NEW YORK CITY — SGLT2 inhibitor use was associated with a reduced risk of dementia in older adults with mood and psychotic disorders, according to a target trial emulation study published in JAMA Network Open. The analysis also found that SGLT2 inhibitor use correlated with lower rates of psychiatric emergency department visits in an intention-to-treat assessment.

Jaime Ramos-Cejudo, PhD, of New York University Grossman School of Medicine, and colleagues utilized data from the Department of Veterans Affairs healthcare system spanning 2016 to 2024. The study evaluated people ages 65 and older with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. The analysis excluded people who had a dementia or a personality disorder diagnosis, as well as those who had previously used an SGLT2 inhibitor.

The researchers identified 112,725 people who met inclusion criteria for the all-cause dementia trial. Participants had a median age of 74.1 years, and the median follow-up period was 3.3 years. During the study, 4.1% of participants developed dementia.

In the intention-to-treat analysis, patients with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder who used SGLT2 inhibitors were less likely to develop all-cause dementia (OR 0.61, 95% CI 0.52-0.73) compared with similar patients who did not use the drugs. These patients also experienced fewer psychiatric emergency department visits (OR 0.80, 95% CI 0.66-0.97). A per-protocol analysis, assessing sustained SGLT2 inhibitor use for three months or longer, found 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).

"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," Ramos-Cejudo said. He added, "What makes this study particularly novel is the population we examined." The researcher noted, "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."

The analysis controlled for covariates including demographic data, lifestyle factors, body mass index, HbA1c levels, medical history, psychiatric diagnosis, and medication history. SGLT2 inhibitor use was analyzed as a single category, with switching between individual SGLT2 inhibitors treated as continuous therapy. Incident all-cause dementia was defined by ICD codes.

"SGLT2 inhibitors are unique among antidiabetic medications in that they induce ketogenesis," Ramos-Cejudo said. "Ketogenic diets have recently been associated with symptomatic improvement among those with psychiatric disorders in some preliminary clinical trials, and this study lends support to the possibility that they offer a pharmacological means of achieving similar benefits."