Dementia Associated With Sodium-Glucose Cotransporter-2 Inhibitors Versus Glucagon-Like Peptide-1 Receptor Agonists: A Population-Based Cohort Study

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain.

Objectives: To compare the risk of dementia between SGLT2 inhibitors and dulaglutide (a GLP-1RA).

Methods: Using the nationwide healthcare data of South Korea between 2010 and 2022, we included patients aged 60 years or older initiating SGLT2 inhibitors or dulaglutide diagnosed with T2D. The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year prior to the date of dementia diagnosis on the basis that the time between the onset of dementia and diagnosis was 1 year. Using a target trial emulation design, the 5-year risk ratios and risk differences comparing SGLT2 inhibitors with GLP-1RAs were estimated within a 1:2 propensity score-matched cohort adjusted for confounders. The causal contrast of interest is the intention-to-treat effect.

Results: Overall, 12 489 patients initiating SGLT2 inhibitors (51.9% dapagliflozin, 48.1% empagliflozin) and 1075 patients initiating dulaglutide were included. In the matched cohort, over the 4.2-year mean follow-up, the primary outcome event occurred in 69 individuals in the SGLT2 inhibitors group and 43 individuals in the dulaglutide group. The estimated risk difference was -0.91% [95% CI, -2.45% to 0.63%], and the estimated risk ratio was 0.81 [95% CI, 0.56 to 1.16].

Conclusions: In conclusion, under conventional statistical criteria, we estimated that, a risk of dementia between 2.5 percentage points lower and 0.6 percentage points greater for SGLT2 inhibitors versus dulaglutide was highly compatible with our data. However, whether these findings generalize to newer GLP-1RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required.