Clinical Phenotypes of Diabetic Peripheral Neuropathy: Implications for Phenotypic-Based Therapeutics Strategies (Diabetes Metab J 2025;49:542-64)

Article information

Diabetes Metab J. 2025;49(6):1354-1355

Publication date (electronic) : 2025 November 1

doi : https://doi.org/10.4093/dmj.2025.0759

Jie-Eun Lee¹, Jong Chul Won^,2

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea

²Division of Endocrinology and Metabolism, Department of Internal Medicine, Gimpo Woori Hospital, Gimpo, Korea

Corresponding author: Jong Chul Won https://orcid.org/0000-0002-2219-4083 Division of Endocrinology and Metabolism, Department of Internal Medicine, Gimpo Woori Hospital, 11 Gamam-ro, Gimpo 10099, Korea E-mail: drwonjc@gmail.com

We sincerely appreciate your thoughtful and thorough response to our recent publication on phenotype-based therapeutic strategies for diabetic peripheral neuropathy (DPN) [1]. Your letter highlights several key issues that dig deeper into the clinical, diagnostic, and therapeutic implications of our proposed model, and we are grateful for your valuable contributions to this important discussion.

We agree that aligning phenotypic classifications with established clinical guidelines would enhance both their clinical relevance and applicability. Your observation regarding the omission of sodium channel blockers, particularly agents such as lacosamide and oxcarbazepine, is very relevant. As you noted, the 2024 and 2025 American Diabetes Association guidelines designate sodium channel blockers alongside tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids as first-line pharmacologic treatments for painful diabetic neuropathy [2]. Their inclusion would undoubtedly enrich the phenotypic framework and expand therapeutic options for patients with DPN.

This is supported by recent evidence from randomized controlled trials and a 2024 network meta-analysis comparing gabapentin, pregabalin, duloxetine, and oxcarbazepine in DPN. The analysis found that oxcarbazepine demonstrated high efficacy, second only to gabapentin, with a substantial proportion of patients achieving a ≥50% pain reduction [3], although it was associated with a higher rate of adverse events such as dizziness and headache. These findings reinforce the potential role of sodium channel blockers as effective alternatives for DPN patients, particularly in those who do not respond adequately to standard first-line therapies [4-6].

Your emphasis on the practicality of diagnostic approaches is equally appreciated. Although advanced techniques such as corneal confocal microscopy and functional neuroimaging provide detailed phenotyping, their limited availability in routine clinical practice highlights the need for more accessible alternatives. In line with your recommendation, we support the integration of feasible tools such as bedside neurological examinations, validated patient-reported outcome measures, and systemic biomarkers like the neutrophil-to-lymphocyte ratio (NLR) to enhance applicability to real-world practice. Notably, a recent meta-analysis of 15 studies reported significantly elevated NLR levels in patients with DPN compared to those without, demonstrating moderate diagnostic accuracy (sensitivity 0.67, specificity 0.70) and underscoring its potential as an inflammatory biomarker for DPN [7].

Furthermore, emerging research on sodium channel variants such as Nav1.7 offers promising avenues for personalized therapeutic approaches. For instance, a double-blind, placebo-controlled trial of a topical Nav1.7 channel antagonist for postherpetic neuralgia revealed greater efficacy in patients with specific Nav1.7 channel polymorphisms. Similarly, sodium channel blockers targeting Nav1.7 have demonstrated efficacy in small fiber neuropathy (SFN) [8,9]. In particular, the phase 2 Efficacy and safety of vixotrigine in idiopathic or diabetes-associated painful small fibre neuropathy (CONVEY) study evaluated vixotrigine, a voltage- and use-dependent sodium channel blocker, in participants with idiopathic or diabetes-associated painful SFN. In this enriched-enrollment randomized withdrawal trial, 200 mg vixotrigine twice daily met the primary endpoint of pain reduction at week 12, while both 200 and 350 mg doses were generally well tolerated. Numerically more participants treated with vixotrigine achieved a ≥30% reduction in average daily pain compared to placebo, supporting the potential of Nav1.7-targeted therapy in neuropathic pain subtypes [10]. These observations contrast with the generally modest efficacy of pharmacological treatments observed in broader overviews of neuropathic pain.

The view that phenotype-based strategies should complement, rather than replace, established evidence-based clinical protocols is one we strongly share. Such an integrative approach facilitates the delivery of personalized care within a rigorously validated framework that prioritizes safety, efficacy, and generalizability.

Thank you once again for your constructive commentary and for advancing the dialogue on precision medicine in diabetic neuropathy. Your insights are highly encouraging, and they reinforce our shared commitment to developing clinically actionable models that bridge the gap between pathophysiologic understanding and patient-centered care.