On a Phenotypic Approach to Diabetic Peripheral Neuropathy (Diabetes Metab J 2025;49:542-64)

Antonio Alcántara Montero

doi:10.4093/dmj.2025.0611

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Letter On a Phenotypic Approach to Diabetic Peripheral Neuropathy (Diabetes Metab J 2025;49:542-64): Antonio Alcántara Montero; Diabetes & Metabolism Journal 2025;49(6):1349-1350.
DOI: https://doi.org/10.4093/dmj.2025.0611
Published online: November 1, 2025

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Trujillo Health Center (Centro de Salud Trujillo), Trujillo (Cáceres), Spain

Corresponding author: Antonio Alcántara Montero

Trujillo Health Center (Centro de Salud Trujillo), Molinillo Square, 2, 10200, Trujillo (Cáceres), Spain E-mail: a.alcantara.montero@hotmail.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the article "Clinical Phenotypes of Diabetic Peripheral Neuropathy: Implications for Phenotypic-Based Therapeutics Strategies" on page 542.

I read with considerable interest the recent publication by Lee and Won [1] on phenotype-based therapeutic strategies in diabetic peripheral neuropathy (DPN). As one of the most prevalent and disabling complications of diabetes, DPN profoundly affects patient quality of life and poses persistent challenges in clinical management. Therefore, any effort aiming to refine the therapeutic paradigm deserves close consideration.

The authors present a classification of DPN based on pain characteristics and underlying mechanisms, aiming to match each phenotype with targeted treatments. This effort reflects a conceptual move toward personalized medicine and is enriched by the use of advanced diagnostic tools—quantitative sensory testing, corneal confocal microscopy, and functional neuroimaging. These technologies, together with detailed sensory descriptors such as burning, paroxysms, or mechanical allodynia, help define clinical subgroups that may benefit from tailored interventions.

While the proposed phenotypic framework is promising and includes several recommended therapeutic classes such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants, it does not explicitly incorporate sodium channel blockers, an evidence-based group endorsed by major guidelines. Their omission narrows the treatment scope and may overlook options with distinct efficacy profiles across phenotypes. Integration with current therapeutic standards could further strengthen clinical applicability. The Standards of Care in Diabetes 2025 from the American Diabetes Association recommend these same drug classes, while discouraging opioids such as tramadol and tapentadol due to limited long-term benefit and safety concerns [2]. This position is reinforced by the American Academy of Neurology’s 2021 guideline, which confirms comparable efficacy among recommended options and strongly advises against opioid use, even in refractory presentations [3].

Incorporating consensus-based guidelines into the phenotypic model would enhance credibility and support safer, scalable implementation. Rather than replacing standard protocols, phenotype-specific considerations may complement guideline-driven treatment by enabling rational adaptation to individual clinical features.

Additionally, the article’s focus on symptom-driven subtypes would be strengthened by discussing response predictors. Neurobiological factors, including dopaminergic connectivity, prefrontal cortical activity, and sodium channel variants like Nav1.7, have emerged as markers of therapeutic response [4,5]. Practical clinical variables such as age, glycemic status, pain duration, and onset may also help tailor decisions more effectively.

A particularly accessible marker is the neutrophil-to-lymphocyte ratio (NLR), which has been found elevated in patients with DPN versus diabetic individuals without neuropathy [4]. While NLR does not predict specific drug outcomes, it may help identify inflammatory profiles relevant to disease progression or multimodal intervention. Including such metrics could facilitate phenotype-based approaches in less specialized care environments.

The temporal dimension of pain also merits consideration. Pregabalin has shown efficacy across all stages of pain duration in pooled analyses of more than 5,700 patients [6], while topical capsaicin appears less effective in chronic, long-standing DPN [7]. These findings suggest that phenotype-based therapy would benefit from aligning with disease chronology to optimize outcomes.

Finally, the proposed diagnostic modalities, though clinically rich, may face constraints outside research settings. For the phenotypic framework to be broadly implemented, it should incorporate pragmatic tools such as bedside neurological assessments, validated questionnaires, and scalable biomarkers. These additions would bridge the gap between theoretical precision and operational feasibility.

In summary, the article offers a valuable conceptual model for personalized treatment in DPN. Its clinical impact would be enhanced by reinforcing alignment with established guidelines, expanding therapeutic scope to include sodium channel blockers, and integrating practical predictors and diagnostic tools. The phenotypic approach should serve as a complementary lens that adds biological context to established protocols and supports individualized care.

DPN remains a multifaceted condition, and its future management must combine diagnostic sophistication with realworld practicality. By bridging phenotypic insight with guideline-informed therapy, predictive markers, and scalable methods, we can advance toward precision medicine that is both intellectually rigorous and clinically actionable.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Lee JE, Won JC. Clinical phenotypes of diabetic peripheral neuropathy: implications for phenotypic-based therapeutics strategies. Diabetes Metab J 2025;49:542-64.Article PubMed PMC PDF
2. American Diabetes Association Professional Practice Committee. 12. Retinopathy, neuropathy, and foot care: standards of care in diabetes-2025. Diabetes Care 2025;48(1 Suppl 1):S252-65.PubMed
3. Price R, Smith D, Franklin G, Gronseth G, Pignone M, David WS, et al. Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary: report of the AAN guideline subcommittee. Neurology 2022;98:31-43.PubMed
4. Alcantara Montero A, Pacheco de Vasconcelos SR. Are we heading towards individualized neuropathic pain treatment? Rev Esp Anestesiol Reanim (Engl Ed) 2022;69:510-1.Article PubMed
5. Alcantara Montero A, Pacheco de Vasconcelos SR. Comment on ‘The effect of lacosamide in peripheral neuropathic pain: a randomized, double-blind, placebo-controlled, phenotype-stratified trial’ by Carmland et al. Eur J Pain 2024;28:174-5.Article PubMed
6. Perez C, Latymer M, Almas M, Ortiz M, Clair A, Parsons B, et al. Does duration of neuropathic pain impact the effectiveness of pregabalin? Pain Pract 2017;17:470-9.Article PubMed PDF
7. Maihofner CG, Heskamp ML. Treatment of peripheral neuropathic pain by topical capsaicin: impact of pre-existing pain in the QUEPP-study. Eur J Pain 2014;18:671-9.Article PubMed PDF

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On a Phenotypic Approach to Diabetic Peripheral Neuropathy (Diabetes Metab J 2025;49:542-64)

Diabetes Metab J. 2025;49(6):1349-1350. Published online November 1, 2025

DOI: https://doi.org/10.4093/dmj.2025.0611

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On a Phenotypic Approach to Diabetic Peripheral Neuropathy (Diabetes Metab J 2025;49:542-64)

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Montero AA. On a Phenotypic Approach to Diabetic Peripheral Neuropathy (Diabetes Metab J 2025;49:542-64). Diabetes Metab J. 2025;49(6):1349-1350.

DOI: https://doi.org/10.4093/dmj.2025.0611.

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