Use of SGLT2 inhibitors was associated with reduced dementia incidence and fewer psychiatric emergency department visits in older adults with mood and psychotic disorders, according to a target trial emulation study published in JAMA Network Open.
Researchers analysed data from the US Department of Veterans Affairs healthcare system covering 2016 to 2024, identifying 112,725 people aged 65 and older with major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder. Participants had a median age of 74.1 years, with 6.8% having SGLT2 inhibitor exposure. Over a median follow-up of 3.3 years, 4.1% developed dementia.
In an intention-to-treat analysis, patients using SGLT2 inhibitors were less likely to develop all-cause dementia (OR 0.61) and had fewer psychiatric emergency department visits (OR 0.80) compared with non-users. A per-protocol analysis showed SGLT2 inhibitor use was associated with lower odds of dementia (OR 0.54) and psychiatric hospitalisations (OR 0.56).
Lead author Jaime Ramos-Cejudo of New York University Grossman School of Medicine noted that whilst SGLT2 inhibitors were developed for diabetes treatment, evidence suggests they may influence biological pathways involved in neurodegeneration, including brain energy metabolism, mitochondrial function, and inflammation.
The researchers highlighted that SGLT2 inhibitors are unique among antidiabetic medications in inducing ketogenesis. Ketogenic diets have shown preliminary associations with symptomatic improvement in psychiatric disorders, suggesting these medications may offer similar benefits pharmacologically.
People with major depression, bipolar disorder, or schizophrenia have substantially increased dementia risk yet remain underrepresented in prevention research. The researchers acknowledged limitations including potential residual confounding and the predominantly male study population, which may limit generalisability.
Source: MedPage Today / JAMA Network Open (2026)
