Type 2 diabetes (T2D) patients receiving a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) concomitantly appear to be at lower risk of dementia compared with those receiving a GLP-1 RA or SGLT-2i monotherapy, according to a study.
In a target trial emulation using data from the TriNetX Collaborative Network, the 10-year incidence of all-cause dementia was 5.56 percent with GLP-1 RA/SGLT-2i dual therapy vs 8.17 percent with GLP-1 RA monotherapy and 5.58 percent with dual therapy vs 6.82 percent with SGLT-2i monotherapy, reported first author Dr Fu-Shun Ko from Taipei City Hospital Zhongxing Branch, Taipei, Taiwan. [EASD 2026, abstract 143]
Dual therapy was associated with a 28-percent to 29-percent dementia risk reduction compared with GLP-1 RA monotherapy (hazard ratio [HR], 0.72, 95 percent confidence interval [CI], 0.64–0.82; p<0.0001) or SGLT-2i monotherapy (HR, 0.71, 95 percent CI, 0.63–0.80).
Ko noted that the greater protective effect of dual therapy was also observed on dementia subtypes and all-cause mortality.
Compared with GLP-1 RA monotherapy, dual therapy was associated with reduced risks of Alzheimer’s disease (HR, 0.71, 95 percent CI, 0.55–0.93), vascular dementia (HR, 0.65, 95 percent CI, 0.50–0.84), and all-cause mortality (HR, 0.70, 95 percent CI, 0.65–0.75).
Results were similar when dual therapy was compared with SGLT-2i (Alzheimer’s disease: HR, 0.73, 95 percent CI, 0.55–0.95; vascular dementia: HR, 0.75, 95 percent CI, 0.58–0.98; all-cause mortality: HR, 0.66, 95 percent CI, 0.61–0.71).
Subgroup analyses showed no differential treatment effects, demonstrating that dual therapy provided consistent protective advantage compared with monotherapy regardless of baseline patient characteristics, according to Ko.
“Our findings suggest that combining the GLP-1 RA and SGLT-2i drug classes overcomes monotherapy limitations, providing robust neuroprotection across diverse T2D patient subgroups,” the author said.
Ko pointed out that the enhanced neuroprotective benefit with dual therapy likely stems from their additive and synergistic effects.
“Both drug classes target shared metabolic risk factors by improving glycaemic control, obesity, insulin resistance, and cardiovascular burden, in addition to reducing oxidative stress and neuroinflammation,” he explained.
“Future randomized controlled trials will be essential to confirm the findings,” Ko said.
For the study, Ko and colleagues identified 662,907 T2D patients ages 40 years and above who initiated treatment with GLP-1 RA, SGLT-2i, or both. They performed propensity score matching, resulting in the inclusion of 35,322 patient pairs in the GLP-1 RA/SGLT-2i dual therapy vs GLP-1 RA monotherapy comparison trial and 35,485 pairs in the dual therapy vs SGLT-2i monotherapy trial. The median follow-up was 801 vs 775 days in the dual therapy vs GLP-1 RA trial and 799 vs 704 days in the dual therapy vs SGLT2i trial.
The primary endpoints were new-onset all-cause dementia, Alzheimer’s disease, and vascular dementia, while the secondary endpoint was all-cause mortality.