SGLT-2 inhibitors may prevent dementia in adults with T2D

Initiation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors results in a 35-percent reduced risk of dementia compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in individuals with type 2 diabetes (T2D) aged 40–69 years, according to a study. In addition, greater benefits are seen with longer treatment duration. 

"As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated,” said the researchers, adding the randomized controlled trials are necessary to confirm these findings.  

This population-based cohort study used data from the Korean National Insurance Service (2013–2021) and included 110,885 propensity score-matched pairs of adults with T2D who initiated either an SGLT-2 or a DPP-4 inhibitor. 

New-onset dementia was the primary outcome, while secondary outcomes were dementia requiring drug treatment and individual types of dementia, such as Alzheimer’s disease and vascular dementia. Control outcomes included genital infections (positive) and osteoarthritis-related clinical encounters and cataract surgery (negative). 

Cox models were used to estimate hazard ratios (HRs) and 95 percent confidence intervals (CIs). The research team also carried out follow-up time stratified analyses (>2 and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk. 

Over a mean follow-up period of 670 days, 1,172 were diagnosed with new-onset dementia (SGLT-2: incidence rate, 0.22 per 100 person-years; DPP-4: incidence rate, 0.35 per 100 person-years; HR for dementia requiring drugs, 0.54, 95 percent CI, 0.46–0.63; HR for Alzheimer’s disease, 0.61, 95 percent CI, 0.53–0.69; HR for vascular dementia, 0.54, 95 percent CI, 0.46–0.63). [BMJ 2024;386:e079475] 

For the control outcomes, the HRs were 2.67 (95 percent CI, 2.57–2.77) for genital infections, 0.97 (95 percent CI, 0.95–0.98) for osteoarthritis-related encounters, and 0.92 (95 percent CI, 0.89–0.96) for cataract surgery. Calibration for residual confounding measured by cataract surgery showed an HR of 0.70 (95 percent CI, 0.62–0.80) for dementia. 

Notably, treatment benefits with SGLT-2 inhibitors were greater for >2 years of treatment duration (HR, 0.57, 95 percent CI, 0.46–0.70) than for ≤2 years (HR, 0.52, 95 percent CI, 0.41–0.66) and persisted across different subgroups. 

“These findings underscore the need for future randomized controlled trials,” the researchers said.  

Neuroprotective effect 

Preclinical studies have showed direct neuroprotective effects with the initiation of SGLT-2 inhibitors through several pathways. [Expert Opin Investig Drugs 2022;31:105-q23; Brain Sci 2019;9:57; Alzheimers Res Ther 2020;12:40; Eur J Endocrinol 2018;178:R113-25] 

Specifically, SGLT-2 inhibitors demonstrated “anticholinergic activity, prevented ultrastructural changes of neurovascular units associated with cognitive decline in mice with diabetes, and ameliorated amyloid β deposition and tau phosphorylation in the brain tissue of mice with Alzheimer’s disease and T2D,” according to the researchers. 

“Based on these preclinical findings, SGLT-2 inhibitors may delay the progression of dementia in people with T2D both for Alzheimer’s disease and for vascular dementia, independent of the cardiorenal benefits exerted by SGLT-2 inhibitors,” they added.