Hydroxyl Free Radical Associated Effects of SGLT-2 Inhibitors in Type 2 Diabetes

Distal symmetric polyneuropathy (DSPN) is one of the most common microvascular complications of type 2 diabetes mellitus (T2D), affecting approximately 50% of patients over the course of their disease. This complex disorder involves both metabolic and vascular insults leading to nerve fiber damage with hyperglycemia-driven oxidative stress, reduced nerve blood flow, and chronic subclinical inflammation contributing to its pathogenesis.

The presence of DSPN impairs quality of life and is associated with increased mortality as well.

Despite achieving optimal glycemic control, diabetic neuropathy frequently progresses due to multifactorial influences, including chronic oxidative stress and microvascular injury. Traditional therapies have focussed on symptomatic relief, such as pain management with anticonvulsants or antidepressants, and on attempts to slow disease progression by targeting hyperglycemia. Consequently, new interventions addressing additional pathogenic factors, including oxidative stress, could offer improved clinical outcomes in DSPN. In the aetiology of diabetic neuropathy, oxidative stress plays a significant role.

Under physiological conditions, phenylalanine is hydroxylated enzymatically at the para position, producing para-tyrosine. However, under conditions of increased oxidative stress, for instance during hydroxyl radical (•OH) attack, phenylalanine can be mis-hydroxylated at the ortho and meta positions, giving rise to ortho-tyrosine (o-Tyr) and meta-tyrosine (m-Tyr). These atypical tyrosine isomers are typically negligible in healthy states; thus, their elevated levels or increased abnormal ratios serve as sensitive biomarkers of hydroxyl radical-mediated oxidative damage, which may be particularly relevant in chronic diseases associated with persistent oxidative stress. Given these oxidative stress pathways, alpha-lipoic acid (ALA) has been explored as an antioxidant therapy that primarily targets free radical production.

ALA has been utilized as a parallel or adjunctive approach to existing glycemic management strategies, with short-term trials showing significant improvements in nerve conduction velocity and neuropathic symptoms. At the same time, ALA therapy as a systemic antioxidant treatment, at the same time may have a beneficial effect on the cardiovascular hard endpoints, as we proved previously.