Neuroinflammation and metabolic dysregulation as predictors of cognitive impairment, depression, and quality of life in type 2 diabetes mellitus patients on SGLT2 inhibitors and sulfonylureas

Cognitive impairment, depression, and a lower quality of life (QoL) are among the metabolic and neuropsychiatric consequences linked to type 2 diabetes mellitus (T2DM). The pharmacological management of T2DM often involves sodium-glucose co-transporter 2 inhibitors (SGLT2i) and sulfonylureas (SUs), both of which have been shown to influence metabolic control and inflammation. However, their differential effects on neuroinflammatory markers and neuropsychiatric outcomes remain poorly understood. This study aims to compare the effects of SGLT2i and SUs on key metabolic (mTOR, PI3K, AkT), neuroinflammatory (HMGB1, TLR4, ADAM-10, TNF-α, IL-1β, IL-6), and neuroprotective biomarkers (Klotho) associated with cognitive impairment, depression, and QoL in patients with T2DM.

A case–control study was conducted with 166 participants divided into three groups: healthy controls (n = 55), SGLT2i-treated patients (n = 57), and SUs-treated patients (n = 54). The study assessed anthropometric measurements, biochemical markers, kidney function, serum neuroinflammatory and metabolic biomarkers, cognitive function (MoCA), depression (PHQ-9), and QoL (SF-36) through standard protocols.

Both SGLT2i and SUs significantly increased neuroinflammatory biomarkers (HMGB1, ADAM-10, TNF-α, IL-1β, IL-6) along with mTOR and Klotho compared to the healthy control group (p < 0.001). However, SGLT2i showed a more favourable reduction in these markers. Cognitive impairment and depression were more pronounced in the SUs group (MoCA: 20.03 ± 2.04, PHQ-9: 8.2 ± 1.67) compared to SGLT2i (MoCA: 22.51 ± 4.2, PHQ-9: 6.5 ± 3.8) (p < 0.001).

SGLT2i are more effective than SUs in modulating metabolic and neuroinflammatory biomarkers and may offer better neuropsychiatric outcomes, potentially improving overall QoL in T2DM patients. Further research is needed to explore the long-term effects of these drugs on neurodegeneration and cognitive health.