Sodium-Glucose Cotransporter 2 Inhibitors and Dementia Risk in Patients With Psychiatric Disorders
David T. Liebers, Tianshe He, Rebecca A. Betensky, Chunlei Zheng, Kaitlin N. Swinnerton, Sean Jacobson, Linden Huhmann, Mary T. Brophy, Nhan V. Do, Paola Gilsanz, Ricardo S. Osorio, Nunzio Pomara, Antonio Convit, Donald C. Goff, Dan V. Iosifescu, Nathanael R. Fillmore, Jaime Ramos-CejudoImportance
Individuals with mood and psychotic disorders are at an increased risk for dementia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of antidiabetic medications with mitochondrial and metabolic properties, may offer protective benefits.
Objective
To evaluate whether treatment with SGLT2 inhibitors is associated with reduced risk of incident dementia and other neuropsychiatric outcomes in patients with psychiatric disorders.
Design, Setting, and Participants
This cohort study used a target trial emulation design and data from the US Department of Veterans Affairs databases from January 1, 2016, to June 1, 2024. Participants were 65 years or older with a diagnosis of major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder but without prior dementia diagnosis at baseline or history of SGLT2 inhibitor use. Analyses used marginal structural models weighted by inverse probability of treatment and censoring.
Interventions
Initiation and noninitiation of SGLT2 inhibitor were calculated using intention-to-treat (ITT) analysis, and sustained and nonsustained use of SGLT2 inhibitor for ≥3 months were estimated using per-protocol (PP) analysis.
Main Outcomes and Measures
The primary outcome was incident all-cause dementia, as defined by
Results
In total, there were 112 725 individuals in the sample, of whom 7631 (6.8%) were exposed to an SGLT2 inhibitor. The sample had a median (IQR) age of 74.1 (69.7-77.6) years and predominantly consisted of males (104 818 [92.8%]); 49.3% of the patients had obesity. In the ITT analysis, SGLT2 inhibitor use was associated with reduced odds of all-cause dementia (odds ratio [OR], 0.61; 95% CI, 0.52-0.73) and PED visits (OR, 0.80; 95% CI, 0.66-0.97) but not psychiatric hospitalizations (OR, 0.68; 95% CI, 0.44-1.04). In the PP analysis, SGLT2 inhibitor use was associated with lower odds of all-cause dementia (OR, 0.54; 95% CI, 0.40-0.73) and psychiatric hospitalizations (OR, 0.56; 95% CI, 0.31-1.00) but not PED visits (OR, 0.74; 95% CI, 0.53-1.05).
Conclusions and Relevance
In this cohort study of older adults with mood and psychotic disorders, SGLT2 inhibitor use was associated with lower risk of dementia and PED visits. The results support a neuroprotective role of SGLT2 inhibitors in a high-risk psychiatric population.