Individuals with mood and psychotic disorders face an elevated risk of dementia, potentially reflecting shared metabolic and neurobiological vulnerabilities, including insulin resistance, mitochondrial dysfunction, neuroinflammation, and impaired brain energetics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic medications with established cardiovascular and renal benefits that also promote ketone production and may enhance neuronal energy metabolism. This study evaluated whether SGLT2 inhibitor treatment was associated with lower risks of dementia and adverse psychiatric outcomes among older adults with major depressive disorder (MDD), bipolar disorder, or schizophrenia spectrum disorders.

Study Design
Investigators conducted a retrospective cohort study using US Department of Veterans Affairs electronic health record data from January 2016 through June 2024. The analysis employed a target trial emulation design intended to approximate a randomized clinical trial while accounting for changes in treatment exposure and clinical characteristics over time. Eligible participants were aged 65 years or older, had at least 2 diagnostic codes for MDD, bipolar disorder, or a schizophrenia spectrum disorder, and had no prior dementia diagnosis or previous SGLT2 inhibitor use. The primary outcome was incident all-cause dementia, defined by 2 diagnostic codes. Secondary outcomes included psychiatric emergency department visits and psychiatric hospitalizations.

The study included 112,725 patients, of whom 7,631 (6.8%) initiated an SGLT2 inhibitor. The median age was 74.1 years, 92.8% of participants were male, and MDD was the most common psychiatric diagnosis. Notably, most SGLT2 inhibitor initiators had type 2 diabetes (92.2%), compared with 39.8% of noninitiators. During a median follow-up of 3.3 years, 4,616 participants developed dementia.

Key Findings
In the intention-to-treat analysis, SGLT2 inhibitor initiation was associated with a significantly lower risk of all-cause dementia compared with noninitiation (odds ratio [OR], 0.61; 95% CI, 0.52-0.73). In the sustained-treatment per-protocol analysis, SGLT2 inhibitor use was similarly associated with lower dementia risk (OR, 0.54; 95% CI, 0.40-0.73). The reported ORs were derived from weighted pooled logistic regression models and were interpreted by the investigators as approximations of hazard ratios for these time-to-event outcomes.

The estimated 5-year cumulative incidence of dementia was 1.6% among SGLT2 inhibitor initiators and 2.9% among noninitiators, corresponding to an absolute risk reduction of 1.3 percentage points. Cumulative incidence curves diverged progressively during follow-up, favoring SGLT2 inhibitor initiation. Findings were directionally consistent in analyses stratified by diabetes status and posttraumatic stress disorder status, as well as in analyses accounting for the competing risk of death.

SGLT2 inhibitor initiation was also associated with fewer psychiatric emergency department visits in the intention-to-treat analysis (OR, 0.80; 95% CI, 0.66-0.97), although this association was not statistically significant in the per-protocol analysis. For psychiatric hospitalization, the intention-to-treat estimate was not statistically significant (OR, 0.68; 95% CI, 0.44-1.04), whereas sustained SGLT2 inhibitor use in the per-protocol analysis was associated with lower odds of hospitalization (OR, 0.56; 95% CI, 0.31-1.00).

OR = odds ratio, from weighted pooled logistic regression models (interpreted by investigators as approximating hazard ratios). ED = emergency department.

Limitations and Caveats
These findings suggest that SGLT2 inhibitors may have neuroprotective potential and may be associated with favorable psychiatric outcomes in older adults with mood and psychotic disorders. However, the results do not establish causality. Despite extensive statistical adjustment and the target trial emulation design, residual confounding may persist, including differences in psychiatric illness severity, baseline cognitive function, medical care utilization, and factors influencing SGLT2 inhibitor prescribing. Generalizability is also limited by the predominantly male veteran population and the large proportion of participants with MDD. Accordingly, SGLT2 inhibitors should not be prescribed specifically to prevent dementia on the basis of these observational findings alone. Prospective clinical trials are needed to determine whether their metabolic effects can meaningfully reduce cognitive decline or improve psychiatric outcomes in high-risk populations.

Reference:
Liebers DT et al. JAMA Netw Open. 2026;9(6):e2619985. Abstract