14 Apr 2025
A recent study has identified that the sodium-glucose cotransporter 2 inhibitor dapagliflozin, a medicine used to treat type 2 diabetes, can help to regenerate small nerve fibre and so reduce or reverse the impacts of diabetic peripheral neuropathy.
This study reinforces the benefits of early detection of small nerve fibre degeneration using Neuropad®, as breakthrough technologies make nerve regeneration a possibility. 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.
About the study
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 anti-diabetic drugs (Group A, N=22) or to continue their existing anti-diabetic 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), intra-epidermal 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 (a blood test used to determine average blood sugar level) 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 (intra-epidermal nerve fibre density) significantly increased in both groups.
- However, CNFD (corneal nerve fibre density), CNBD (corneal nerve branch density) and CNFL (corneal nerve branch density) 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.