Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which are used to treat type 2 diabetes, may have the potential to prevent dementia, offering increased benefits with prolonged use, according to a large study from Korea published by The BMJ.

As this study was observational, the researchers note that the effect size could have been overestimated. They say randomised controlled trials are now necessary to confirm these findings.

According to the World Health Organization, the global number of people with dementia is expected to reach 78 million by 2030, and there is an association between type 2 diabetes and a higher risk of developing dementia.

A recent study of individuals over 65 with type 2 diabetes suggested a lower risk of dementia associated with SGLT-2 inhibitors compared to another type of diabetes drug, dipeptidyl peptidase-4 (DPP-4) inhibitors. However, the impacts on younger individuals and specific types of dementia (such as Alzheimer’s disease and vascular dementia) are still not fully understood.

Researchers used the Korea National Health Insurance Service database to identify 110,885 pairs of adults aged 40-69 with type 2 diabetes. The adults were free of dementia and began taking either an SGLT-2 inhibitor or a DPP-4 inhibitor between 2013 and 2021.

All participants (with an average age of 62; 56% of whom were men) were matched by age, sex, use of the diabetes drug metformin, and baseline cardiovascular risk. They were followed up for an average of 670 days to determine the development of dementia.

Potentially influential factors, such as personal characteristics, income level, underlying risk factors for dementia, other conditions, and related medication use, were also considered.

During the follow-up period, a total of 1,172 participants who had been newly diagnosed with dementia were identified.

Dementia rates per 100 person-years were 0.22 for those using SGLT-2 inhibitors and 0.35 for those using DPP-4 inhibitors. This corresponds to a 35% reduced risk of dementia associated with the use of SGLT-2 inhibitors compared with DPP-4 inhibitors.

The researchers also found a 39% reduced risk for Alzheimer’s disease, and a 52% reduced risk for vascular dementia associated with SGLT-2 inhibitors compared with DPP-4 inhibitors.

What’s more, the effect of SGLT-2 inhibitors seemed more pronounced with longer treatment duration. A 48% reduced risk of dementia was seen for more than two years of treatment versus a 43% reduced risk for two years or less.

“This study is observational, so no definite conclusions can be made about cause and effect. The authors also mention that specific details about health behaviors (such as smoking and alcohol consumption) and the duration of type 2 diabetes were not fully available.”

However, the researchers emphasize that this was a significant study based on nationally representative data, which included relatively younger individuals with type 2 diabetes, and the results were highly consistent across subgroups.

As such, they say SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment, and they call for randomised controlled trials to confirm these findings.

Researchers from Taiwan stated in a connected editorial that this study presents encouraging results with significant implications for clinical practice and public health.

They agree that further trials are needed to confirm these findings, and suggest that studies are also needed “to explore the underlying mechanisms of any neuroprotective effects of SGLT-2 inhibitors.”

As no cure currently exists for dementia and few effective treatment options are available, strategies that can potentially prevent onset are critically important, they write. 

The substantial socioeconomic and public health burdens associated with both dementia and type 2 diabetes highlight the need for regular updates to clinical guidelines and healthcare policies. These updates should incorporate the latest evidence on the potential benefits of SGLT-2 inhibitors, including the reduced risk of dementia.