Meta-analysis favours glucose-lowering with GLP-1RA for dementia risk

In the management of diabetes, users of glucagon-like peptide-1 receptor agonists (GLP-1RAs) appear to have a lower risk of all-cause dementia compared with users of other glucose-lowering medications, according to a systematic review and meta-analysis.

Pooled data from 23 trials that involved 160,191 participants showed that GLP-1RAs were associated with significantly reduced likelihood of all-cause dementia or cognitive impairment compared with control (eg, placebo, usual care, or no glucose-lowering therapy) (odds ratio [OR], 0.55, 95 percent confidence interval [CI], 0.35–0.86). [JAMA Neurol 2025;doi:10.1001/jamaneurol.2025.0360]

The neuroprotective benefit was not observed with sodium-glucose cotransporter-2 inhibitors (SGLT2is) (OR, 1.20, 95 percent CI, 0.67–2.17) or with the use of cardioprotective glucose-lowering therapy overall (OR, 0.83, 95 percent CI, 0.60–1.14).

Focusing on the subtypes of dementia, glucose-lowering therapy exerted no significant effect on vascular, Alzheimer's, or Lewy body dementia. This was consistent across drug classes.

Furthermore, in the three trials that reported on change in cognitive score, exenatide and pioglitazone vs placebo were not associated with improvements in cognitive score as measured using the Scales for Outcomes in Parkinson’s Disease Cognition, Mattis Dementia Rating Scale, over Modified Mini-Mental State Examination over a follow-up period ranging from 10.1 to 57.6 months.

Twenty-six studies met the eligibility criteria, but only 23 of these reported on the incidence of a composite of dementia or cognitive impairment on follow-up and were included in the primary meta-analysis. Three studies were included for the secondary outcome of change in cognitive score only.

A total of 164,531 participants were included from 26 trials. The mean age of the participants was 64.4 years, and 34.9 percent were women. The mean duration of follow-up was 31.4 months, with publication years ranging from 2015 to 2024. Almost all of the trials were conducted at international sites, and only two were conducted in North America. The overall risk of bias was categorized as low across all trials.

Neuroprotective potential

In a linked commentary, Dr Diana Thiara from the University of California San Francisco in San Francisco, California, US, noted that while GLP-1RAs such as semaglutide are well-established for their glycaemic control, weight loss, and cardioprotective benefits, their neuroprotective effects are increasingly being understood. [JAMA Neurol 2025;doi:10.1001/jamaneurol.2025.0237]

GLP-1RAs not only mitigate cardiometabolic risks that contribute to cognitive decline but also possess other neuroprotective mechanisms of action, Thiara noted. In preclinical studies, this class of glucose-lowering medications has been shown to increase synaptic plasticity as well as reduce tau phosphorylation and amyloid-β accumulation, which can be promising against Alzheimer’s and Parkinson’s disease. [Front Neurosci 2022;16:970925; https://aaic.alz.org/releases-2024/glp-drug-liraglutide-may-protect-against-dementia.asp; N Engl J Med 2024;390:1176-1185]

The current meta-analysis provided evidence that treatment with GLP-1RAs may result in significant reduction in all-cause dementia and cognitive impairment, whereas SGLT2is did not. However, Thiara pointed out that limitations such as the short follow-up durations, low event rates, and potential for confounding across the included studies may have underestimated the long-term effects of GLP-1RAs on dementia prevention.

“We must remember that we are only at the precipice of using GLP-1RAs. As we continue to explore combinations with other incretins and nutrient-stimulating hormones, we are achieving greater levels of weight loss and haemoglobin A1c reduction with innovative drugs [such as the novel GLP-1/glucose-dependent insulinotropic polypeptide receptor (GIP) dual agonist tirzepatide],” Thiara said.

“It is possible that these new drugs, with enhanced mechanisms of action like dual or triple agonism, could have even more potent neuroprotective effects. By targeting multiple pathways simultaneously, these next-generation drugs may further enhance brain health, improve vascular integrity, and potentially provide stronger protection against conditions like cognitive impairment, vascular dementia, and Alzheimer’s disease and related dementias. However, their neuroprotective effects will need to be validated through rigorous clinical trials,” she added.