SGLT-2 Inhibitors May Lower Dementia Risk in Type 2 Diabetes Patients, Study Finds

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMSep 9 2024

Type 2 diabetes is believed to increase the risk of dementia by 60%. Multifactorial mechanisms involving hypoglycemic episodes and insulin resistance are implicated in the increased predisposition to vascular dementia and Alzheimer’s disease.

In a recent study published in BMJ, researchers from the Seoul National University, South Korea, observed type 2 diabetes patients between the ages of 40 and 69 years being treated with dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT-2) inhibitors and compared the dementia risk associated with each treatment.

​​​​​​​Study: Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study. Image Credit: fizkes/Shutterstock.com

Background

Dementia is a growing health concern, and statistics by the World Health Organization from 2021 indicated that by the year 2030, close to 78 million people across the world will have dementia.

Dementia is linked to damage to the parenchyma in the brain, which degrades cortical function and also impacts behaviors and moods.

Furthermore, although dementia is linked to severe symptoms that impact the quality of life, the research on drugs to treat dementia has not been very successful, and very few disease-modifying options are currently available.

However, considerable research has been conducted on identifying modifiable risk factors for dementia, such as type 2 diabetes. Numerous mechanisms have been found linking dementia and type 2 diabetes, including vascular compromise, hypoglycemia, and insulin resistance. Therefore, anti-glycemic drugs could potentially have neuroprotective effects in type 2 diabetes patients.

About the Study

In the present study, the researchers compared the impact of two antiglycemic drugs, SGLT-2 inhibitors and DPP-4 inhibitors, on dementia risk in individuals with type 2 diabetes.

While SGLT-2 inhibitors prevent the reabsorption of glucose in the proximal tubules of the kidneys, DPP-4 inhibitors prevent the degradation of peptides such as incretins and glucagon-like peptide-1.

Research has indicated that SGLT-2 inhibitors could have neuroprotective properties based on their ability to penetrate the blood-brain barrier and acetylcholinesterase inhibition, as well as the expression of SGLT-2 in brain tissue.

Although previous studies have compared the neuroprotective effects of DPP-4 inhibitors with other antiglycemic drugs and placebos, including SGLT-2 inhibitors, the impact of these treatments on younger patient populations and in specific dementia types has not been studied.

In the present cohort study, the researchers used data from the country's National Health Insurance Service, spanning the years from 2013 to 2021.

The participants included in the study were between 40 and 69 years of age and had type 2 diabetes but no dementia.

The included participants had not used either of the two treatment options for one year before being enrolled in the study and did not have end-stage renal disease or human immunodeficiency virus.

Incident dementia was the primary outcome examined in the study, while prescriptions for dementia drugs and the specific types of dementia were evaluated as secondary outcomes.

Other diseases, such as osteoarthritis and genital infections, were included in the analysis as positive and negative control outcomes to assess potential bias in the study.

Over a hundred covariates related to the risk factors for dementia, the severity of diabetes, healthcare use, and personal and sociodemographic characteristics were included in the analysis.

Major Findings

Similar to findings from previous studies, the results indicated that SGLT-2 inhibitors lowered the risk of dementia by 35% compared to DPP-4 inhibitors in type 2 diabetes patients between the ages of 40 and 69 years. Furthermore, the decrease in dementia risk was consistent across various population subgroups and for different types of dementia.

Longer follow-up times reported a stronger effect of SGLT-2 inhibitors in lowering the risk of dementia after a treatment period of two years.

Additionally, multiple sensitivity analyses upheld the findings, indicating the robustness of the results. The results also remained stable when other hypoglycemic drugs were used concurrently.

No associations were observed between individual characteristics such as sex, age, or cardiovascular risk and the impact of the treatment, indicating that the cognitive benefits provided by SGLT-2 inhibitors were independent of cardiovascular health.

However, despite the strength of the findings, the rigorous statistical methods, and the inclusion of a nationally representative study population, the observational design of the study could have caused potential residual confounding, limiting the interpretation of the results.

Furthermore, the exact mechanisms through which SGLT-2 inhibitors provide the neuroprotective and cognitive benefits to patients with type 2 diabetes remain unclear.

Conclusions

Overall, the study showed that the use of SGLT-2 inhibitors to treat type 2 diabetes significantly lowered the risk of dementia by 35% as compared to other antiglycemic drugs, such as DPP-4 inhibitors.

The beneficial effects of SGLT-2 inhibitors were also found to increase with the duration of treatment and were consistent across factors such as sex, age, and cardiovascular health.