New Insights into the Role of SGLT-2 Inhibitors in the Prevention of Dementia

Abstract

Diabetes mellitus (DM) is a chronic disease associated with numerous complications, including cardiovascular diseases, nephropathy, and neuropathy. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, a class of novel antidiabetic agents, have demonstrated promising therapeutic effects beyond glycemic control, with potential benefits extending to the cardiovascular and renal systems. Recently, research has increasingly focused on exploring the potential role of SGLT-2 inhibitors in preventing dementia. The aim of this review is to summarize the current research suggesting that SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, may have neuroprotective effects that reduce dementia risk and improve cognitive function in type 2 diabetes patients. These benefits are likely due to better glycemic control, reduced oxidative stress, and less advanced glycation end-product (AGE) formation, all linked to neurodegeneration. Despite these promising findings, existing studies are limited by small sample sizes and short follow-up durations, which may not adequately capture long-term outcomes. To establish more robust evidence, larger-scale, long-term randomized controlled trials (RCTs) involving diverse populations are needed. These studies should involve diverse populations and focus on understanding the mechanisms behind the neuroprotective effects. Addressing these limitations will provide clearer guidelines for using SGLT-2 inhibitors in dementia prevention and management. This will help improve therapeutic strategies for cognitive health in diabetic patients.

Keywords: Alzheimer’s disease; SGLT-2 inhibitors; dementia; diabetes mellitus; gliflozins.

Figure 1

Pathophysiological mechanisms linking type 2 diabetes and dementia. Chronic hyperglycemia triggers the formation of advanced glycation end-products (AGEs), insulin resistance, and vascular damage, all of which play a role in cognitive decline. Additionally, inflammation and oxidative stress further exacerbate vascular and neurodegenerative changes, accelerating the progression toward dementia.

Figure 2

Mechanisms underlying the neuroprotective effects of SGLT-2 inhibitors. This figure illustrates the proposed mechanisms by which SGLT-2 inhibitors may exert neuroprotective effects. These mechanisms include multi-organ protective effects that indirectly support brain function and enhanced glucose metabolism and insulin signaling, which improve neuronal health. SGLT-2 inhibitors also help maintain the integrity of the blood–brain barrier, preventing neurotoxic insults, and exhibit anti-inflammatory and antioxidant properties, which reduce neuroinflammation and oxidative stress. Furthermore, they promote mitochondrial function by improving energy production and reducing mitochondrial dysfunction. Lastly, SGLT-2 inhibitors may attenuate pathological hallmarks of Alzheimer’s disease, such as amyloid-beta and tau pathology. The arrows depict the connections between SGLT-2 inhibitors and their specific roles in achieving these neuroprotective effects.