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Review
. 2025 Jun;16(6):1077-1105.
doi: 10.1007/s13300-025-01712-z. Epub 2025 Mar 28.

The Therapeutic Potential of Dipeptidyl Peptidase 4 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in Diabetic Peripheral Neuropathy

Theodoros Panou  1 , Evanthia Gouveri  1 , Djordje S Popovic  2 , Dimitrios Papazoglou  1 , Nikolaos Papanas  3
Affiliations
Review

The Therapeutic Potential of Dipeptidyl Peptidase 4 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in Diabetic Peripheral Neuropathy

Theodoros Panou et al. Diabetes Ther. 2025 Jun.

Abstract

Diabetic peripheral neuropathy (DPN) is one of the commonest complications of diabetes mellitus (DM). Current therapeutic approaches largely focus on pain management. However, less evidence is available on the clinical potential of two widely prescribed drug categories in DM management: dipeptidyl peptidase 4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs). In this review, we discuss evidence from both experimental and clinical studies on the potential utility of these drugs in the management of DPN. Immunohistochemical data indicate that agents in both categories promote neurite outgrowth, ion conduction, neuronal survival and Schwann cell function. Furthermore, intra-epidermal nerve fibre density has been reported to increase with DPP-4is or GLP-1RAs treatment. Moreover, electrophysiological studies have indicated a diverse, but mostly beneficial, effect on motor or sensory nerve conduction velocity. Clinical tests, such as the muscular grip or paw jumping control resembling neuropathic symptoms, have also confirmed the advantageous effect of DPP-4is and GLP-1RAs. Finally, limited but promising clinical data have shown improved somatosensory-evoked potentials and vibration perception threshold, as well as restored excitability and nerve size parameters. Nevertheless, further clinical studies are required to elucidate the exact role of DPP-4is and GLP-1RAs in DPN.

Keywords: Diabetic peripheral neuropathy; Dipeptidyl peptidase 4 inhibitors; Glucagon-like peptide-1 receptor agonists; Type 1 diabetes mellitus; Type 2 diabetes mellitus.

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Conflict of interest statement

Declarations. Disclosures: Theodoros Panou has nothing to disclose. Evanthia Gouveri has attended conferences sponsored by Berlin-Chemie, Sanofi, AstraZeneca, Novo Nordisk, Lilly and Boehringer Ingelheim; and received speaker honoraria from Boehringer-Ingelheim, Sanofi and Menarini. Djordje S Popovic declares associations with Abbott, Alkaloid, Amicus, AstraZeneca, Boehringer Ingelheim, Berlin-Chemie, Eli Lilly, Galenika, Krka, Merck, Novo Nordisk, PharmaSwiss, Sanofi-Aventis, Servier, Viatris and Wörwag Pharma. Dimitrios Papazoglou declares associations with Menarini, Novo Nordisk, Astra-Zeneca, Boehringer Ingelheim and Sanofi-Aventis. Nikolaos Papanas has been an advisory board member of Astra-Zeneca, Bayer, Boehringer Ingelheim, Menarini, MSD, Novo Nordisk, Pfizer, Takeda and TrigoCare International; has participated in sponsored studies by Astra-Zeneca, Eli-Lilly, GSK, MSD, Novo Nordisk, Novartis and Sanofi-Aventis; has received honoraria as a speaker for Astra-Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Elpen, Menarini, MSD, Mylan, Novo Nordisk, Pfizer, Sanofi-Aventis and Vianex; and has attended conferences sponsored by TrigoCare International, Eli-Lilly, Galenica, Menarini, Novo Nordisk, Pfizer and Sanofi-Aventis. Nikolaos Papanas is an Editorial Board member of Diabetes Therapy. Nikolaos Papanas was not involved in the selection of peer reviewers for the manuscript or any of the subsequent editorial decisions. Ethical approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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