Diabetic neuropathy (DN) affects 50–90% of patients with diabetes  and is an independent predictor of all-cause and diabetes-related mortality . It is also implicated in 50–75% of non-traumatic amputation. DN and vasculopathy are the two major causes of diabetic foot ulceration , and once an index foot ulcer develops, the 5-year mortality is greater than most cancers and comparable to that of lung cancer (5-year mortality ~50%) .
A lack of treatment options
No treatments targeting the pathogenesis of DN are approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Therefore, management of DN fundamentally involves targeting its risk factors to prevent progression, with particular emphasis given to improving and attaining good glycemic control. The American Diabetes Association (ADA) recommends timely neuropathy recognition.
Screening: A missed opportunity?
Early neuropathy identification is paramount to prevent progression, particularly given the lack of treatments targeting its pathogenesis. For diabetic complications such as retinopathy and nephropathy, we have screening methods that are appropriate and able to detect subclinical pathology, which allows clinicians to instigate early intervention(s) and individualized risk-based screening. By contrast, patients diagnosed with DN will be routinely followed up, commiserated with, and reviewed again in a year.
A valid neuropathy screening program is needed given the prevalence of neuropathy at diagnosis of type 2 diabetes (up to 50%) [5-7], in short-duration type 2 diabetes in youth (~22%) , and the preponderance of neuropathy in patients with impaired glucose tolerance [9, 10]. Our systematic review of published data suggests a neuropathy prevalence of ~18% in those with prediabetes (unpublished data). Indeed, this is much higher in studies quantifying small nerve fibers with sensitive tests such as skin biopsy or corneal confocal microscopy (CCM) [11, 12].
Bedside diagnostic testing
Clinical bedside diagnostic tests to identify foot ulceration risk include vibration perception with tuning fork, pinprick testing, and use of the 10 g monofilament. These tests present a number of issues:
- They are highly subjective;
- They only identify established neuropathy;
- Commonly used vibration sensation inappropriately targets the large nerve fibers, while 10 g monofilament detects the established at-risk diabetic foot.
Small fibers remain pivotal as they:
- constitute the majority of axons in the peripheral nervous system;
- are earliest to be damaged and regenerate; and
- have direct pathophysiological relevance to neuropathic pain generation , autonomic dysfunction-induced vasodilation , predisposition to foot ulceration, and may rapidly degenerate immediately prior to foot ulceration .
What have large clinical trials shown?
ACCORD and VADT failed to show significant neuropathy improvement with intensive glycemic control, using the Michigan Neuropathy Screening Instrument (MNSI) and neuropathy disability score (NDS) [15, 16]. Furthermore, the STENO-2 study, which targeted multiple risk factors in a population with type 2 diabetes and microalbuminuria, demonstrated significantly reduced cardiovascular disease incidence in the intervention group . STENO-2 secondary endpoints measured DN via vibration perception threshold, a large fiber test, whereas autonomic function was appropriately measured with surrogate cardiac autonomic function tests . Unsurprisingly, the relative risk of progression to autonomic neuropathy was lower in the intensively treated arm, but there was no statistical difference in the relative risk for DN . Failure to show any improvement in neuropathy may be attributed to the use of inappropriate surrogate endpoints.
Electrophysiology: An inappropriate surrogate endpoint for DN?
Inappropriate surrogate endpoints, primarily electrophysiology, that target large nerve fibers may have contributed to dramatic failures of phase III clinical trials of pathogenetic treatments. Electrophysiology has long been considered the “reference standard” surrogate endpoint in such trials, given its sensitivity, specificity, and reproducibility . Electrophysiology is still advocated by the FDA as a surrogate endpoint in DN clinical trials despite the ADA’s position statement . Compared with single-physician clinical diagnosis, nerve conduction study is excessively variable and frequently inaccurate, with overestimation of DN . Furthermore, there continues to be concern over the inter-observer variability of nerve conduction studies used in clinical trials .
Bringing small fiber neuropathy into the spotlight
Continued focus on large fiber modalities will exclude individuals with small fiber neuropathy (SFN) and subclinical disease. The earliest pathology in the diabetic peripheral neuropathy spectrum is SFN, with initial injury of small myelinated Aδ and unmyelinated C fibers, which progresses to larger nerves .
Does quantitative sensory testing hold the key?
Quantitative sensory testing of thermal thresholds is a non-invasive modality assessing small fiber dysfunction. This reliable, reproducible test can identify neuropathy in patients whose nerve conduction study appears normal [22, 23]. However, it is not widely used clinically due to the requirement for an array of instruments with a variety of specifications, algorithms, and normal values; hence, caution is needed in selecting test equipment and interpreting results . Additionally, this is a functional, subjective test, which does not directly quantify small nerve fibers, nor does it distinguish between central and peripheral dysfunction.
Small nerve fibers: A moving target
Modifying risk factors may reverse SFN. Smith et al. showed improved intra-epidermal nerve fiber density in patients with prediabetes following 12 months of diet and lifestyle modification . The current “reference standard” test for SFNs is intra-epidermal nerve fiber density measurement through skin biopsy . This allows direct visualization of thinly myelinated and unmyelinated nerve fiber damage and repair. Despite being a minimally invasive procedure, specialized laboratory services are required for its analysis. Skin biopsy is advocated in clinical practice in the USA , and as a clinical trial endpoint . But the lack of clinical laboratory services in the UK, for example, limits the availability of routine intra-epidermal nerve fiber skin biopsies in this territory.
Is CCM a game changer?
The lack of reproducible, quantitative, non-invasive SFN tests has triggered a search for novel surrogate markers for use in clinical trials and to aid early diagnosis.
…Corneal confocal microscopy’s reproducibility makes it an ideal endpoint to identify early neuropathy, define at-risk individuals, and monitor diabetic neuropathy progression.
Over the past 2 decades the use of corneal nerve imaging in systemic disorders, including diabetes, has become widespread . CCM has since become an established surrogate endpoint in diabetic peripheral neuropathy assessment [29, 30]. CCM is a rapid, non-invasive, objective technique, allowing direct small nerve fiber visualization in vivo . It is highly sensitive and specific in diagnosing early nerve fiber damage  and repair . CCM can detect subclinical small nerve fiber damage in patients with impaired glucose tolerance , and predict DN development , foot ulceration, and Charcot foot . CCM can identify nerve fiber regeneration after resolution to normoglycemia and renal function with simultaneous pancreas–kidney transplantation . Hence, CCM’s reproducibility makes it an ideal endpoint to identify early neuropathy, define at-risk individuals, and monitor DN progression .
The paucity of well-designed clinical trials with appropriate surrogate endpoints has contributed to the dramatic failure of novel pathogenetic therapies for DN. Two intertwined issues need to be urgently addressed:
- We need an appropriate surrogate measure of DN that can be utilized in interventional clinical trials and employed clinically to detect early subclinical disease, and determine disease development, progression, and improvement.
- We need a valid, individualized, risk-based DN population screening method.
Continued advocacy of measures that do not satisfy the principle definition of a surrogate endpoint (a clinical meaningful biomarker) for DN  is highly debatable . These considerations warrant considerable attention by the FDA, EMA, and the National Institute for Health and Care Excellence (NICE) as well as policy makers, if new therapies targeting DN pathogenesis are ever to be approved.