SGLT2 Inhibitors, GLP-1 Agonists Similarly Reduce Dementia Risk for Patients With Diabetes

New research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors do not reduce the risk of dementia for patients with diabetes significantly more than the glucagon-like peptide 1 (GLP-1) receptor agonist dulaglutide (Trulicity).¹

These findings were published in the Annals of Internal Medicine and add to the ongoing research about the possible neuroprotective effects of SGLT2 inhibitors and GLP-1s and how well they can lower the risk of dementia in patients with type 2 diabetes.² The study included patients 60 years and older from South Korea, with data collected from the National Health Insurance Service between 2010 and 2022. Of the 12,489 patients initiating SGLT2 inhibitors, about half received dapagliflozin and half received empagliflozin, and 1075 patients initiated the GLP-1 receptor agonist dulaglutide.

The primary outcome was the presumed clinical onset of dementia, and the date of onset was defined as the year before dementia was officially diagnosed. Over a median follow-up of 4.4 years, dementia onset occurred in 69 patients taking an SGLT2 inhibitor and 43 patients on dulaglutide, reflecting dementia risks of 3.87% and 4.78%, respectively.

These findings add to the ongoing research about the possible neuroprotective effects of SGLT2 inhibitors and GLP-1s | Image credit: freshidea – stock.adobe.com

The estimated 5-year risk difference for dementia onset was –0.91 percentage point (95% CI, –2.45 to 0.63), and patients on SGLT2 inhibitors had a 19% lower risk of developing dementia compared with those on dulaglutide (estimated risk ratio [eRR], 0.81; 95% CI, 0.56-1.16). Final data showed a risk for dementia between 2.5 percentage points lower and 0.6 percentage points greater for SGLT2 inhibitor than for dulaglutide, suggesting no statistically significant difference in dementia risk between the drugs. During the follow-up period, the overall dementia risk was about 20% lower in the SGLT2 group compared with the dulaglutide group (estimated HR, 0.80; 95% CI, 0.54-1.16).

For secondary outcomes, SGLT2 inhibitors were associated with a 20% lower risk of Alzheimer disease compared with dulaglutide, but the results weren’t strong enough to be definitive (eRR, 0.80; 95% CI, 0.55-1.15). However, for vascular dementia, the risk was actually higher in those using SGLT2 inhibitors, although this finding had a wide range of uncertainty (eRR, 1.74; 95% CI, 0.22-13.83). Graphs tracking dementia risk over time showed that differences between the 2 treatments started to become noticeable around 2 years for general dementia and Alzheimer disease, and after 3 years for diagnosed dementia.

“However, whether these findings generalize to newer GLP-1 [receptor agonists] is uncertain, the authors noted. “Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required.”

Both SGLT2 inhibitors and GLP-1 receptor agonists have shown protective effects on the brain, like reducing inflammation, improving nerve connections, and supporting neuron health. However, SGLT2 inhibitors may have unique advantages that explain the slightly lower dementia rates seen in patients taking them, according to the study authors. Animal studies found that drugs like dapagliflozin and empagliflozin reduced the buildup of harmful brain proteins—amyloid plaques and tau tangles—which are key features of Alzheimer disease. On the other hand, GLP-1 drugs like liraglutide didn’t prevent these proteins from building up.

Additionally, SGLT2 inhibitors helped regulate brain activity and improved blood flow to the brain, which may slow down dementia progression, and also seemed to mimic the effects of existing Alzheimer medications by blocking enzymes linked to memory loss. However, more research is needed to confirm these effects in humans and understand how SGLT2 inhibitors might protect against dementia.

References

1. Hong B, Bea S, Ko HY, Kim WJ, Cho YM, Shin JY. Sodium–glucose cotransporter-2 inhibitors, dulaglutide, and risk for dementia: a population-based cohort study. Ann Intern Med. Published online August 27, 2024. doi:10.7326/M23-3220
2. Wu CY, Iskander C, Wang C, et al. Association of sodium-glucose cotransporter 2 inhibitors with time to dementia: a population-based cohort study. Diabetes Care. 2023;46(2):297-304. doi:10.2337/dc22-1705