Alpha-Lipoic Acid and Benfotiamine in Diabetic Peripheral Neuropathy: A Critical Review of Mechanistic Rationale and Clinical Evidence Within a Nutritional Therapeutic Framework

Background: Diabetic peripheral neuropathy (DPN) affects up to 50% of diabetes patients and is driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, polyol pathway activation, advanced glycation end-product formation, and inflammation. Current management is largely symptomatic, prompting interest in metabolic/nutritional therapies. This review critically evaluates the mechanistic rationale and clinical evidence for alpha-lipoic acid (ALA) and benfotiamine as adjunctive treatments for DPN. Methods: A structured narrative review of PubMed/MEDLINE was conducted using predefined keywords for DPN, oxidative stress, metabolic therapy, and thiamine derivatives. Randomized controlled trials, clinical studies, systematic reviews, and relevant experimental studies were included. Evidence was synthesized qualitatively with emphasis on mechanistic plausibility, clinical efficacy, intervention duration, and methodological rigor. Results: ALA consistently improves short-term symptoms across multiple randomized trials. The long-term NATHAN 1 trial reported a marginal, borderline significant effect on the primary composite endpoint (NIS-LL, p = 0.05) without significant improvements in nerve conduction studies; therefore, evidence for functional stabilization is very limited and inconclusive. ALA’s effects are attributed to antioxidant activity, mitochondrial protection, and improved microvascular function. Benfotiamine has a strong biochemical rationale (transketolase activation, diversion of glycolytic intermediates from damaging pathways), but clinical evidence remains limited to short-duration, symptom-based studies, with no large-scale, long-term trials published. Conclusions: Both agents target key pathways in DPN pathogenesis. ALA is the most established adjunctive metabolic therapy for symptomatic DPN, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. Benfotiamine is biologically plausible but requires further validation in long-term randomized trials with structural and biomarker-based endpoints. Outside of documented thiamine deficiency, its routine use cannot be recommended based on current evidence.