A target trial emulation study utilizing data from the Department of Veterans Affairs healthcare system between 2016 and 2024 has found that SGLT2 inhibitor use is associated with lower odds of developing all-cause dementia and fewer psychiatric emergency department visits among older adults with certain psychiatric conditions.

The study identified 112,725 individuals who met the inclusion criteria for the all-cause dementia trial. The analysis focused on people aged 65 and older diagnosed with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. Individuals previously diagnosed with dementia or a personality disorder were excluded from the analysis, as were those who had prior SGLT2 inhibitor use. Over a median follow-up period of 3.3 years, 4.1% of participants developed dementia.

An intention-to-treat analysis indicated that SGLT2 inhibitor users had a lower likelihood of developing all-cause dementia compared to similar patients who did not use the drugs. This analysis showed an odds ratio (OR) of 0.61, with a 95% confidence interval (CI) of 0.52-0.73. Additionally, an intention-to-treat analysis found that SGLT2 inhibitor users experienced fewer psychiatric emergency department visits compared to non-users (OR 0.80, 95% CI 0.66-0.97).

Further, a per-protocol analysis supported these findings, demonstrating that SGLT2 inhibitor use was associated with lower odds of all-cause dementia (OR 0.54, 95% CI 0.40-0.73). The per-protocol analysis also showed an association between SGLT2 inhibitor use and lower odds of psychiatric hospitalizations (OR 0.56, 95% CI 0.31-1.00).

Jaime Ramos-Cejudo, a PhD at New York University Grossman School of Medicine, stated, "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 added, "SGLT2 inhibitors are unique among antidiabetic medications in that they induce ketogenesis."

The study models were adjusted for factors including demographic data, lifestyle factors, body mass index, HbA1c levels, medical history, psychiatric diagnosis, and medication history. Incident all-cause dementia was identified using ICD codes.

Why It Matters

This study provides information regarding the potential benefits of SGLT2 inhibitors for older adults specifically with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. Individuals with these psychiatric conditions are at an increased risk of developing dementia and, according to a researcher involved in the study, are often not included in dementia prevention research. The findings suggest a possible pharmacological approach for this population, where SGLT2 inhibitors' ability to induce ketogenesis might offer benefits similar to those observed with ketogenic diets in preliminary trials for psychiatric disorders.