Diabetic Peripheral Neuropathy: An Unmet Clinical Need

January 08, 2014

MELBOURNE, Australia — Pharmaceutical options for diabetic peripheral neuropathy are sorely required, says one expert in the field.

Speaking at the International Diabetes Federation World Diabetes Congress 2013 in Melbourne last month, Rayaz A. Malik, MBChB, FRCP, PhD, from the Central Manchester University Teaching Hospitals and University of Manchester, United Kingdom, said: "We have no licensed treatment for diabetic neuropathy. We have witnessed failure after failure of numerous clinical trials despite great experimental data. None of these drugs has been translated into therapies we can prescribe to our patients."

One issue is that many of the trials of such agents have included patients who already have quite advanced neuropathy. The lack of simple, objective, sensitive tests to assess early nerve damage and repair is a limiting factor, said Dr. Malik. "The currently advocated tests, such as neurophysiology, focus on the large fibers, instead of the more abundant and clinically relevant small fibers," he noted.

"We need to critically look at the way we run these clinical trials and the end points used. If you have a test that is not sensitive enough for assessing early improvement, then despite million-dollar trial programs, the drug fails."

Neuropathy: A Microvascular Complication, Often Painful

Dr. Rayaz A. Malik

Dr. Malik, who specializes in treating diabetic peripheral neuropathy, explained that type 1 and type 2 diabetes are the commonest causes of painful neuropathy in the Western world, with 50% of patients with diabetes suffering from neuropathy, which can be painless or painful. Others causes of neuropathy include HIV neuropathy and chemotherapy-induced neuropathy (CIPN).

Around 20% of patients with diabetic neuropathy will suffer from pain, "which can be anything from mild discomfort to debilitating, can't-sleep-at-night pain, predominantly in the lower limbs and feet — sharp, jabbing pains, to the point where some patients can't even have bed sheets over their feet." He estimates that 5% of patients are "very badly affected."

As well as the pain, other complications of neuropathy include falls and foot ulcers, with the latter leading to digit, foot, or limb amputation if not managed correctly. The development of infections and ulcers can be reduced with good screening and surveillance programs.

Dr. Malik said it has become clear that neuropathy is "a microvascular complication" of diabetes, "just like nephropathy and retinopathy," and recent data have indicated that cardiovascular risk factors such as blood pressure and lipids are in fact stronger predictors of whether a patient will develop peripheral neuropathy than glucose control.

"Glucose control is advocated but at best has been shown to prevent progression in type 1 diabetes (in the DCCT studies) but not in type 2 diabetes [data from UKPDS, ACCORD, ADVANCE, and VADT]."

Improved blood-pressure control has been shown to work "in 2 small trials," he added, one with the ACE inhibitor trandolapril (Mavik, Abbott Laboratories) (Lancet.1998;352:1978-1981) and the other with a combination of the ACE inhibitor delapril and the calcium-channel blocker manidipine (Hypertension. 2011;58:776-783).

New UK Guidance for Diabetic Neuropathy Pain

There are treatments for the pain associated with neuropathy, however, although this is merely symptom relief and does not address the underlying nerve damage.

The therapeutic choices for pain relief are tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, and the antiepileptics gabapentin and pregabalin (Lyrica, Pfizer), Dr. Malik explained to Medscape Medical News.

Although the efficacy of all of these agents has been proven compared with placebo in randomized clinical trials, the evidence for gabapentin and tricyclic antidepressants in particular is "limited," he noted. And there have been very few head-to-head trials comparing these different treatments.

In fact, the treatment of painful diabetic neuropathy is "far from adequate, but…we make do with at least something, and at best 50% of patients get 50% pain relief," he observes. Side effects are also an issue, said Dr. Malik, especially from the centrally acting agents; these include "sedation, nausea, and off-target anticholinergic effects of the tricyclics such as postural hypotension and urinary retention."

Only duloxetine and pregabalin are actually licensed for use in diabetic neuropathy pain, he pointed out, with use of gabapentin and tricyclics being off-label for this condition. Most organizations worldwide recommend a choice of one of these agents, with slight variations in terms of which is first-, second-, or third-line choice of therapy.

In fact, in the United Kingdom, the National Institute for Health and Care Excellence (NICE) has just issued new guidance stating that duloxetine, pregabalin, gabapentin, and tricyclic antidepressants "can now all be considered as first-line agents," he explained. Until recently, duloxetine was indicated as first-line therapy for diabetic painful neuropathy there.

The new UK guidance — the pharmacological management of neuropathic pain in adults in nonspecialist settings — covers all types of neuropathic pain, not just diabetic.

The American Diabetes Association (ADA) has also recently drawn attention to the difficulties of treating diabetic painful neuropathy in its annually revised clinical-practice guidelines Standards of Medical Care in Diabetes — 2014. This year's report has a newly expanded section on diabetic neuropathy, going into greater detail about the various treatments and their limitations.

The section encourages physicians to be more persistent in urging patients to stay on pain medications long enough to give them a chance to work and using an individualized "trial-and-error" approach with different drugs and drug combinations.

"Neuropathy is a difficult condition to treat, and the meds we have aren't that good... This is an area that really requires communication between the care team and the patient," Richard Grant, MD, MPH, a research scientist at the Kaiser Permanente Division of Research, Oakland, California, and chair of the ADA Professional Practice Committee, told Medscape Medical News last month.

Fenofibrate and Corneal Confocal Microscopy

One building story is the potential role of triglycerides in diabetic peripheral neuropathy. Fenofibrate (Lipidil, Abbott), a triglyceride-lowering agent, has just been approved in its first market worldwide, Australia, for the treatment of diabetic retinopathy based on data from the FIELD study. The same study also showed that fenofibrate reduced minor amputations by 50%, explained Dr. Malik, noting that amputations were a prespecified end point of this trial.

Dr. Malik said some doctors do currently use fenofibrate for diabetic peripheral neuropathy, off-label, but that to gain an indication specifically for this use "will require a large clinical trial using the right end points."

Companies are reluctant to fund trials with amputations as an end point, as the studies take too long, he explained. "Instead, neuropathy end points have predominantly been clinical neurological examination for deficits (very variable and poorly reproducible) or neurophysiology (which assesses only large fibers that constitute 10% of nerve fibers and is also not very reproducible)."

Another reason many trials have failed in this field is that the patients included already had advanced neuropathy when they participated, he noted.

"More sensitive and quantitative measures of early nerve repair are needed to identify patients who are responding to treatment, providing a signal to continue, rather than abort a trial prematurely," he stressed.

One potentially useful technique that his team and others around the world have been pioneering is called corneal confocal microscopy (CCM). "This is an ophthalmic instrument that allows us, in a noninvasive way, to assess nerve fiber structure very sensitively."

Another sensitive technique is skin biopsy, but this has the disadvantage of being invasive. "When you have 2 tests with similar sensitivity: skin biopsy or CCM, which is totally noninvasive, the latter seems to be the logical route to go down."

Dr. Malik added that CCM can also show repair of nerves "even in patients with advanced neuropathy who have undergone pancreas and renal transplantation." The technique can also be employed in in a range of other neuropathies.

A review on this emerging technique, "An Eye on the Foot," on which he was senior author, was published in September last year (J Diabetes Sci Technol. 2013;7:1179–1189).

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