actually then is linked to a lower risk of dementia,” said Dr. Naveed Sattar, professor of cardiometabolic medicine/honorary consultant at the University of Glasgow. “Hopefully, far more robust trial evidence – needed before any clinical implications are drawn – should be forthcoming in the near future.”
The next steps of this research will involve evaluating the neuroprotective effects of GLP1-RAs and SGLT2is in randomized clinical trials. In addition, both studies involved patients with Type 2 diabetes, so there is a need for studies in a broader patient population.
EVOKE and EVOKE Plus are two placebo-controlled Phase 3 trials that have been initiated to investigate the potential disease-modifying effect of oral semaglutide in participants with early-stage symptomatic Alzheimer's disease. Completion of the trials’ main phase is expected in September 2025 and the 52-week extension will continue to October 2026.
References
Tang H, Donahoo WT, DeKosky ST, et al. GLP-1RA and SGLT2i medications for Type 2 diabetes and Alzheimer disease and related dementias. JAMA Neurol. 2025. doi: 10.1001/jamaneurol.2025.0353
Seminer A, Mulihano A, O’Brien C, et al. Cardioprotective glucose-lowering agents and dementia risk: A systematic review and meta-analysis. JAMA Neurol. 2025. doi: 10.1001/jamaneurol.2025.0360
