US Veterans Study Links SGLT2 Inhibitors to Lower Dementia Risk in Older Adults With Psychiatric Disorders
Key Clinical Summary:
- Sodium-glucose cotransporter 2 (SGLT2) inhibitor use was associated with a lower risk of incident all-cause dementia among older US veterans with mood and psychotic disorders.
- In a cohort of 112,725 adults aged 65 years or older, SGLT2 inhibitor exposure was also associated with fewer psychiatric emergency department visits in the intention-to-treat analysis.
- The observational findings support further research into the potential neuroprotective effects of SGLT2 inhibitors and shared metabolic mechanisms underlying psychiatric disorders and dementia.
Older adults with mood and psychotic disorders face an elevated risk of dementia, prompting interest in therapies that may provide neuroprotective benefits. A cohort study published in JAMA Network Open found that sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of antidiabetic medications, were associated with reduced risks of dementia and other neuropsychiatric outcomes in older adults with mood and psychotic disorders.
Study Findings
Researchers conducted a target trial emulation using US Department of Veterans Affairs data from January 1, 2016, to June 1, 2024. The study included 112,725 adults aged 65 years or older with major depressive disorder (MDD), bipolar disorder (BD), or schizophrenia spectrum disorder who had no prior dementia diagnosis or previous SGLT2 inhibitor use at baseline.
Among participants, 7631 (6.8%) initiated an SGLT2 inhibitor. The cohort had a median age of 74.1 years, 92.8% were male, and 49.3% had obesity.
The primary outcome was incident all-cause dementia identified through International Classification of Diseases-coded diagnoses. Secondary outcomes included time to psychiatric emergency department visits and psychiatric hospitalizations.
In the intention-to-treat analysis, SGLT2 inhibitor use was associated with significantly lower odds of all-cause dementia (OR, 0.61; 95% CI, 0.52–0.73) and psychiatric emergency department visits (OR, 0.80; 95% CI, 0.66–0.97). No statistically significant association was observed for psychiatric hospitalizations (OR, 0.68; 95% CI, 0.44–1.04).
In the per-protocol analysis, sustained SGLT2 inhibitor use for at least 3 months was associated with 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 the association with psychiatric emergency department visits was not statistically significant (OR, 0.74; 95% CI, 0.53–1.05).
Clinical Implications
These findings suggest that SGLT2 inhibitors may have potential neuroprotective benefits in older adults with mood and psychotic disorders. The observed associations with reduced incident dementia and fewer psychiatric emergency department visits highlight the need for additional investigation into the broader effects of these medications beyond glycemic control.
Because this was an observational cohort study using a target trial emulation design, the results demonstrate an association rather than causation. Still, the consistency of the reduced dementia risk across both intention-to-treat and per-protocol analyses supports further evaluation of SGLT2 inhibitors in prospective studies.
Expert Commentary
“Our findings point to SGLT2 inhibitors as candidate therapeutics in mood and psychotic disorders as well as populations with high neuropsychiatric risk and limited treatment options,” wrote David T. Liebers, MD, Department of Psychiatry, New York University (NYU) Grossman School of Medicine, New York, and study coauthors.
“These findings support the hypothesis of shared metabolic vulnerability across psychiatric and neurodegenerative diseases,” the researchers concluded. “Further investigation is warranted of SGLT2 inhibitors as potential transdiagnostic treatment options in individuals with high-risk psychiatric disorders.”
