SGLT2 inhibitors linked to lower dementia risk in adults with traumatic brain injury and type 2 diabetes

A recent retrospective study suggests that SGLT2 inhibitors may be associated with a reduced risk of dementia in adults with type 2 diabetes and a history of traumatic brain injury, prompting calls for further research.

A class of diabetes medicines known as SGLT2 inhibitors was linked to a lower risk of dementia in adults with type 2 diabetes and a history of traumatic brain injury, according to a retrospective cohort study published in Diabetes, Metabolic Syndrome and Obesity. The analysis compared new users of SGLT2 inhibitors with patients starting DPP-4 inhibitors, a common alternative glucose-lowering drug class, and found fewer dementia diagnoses and deaths among those given SGLT2 treatment.

Researchers used TriNetX electronic health record data from mainly US healthcare organisations and focused on adults aged 50 and over who had both type 2 diabetes and a recorded traumatic brain injury at least 3 months before the start of treatment. After propensity score matching, 3,877 patients were included in each group, and the two cohorts were balanced across measured characteristics, including hypertension, heart disease, obesity and kidney disease.

The main analysis showed that starting an SGLT2 inhibitor was associated with a 29% lower risk of incident dementia than starting a DPP-4 inhibitor. The study also found a lower risk of vascular dementia, but not Alzheimer’s disease, alongside reduced all-cause mortality and a lower risk of advanced chronic kidney disease. A negative control outcome, benign skin tumours, was not associated with either treatment, which the authors said supported the internal consistency of the findings.

The signal held up in several sensitivity analyses, including a model limited to empagliflozin users and another restricted to patients with repeated healthcare visits. The association also remained broadly similar in a subgroup with non-concussion intracranial injuries. Even so, the authors stressed that these were observational results and not proof that SGLT2 inhibitors prevent dementia after head injury.

The findings add to a growing but mixed evidence base. Other recent research has also suggested lower dementia risk with SGLT2 inhibitors than with DPP-4 inhibitors in type 2 diabetes, and a meta-analysis reported a roughly 33% reduction in all-cause dementia risk. But randomised trial data have not shown a clear dementia benefit, and some studies have suggested DPP-4 inhibitors themselves may carry lower dementia risk than older diabetes drugs. Against that backdrop, the new study points to a possible protective association in a particularly vulnerable group, while leaving open whether the effect reflects biology, better overall health outcomes or the limits of real-world data.

The authors said the result should be treated as hypothesis-generating. They called for prospective studies with formal cognitive testing, better measures of brain injury severity and more robust competing-risk methods before any conclusions can be drawn about whether these medicines change the long-term course of cognitive decline after traumatic brain injury.