Therapeutic and Diagnostic Landscape of Diabetic Neuropathy: A Systematic Review of Clinical Studies

Diabetic neuropathy (DN) is one of the most prevalent complications of diabetes mellitus, affecting up to half of patients and contributing to disability, poor quality of life, and the risk of foot ulceration. Despite extensive research, its heterogeneous manifestations and complex pathophysiology continue to challenge timely diagnosis and effective treatment. This systematic review aimed to synthesize recent clinical evidence on diagnostic and therapeutic strategies for DN. A comprehensive search of PubMed, EMBASE, CENTRAL, and Web of Science identified 76 eligible clinical studies published between 2020 and 2025, including randomized controlled trials, observational studies, and case reports. Data extraction and risk-of-bias assessment were performed according to PRISMA guidelines. Pharmacological agents, particularly pregabalin, duloxetine, and α-lipoic acid, demonstrated the most consistent efficacy, with significant pain reduction and improvements in nerve conduction velocity. Neuromodulation with high-frequency spinal cord stimulation provided sustained pain relief in refractory cases, while structured, exercise-based rehabilitation improved gait velocity and balance. Advanced wound care strategies, such as platelet-rich plasma dressings and bioengineered skin substitutes, accelerated ulcer healing. Complementary therapies (e.g., acupuncture and balneotherapy) and emerging biologics (e.g., gene- and cell-based interventions) showed preliminary promise but require further validation. Nerve conduction studies and validated scoring instruments remain the most reliable diagnostic tools, with biomarker- and microvascular-based measures emerging as valuable adjuncts. Current evidence underscores the value of integrating pharmacological, device-based, and rehabilitative strategies, while highlighting critical gaps in small-fiber and autonomic neuropathies. Robust, multicenter trials are needed to establish disease-modifying therapies and optimize comprehensive care pathways for DN.