(059) Novel Glucose-lowering Drugs and Incident Dementia Among Patients With Type 2 Diabetes and Comorbid Mental Disorders: A Population-based Cohort Study

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated neuroprotective effects in patients with type 2 diabetes (T2D). However, whether the neuroprotective effects associated with these drugs persist in patients with T2D and comorbid mental disorders, who are considerably more susceptible to dementia, remains uncertain.

Objectives: To evaluate whether the use of SGLT2 inhibitors and GLP-1RAs is associated with a lower risk of dementia in patients with T2D and comorbid mental disorders.

Methods: Using the nationwide healthcare data of South Korea between 2010 and 2022, we constructed two independent new user cohorts of patients with T2D and comorbid mental disorders initiating drugs of interest (SGLT2 inhibitors or GLP-1RAs) versus active comparator (Dipeptidyl Peptidase IV (DPP4) inhibitors). DPP4 inhibitors have been previously shown to have no effects on cognitive function in randomized controlled trials. The primary outcome was incident dementia, defined using a previously validated algorithm with a positive predictive value of 94.7%. Patients were followed from one year after the index date until the earliest occurrence of dementia, death, or the study end date (December 31, 2022), following the intention-to-treat definition. In each cohort, hazard ratios (HRs) and rate differences (RDs) per 1000 person-years of dementia were estimated after weighting by propensity score fine stratification method. Subgroup analyses stratified by age, sex, and severity of mental disorders were conducted in each cohort.

Results: The first cohort included 42 874 patients initiating SGLT2 inhibitors and 385 045 patients initiating DPP4 inhibitors, and the second cohort included 1733 patients initiating GLP1RAs and 461 425 patients initiating DPP4 inhibitors. Over a 4.8-year median follow-up, SGLT2 inhibitors were associated with a 12% lower risk of dementia compared with DPP4 inhibitors (11.31 vs. 12.86 events per 1000 person years; HR 0.88, 95% CI 0.84 to 0.92; RD -1.55, -2.13 to -0.97). Over a 5.1-year median follow-up, the risk of dementia was not significantly different between GLP-1RAs and DPP4 inhibitors (13.45 vs. 14.16 events per 1000 person years; HR 0.95, 95% CI 0.75 to 1.20; RD -0.71, -3.88 to 2.46). However, GLP-1RAs were associated with a 39% lower risk of dementia in male patients (HR 0.61, 95% CI 0.38 to 0.99).

Conclusions: SGLT2 inhibitors were associated with a lower risk of incident dementia compared with DPP4 inhibitors in patients with T2D and comorbid mental disorders. Furthermore, GLP-1RAs were associated with a lower risk of dementia in male patients only. The findings need to be considered when physicians prescribe for these patients.