Dapagliflozin promotes small nerve fibre regeneration in diabetic peripheral neuropathy

Aims: To evaluate the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on small nerve fibre regeneration in individuals with type 2 diabetes (T2DM) and diabetic peripheral neuropathy (DPN).

Methods: Forty participants with DPN were randomised to receive either 10 mg dapagliflozin in addition to standard oral antidiabetic drugs (Group A, N=22) or to continue their existing antidiabetic therapy alone (Group B, N=18).  Both groups were comparable in age, duration of diabetes and weight.

Neuropathy was assessed at baseline and after 6 months using the Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT), intraepidermal nerve fibre density (IENFD) from skin biopsy, and corneal confocal microscopy (CCM) which quantified corneal nerve fibre density (CNFD), branch density (CNBD) and length (CNFL), Oxidative stress markers were also measured.

Results: HbA1c improved in both groups, with no significant changes in weight, body mass index, or lipid profiles. Group A showed an increase in neuropathic symptoms and signs, while group B remained stable. IENFD significantly increased in both groups. However, CNFD, CNBD and CNFL only improved in group A with no change in group B. In terms of oxidative stress, glutathione peroxidase levels significantly increased in group A, while malondialdehyde levels decreased in both groups.

Conclusions: These findings show that dapagliflozin contributes to small nerve fibre regeneration and improvements in oxidative stress markers, suggesting that SGLT2i therapy may offer neuroprotective benefits beyond glycaemic control.

Comments: SGLT2i therapy is now considered standard of care in the management of T2DM, with well-documented benefits in cardiovascular and renal protection (Zelniker TA et al Lancet. 2019;393:31-39; Heerspink et al N Engl J Med. 2020;383:1436-1446). However, its role in DPN remains uncertain. While preclinical studies have suggested neuroprotective effects through improvements in mitochondrial function, oxidative stress, and inflammation (Tsai et al., 2021), clinical evidence has been inconsistent reporting potential detrimental effect on DPN associated with SGLT2i use.

This study is a valuable contribution providing evidence that dapagliflozin may promote small nerve fibre regeneration in humans. A major strength lies in the use of objective and sensitive biomarkers – skin biopsy and CCM – adding rigour and credibility to the findings. The significant increase in CNFD, CNBD, CNFL and IENFD, alongside improvements in oxidative markers, supports a potential mechanistic link between SGLT2i inhibition and neural repair.

However, several limitations should be acknowledged, including the small sample size, relatively short follow-up duration (6 months), and open-label design, all of which may introduce potential bias and limit generalisability. The worsening of neuropathic symptoms and signs in the dapagliflozin group, despite the improvement in IENFD and CCM parameters, raises questions. This may reflect either measurement variability given the inclusion of both objective and subjective elements, or possibly reflect regeneration associated discomfort rather than a true symptom worsening.

Overall, this is an important study that highlights a potential neuroprotective effect of SGLT2i therapy and supports the need for larger, double-blind, and longer-term trials.

Alise Kalteniece

Reference: Adhikari U, Gad H, Chatterjee D, Malhotra C, Bhadada SK, Malik RA, Rastogi A. Dapagliflozin for Small Nerve Fibre Regeneration in Diabetic Peripheral Neuropathy: A Randomised Controlled Study (DINE). J Peripher Nerv Syst. 2025 Mar;30(1):e70011. doi: 10.1111/jns.70011. PMID: 40044634.

🔗 https://onlinelibrary.wiley.com/doi/10.1111/jns.70011