Incretin-Based Drugs May Reduce Risk of Dementia in Patients With Type 2 Diabetes

Results from a population-based study published by investigators in Drug Safety demonstrate that dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) could reduce the risk of dementia compared with sulfonylureas in patients with type 2 diabetes (T2D). The data highlight the possible neuroprotective effects of incretin-based therapies, which are often prescribed for blood glucose control in patients with T2D.^1,2

Neuroprotective Effects With Incretin-Based Therapies

Patient data were gathered from the United Kingdom’s Clinical Practice Research Datalink. Two cohorts of patients aged at least 50 years with T2D who initiated either incretin-based drugs or sulfonylureas between 2007 and 2021, respectively, were created. A total of 275,144 patients who began DPP-4 inhibitors or sulfonylureas were followed for 740,846 person-years.¹

The investigators found that DPP-4 inhibitors were linked to a reduced risk of dementia compared with sulfonylureas (4.4 versus 5.7 events per 1000 person–years; hazard ratio [HR], 0.77; 95% CI, 0.71–0.85). Notably, the longer that individuals used DPP-4 inhibitors and the higher the dose, the stronger the association with dementia reduction became. Similar observations were made across dementia subtypes and individual DPP-4 inhibitors, according to the study authors.^1,2

For the 181,215 initiators of GLP-1 RAs or sulfonylureas, who were followed for 530,415 person-years, GLP-1 RAs were associated with a similar reduction in dementia risk compared with sulfonylureas (2.3 versus 3.1 events per 1000 person-years; HR, 0.74; 95% CI, 0.46–1.18). Although the magnitude of the association was significant and increased with cumulative duration of use and dose, there was high uncertainty in these results, due in part to the smaller proportion of patients using GLP-1 RAs compared with DPP-4 inhibitors or sulfonylureas.^1,2

Filling Gaps Present in Research

“These are very promising results,” Christel Renoux, MD, PhD, an associate professor at McGill University’s Department of Neurology and Neurosurgery and senior investigator at the Lady Davis Institute for Medical Research, said in a news release accompanying the results. “By measuring factors that were unaccounted for in earlier studies, our results provide more reliable evidence of the potential cognitive benefits.”²

These newly included factors were pivotal in yielding the insightful results observed in the trial. In past studies, detailed information on patient health—such as their diabetes severity, which alone is a significant indicator of dementia—has been excluded from analysis. Despite earlier studies demonstrating the cognitive potential of incretin-based therapies, the present analysis enabled control of biases and other factors, yielding a more reliable comparison.^1,2

Renoux notes that longer-term studies are necessary to confirm these results, especially in patients who are now using GLP-1 drugs for weight loss. Randomized controlled trials can also expand the knowledge base of potential neuroprotective effects of incretin-based therapies, allowing for more direct comparisons than in observational studies. But Renoux is optimistic that these kinds of drugs “may have benefits far beyond blood sugar control that we are only beginning to understand.”^1,2

What Are DPP-4 Inhibitors?

DPP-4 is a widely expressed serine peptidase. DPP-4 inhibitors are designed to limit the elevation of GLP-1 and gastric inhibitory peptide (GIP) RAs, but do so to a lesser extent than pharmacological supplementation using GLP-1 analogues. These medicines suppress glucagon secretion, which is produced by the pancreas and raises blood sugar. DPP-4 inhibitors are often most effective when used with other diabetes medications such as metformin or insulin injections.^3,4

“While there has been enormous attention on GLP-1 drugs, these findings suggest DPP-4 inhibitors also deserve a closer look,” Renoux continued.²

Pharmacists play a pivotal role in counseling patients on incretin-based therapies, such as DPP-4 inhibitors or GLP-1 RAs, about the possibility of neuroprotective cognitive effects with extended use. However, patients should be aware that studies in this context remain ongoing.

REFERENCES

1. Wang YH, Johnson K, Beradid S, et al. Incretin-based drugs and the risk of dementia among patients with type 2 diabetes. Drug Saf. 2025. doi:10.1007/s40264-025-01623-9

2. Findings suggest that certain medications for type 2 diabetes reduce the risk of dementia. News Release. McGill. Relased January 15, 2026. Accessed January 19, 2026. https://www.mcgill.ca/newsroom/channels/news/findings-suggest-certain-medications-type-2-diabetes-reduce-risk-dementia-370312

3. Waldrop G, Zhong J, Peters M, et al. Incretin-based therapy for diabates: What a cardiologist needs to know. J Am Coll Cardiol. 2016;67(12):1488-1496. doi:10.1016/j.jacc.2015.12.058

4. DPP-4 inhibitors. Cleveland Clinic. Last Updated October 10, 2025. Accessed January 19, 2026. https://my.clevelandclinic.org/health/treatments/dpp-4-inhibitors