Neuroprotective Potential of SGLT2 Inhibitors in Animal Models of Alzheimer’s Disease and Type 2 Diabetes Mellitus: A Systematic Review

TL;DR

This review finds that SGLT2 inhibitors may protect the brain in animal models of Alzheimer's and type 2 diabetes by improving memory and reducing harmful proteins and inflammation.

Contribution

The study systematically reviews and meta-analyzes the neuroprotective effects of SGLT2 inhibitors in animal models of Alzheimer’s and T2DM.

Findings

SGLT2 inhibitors significantly improved spatial memory in both T2DM and Alzheimer’s disease animal models.

Treatment reduced amyloid-beta accumulation, oxidative stress, and inflammation in brain regions like the hippocampus and cortex.

Escape latency and target quadrant time in the Morris Water Maze test improved with SGLT2 inhibitor use.

Abstract

Background: Alzheimer’s disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium–glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I2, and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models.

Figures