Oral, intravenous, or sequential alpha-lipoic acid for diabetic peripheral neuropathy? A Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVE

Alpha-lipoic acid (ALA) is widely utilized for diabetic peripheral neuropathy (DPN); however, optimal administration routes (oral, intravenous [IV], or sequential) remain debated. This study evaluates and ranks their efficacy and safety through a Bayesian network meta-analysis (NMA) equipped with rigorous bias-exclusion frameworks.

METHODS

The PubMed, Embase, Web of Science, Cochrane Library, and Scopus databases were systematically searched (up to 2025) to identify randomized controlled trials (RCTs) comparing oral, intravenous, and sequential ALA therapies, as well as placebo, encompassing varying dosages (600-1,800 mg/d) and treatment durations (3 to 208 weeks), for DPN. Core outcome measures included the Total Symptom Score (TSS), Neuropathy Impairment Score (NIS), Neuropathy Impairment Score in the Lower Limbs (NIS-LL), and Global Satisfaction (GS). The NMA was conducted using a Bayesian framework in R software. Interventions were ranked by calculating the surface under the cumulative ranking curve (SUCRA), and a dual-outcome plot was constructed to evaluate the benefit-risk ratio. Evidence certainty was evaluated via CINeMA, and sensitivity analyses were executed by excluding high-bias studies.

RESULTS

Nine high-quality RCTs were included. Initially, sequential ALA therapy demonstrated overwhelming superiority in improving TSS and NIS. However, CINeMA evaluations revealed severe within-study bias, and sensitivity analyses exposed this initial superiority as an artifact. In the unbiased network, IV ALA emerged as the absolute optimal intervention for rapidly alleviating subjective symptoms (TSS) and overall objective signs (NIS), achieving a "dual-optimal" efficacy-safety profile that completely bypasses gastrointestinal risks. Confronting the most refractory distal impairment (NIS-LL), oral ALA stood alone as the sole surviving intervention supported by robust, completely homogeneous evidence (I2 = 0%, SUCRA: 97.4%) for structural repair. Both standalone IV and oral routes significantly enhanced global patient satisfaction.

CONCLUSION

The optimal ALA administration is stage-dependent. IV ALA delivers unmatched acute neurovascular rescue, while oral ALA serves as the indispensable cornerstone for long-term distal structural repair. Importantly, rather than negating sequential therapy, these distinct phase-specific benefits fundamentally validate its core "induction-maintenance" clinical rationale. While unbiased evidence for the integrated sequential regimen remains sparse-necessitating future large-scale, double-blinded RCTs-the sequential framework itself is robustly justified by the verified strengths of its constituent phases.

SYSTEMATIC REVIEW REGISTRATION: CRD420261411001.