Diabetic peripheral neuropathy is a length dependent axonal neuropathy that affects at least
50% of patients with diabetes mellitus. It is characterized by sensory loss and pain that
initially affects small unmyelinated C fibers which is followed by involvement of the large
myelinated fibers as diabetes progresses. DPN is often asymptomatic during the early stages
of diabetes ,however, once symptoms and overt deficits have developed, it cannot be reversed.
Early diagnosis of neuropathy is thus important because early diagnosis and timely
intervention might prevent the development and progression if diabetic neuropathy and might
provide us with a means to identify patients at high risk for future complications of DPN
which includes risk of foot ulcers and lower limb amputation.
Methods to quantify neuropathy include clinical scores based on symptoms and neurological
tests, quantitative sensory testing, electrophysiological measurements, in the form of nerve
conduction studies and intraepidermal nerve fiber density in skin biopsy specimens. The
neurological examination involves an assessment, such as modified neuropathy disability
score, a composite score that assesses touch, temperature and vibration perception and
reflexes, which require expert clinical judgement, a strong element of subjectivity and hence
poor reproducibility. Neurophysiology is objective and reproducible and is currently
considered to be the most reliable measurements for confirming the diagnosis of diabetic
neuropathy. However, these measures mainly assess large nerve fibers, making them less
sensitive to early DPN,which is more likely to involve the small fibers to begin with.
Objective measures are thus required to accurately determine nerve pathology to detect early
stages of DPN, which may be more susceptible to intervention than late-stage sequelae. Small
fibers, which constitute 70-90% of peripheral nerve fiber, may be measured in skin biopsies by
assessing intraepidermal nerve fiber density, which is considered to be the gold standard for
the evaluation of small fibers damage. Indeed, the European Federation of the Neurological
Societies and the Peripheral Nerve Society endorse intraepidermal nerve fiber quantification
to confirm the clinical diagnosis of small fiber neuropathy with a strong (Level
A)recommendation.
Recently, corneal confocal microscopy (CCM), a noninvasive modality for the study of the
human cornea, has emerged as a promising technique for the detection of small nerve fiber
alterations. CCM is a rapid non-invasive imaging technique for the quantitative assessment of
small fiber damage. Several studies have shown that it has good diagnostic utility for
sub-clinical DPN, predicts incident DPN and correlates with other measures of neuropathy .
Furthermore, automated quantification of corneal nerve parameters allows rapid, unbiased and
objective assessment of small fiber damage with comparable diagnostic capability to
intraepithelial nerve fiber density (IENFD). Recent data also suggest that CCM shows good
reproducibility and could be useful to document nerve regeneration after treatment and
simultaneous pancreas and kidney transplantation.
There is currently no Food and Drug Administration (FDA) approved therapy to prevent or
reverse human DPN. The current management approach focuses on reasonable glycemic control,
and management of associated pain. Sodium-glucose cotransporter 2 (SGLT2) inhibitors as oral
hypoglycemic agents have been approved for treating type 2 diabetes mellitus (T2DM). The
insulin-independent action mechanism and extra-metabolic benefits of these agents have
encouraged ongoing preclinical and clinical trials for evaluating the efficacy and safety of
SGLT2 inhibitors. In addition to glucose-lowering effects without hypoglycemia, SGLT2
inhibitors retard the development and progression of diabetic complications. However, it is
uncertain whether this effect of SGLT2 inhibitors is due to their glucose-lowering effect or
not. In addition, unlike diabetic nephropathy, the effects of SGLT2 inhibitors on diabetic
peripheral neuropathy are unexplored.
To date, only three studies regarding the effects of SGLT2 inhibitors for DPN in T2DM animal
models are reported. Investigators evaluated neuronal effects in terms of simple functional
parameters, such as motor nerve conduction velocity and tail flick test. Results of these
studies verified the beneficial effects of SGLT2 inhibitors for DPN, and these effects were
considered to indirect effects of the improvement of hyperglycemia.
Since no human studies have yet been conducted using SGLT2 inhibitors in the prevention and
progression of diabetic neuropathy, hence, investigators plan to conduct a randomized
controlled trial evaluating the efficacy of dapagliflozin in diabetic peripheral neuropathy
