NEW YORK CITY — A study published in JAMA Network Open reported that SGLT2 inhibitors were associated with lower odds of all-cause dementia and psychiatric emergency visits in patients with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. Jaime Ramos-Cejudo, a PhD at New York University Grossman School of Medicine, and his co-authors presented the findings.

In an intention-to-treat analysis, patients taking SGLT2 inhibitors were less likely to develop all-cause dementia (OR 0.61, 95% CI 0.52-0.73) compared with similar patients not using the drugs. The same analysis indicated fewer psychiatric emergency department visits (OR 0.80, 95% CI 0.66-0.97) among those using SGLT2 inhibitors. In a per-protocol analysis, the use of SGLT2 inhibitors was linked to 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). The per-protocol analysis did not show a reduction in psychiatric emergency department visits (OR 0.74, 95% CI 0.53-1.05).

Researchers utilized a target trial emulation framework, drawing data from the Department of Veterans Affairs healthcare system between 2016 and 2024. The study focused on individuals aged 65 and older diagnosed with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. The analysis excluded individuals with a pre-existing dementia or personality disorder diagnosis, as well as those who had previously used an SGLT2 inhibitor. The study identified 112,725 individuals who met the inclusion criteria for the all-cause dementia trial, with a median age of 74.1 years. During a median follow-up period of 3.3 years, 4.1% of participants developed dementia.

During the study, 92.8% of participants were men, and 49.3% had obesity. Approximately 6.8% of participants had exposure to SGLT2 inhibitors, and 86.9% had a diagnosis of major depressive disorder. Modeling adjusted for several factors, including demographic data, lifestyle factors, body mass index, HbA1c levels, medical history, psychiatric diagnosis, and medication history. The initiation and non-initiation of SGLT2 inhibitors were evaluated using an intention-to-treat analysis, while sustained and non-sustained use for three months or longer were assessed via a per-protocol analysis. SGLT2 inhibitor use was treated as a single category, with switches between different SGLT2 inhibitors considered continuous therapy. Incident all-cause dementia was defined by ICD codes.

Ramos-Cejudo noted the specific patient population examined. "What makes this study particularly novel is the population we examined," Ramos-Cejudo said. "People living with conditions such as major depression, bipolar disorder, and schizophrenia are known to be at substantially increased risk of dementia, yet they are often underrepresented in dementia prevention research." He also explained the potential connection between SGLT2 inhibitors and neurodegeneration. "While SGLT2 inhibitors were originally developed to treat diabetes, accumulating evidence indicates they may also influence biological pathways involved in neurodegeneration, including brain energy metabolism, mitochondrial function, and inflammation."