1. health and fitness
2. disease
3. diabetes

PROCEEDINGS
CURRENT AND EMERGING TREATMENTS FOR
DIABETIC PERIPHERAL NEUROPATHY*
—
Andrew J. M. Boulton, MD, DSc(Hon), FRCP†
ABSTRACT
Nonpharmacologic management of diabetic
peripheral neuropathy (DPN) includes early, frequent,
and conscientious foot examination, provision of
proper footwear, and counseling of patients who may
be insensate to injury of their feet. In addition, several
studies have revealed that both the risk and manifestations of DPN can be reduced with improved blood
glucose control. With respect to the pharmacologic
management of DPN, treatments generally fall into 2
main categories: those treatments that provide symptomatic relief for the pain, burning, paresthesias,
numbness, and tingling that mark this condition, and
those that actually influence the natural history of the
disease, which is progressive loss of limb function.
Because they may affect various important mechanisms of pain signaling, antidepressants, anticonvulsants, and analgesics all may be useful in the
treatment of DPN. In addition, a number of other
pathogenetic treatments are emerging. These include
the use of angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers. Lastly, a number of
non–Food and Drug Administration-approved investigational agents are being evaluated for use in averting or delaying microvascular complications. These
include: advanced glycation end-product receptor
blockers, aldose reductase inhibitors, α-lipoic acid,
poly (ADP-ribose) polymerase inhibitors, and protein
kinase C β inhibitors.
(Adv Stud Med. 2005;5(10D):S1038-S1046)
*Based on proceedings from a symposium that took
place on August 6, 2005, in Orlando, Florida.
†Professor of Medicine, University of Manchester,
Manchester, United Kingdom; University of Miami, Miami,
Fla; Chairman of the Diabetic Foot Study Group; Chairman
of Postgraduate Education, European Association for the
Study of Diabetes.
Address Correspondence to: Andrew J. M. Boulton,
MD, DSc(Hon), FRCP, Diabetes Research Unit, University of
Miami, PO Box 016960 (D110), Miami, FL 33101.
E-mail: [email protected].
S1038
A
number of treatment options exist for
diabetic peripheral neuropathy (DPN),
including early, frequent, and conscientious foot examination, provision of
proper footwear, and counseling of
patients who may be insensate to injury of their feet
(up to 50% of patients), placing them at high risk of
developing an ulcer that may lead to amputation. In
addition, the pharmacologic management of DPN
generally falls into 2 main categories: those treatments
that provide symptomatic relief for the pain, burning,
paresthesias, numbness, and tingling that mark this
condition; and those that actually influence the natural history of the disease, which is progressive loss of
limb function (Table 1).1
To begin, it is essential to exclude nondiabetic
causes. These may include: a paraneoplastic syndrome
and neuropathy associated with underlying malignancy, such as bronchogenic carcinoma. It also may result
from toxic exposure to such chemicals as alcohol, or a
long list of iatrogenic (specifically medication-related)
etiologies. For example, many drugs used in the treatment of infectious or malignant disease will lead to
loss of reflexes and perhaps to symptoms that resemble
those of DPN. Isoniazid used in management of
tuberculosis and the vinca alkaloids used in the treatment of Hodgkin's disease are 2 examples; however,
clinicians and patients must consider the risk-to-benefit ratio in these situations. If a patient is cured of an
underlying malignancy, peripheral neuropathy certainly may be considered the lesser of 2 evils. Both HIV
infection and HIV treatment also may account for
some cases of peripheral neuropathy. Furthermore,
other causes unrelated to diabetes should be investigated according to findings on clinical examination,
and may include laboratory examination for serum
B12, thyroid function, blood urea nitrogen, and serum
creatinine to rule out vitamin deficiency, hypothy-
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roidism, and uremia, respectively. If other conditions
have been excluded, a combination of typical symptomatology and distal sensory loss with absent reflexes,
or signs in the absence of symptoms, is highly suggestive of DPN.2 Once the diagnosis has been established,
the next step in treatment is to assess the level and stability of glycemic control.
ESTABLISHING AND MAINTAINING
GLYCEMIC CONTROL
The Diabetes Control and Complications Trial
(DCCT) has shown definitively that in patients with
type 1 diabetes, the risk of DPN can be reduced with
improved blood glucose control. Although not as
strong for patients with type 2 diabetes, data from a
small number of trials and from epidemiologic studies
strongly suggest that optimal blood glucose control
helps prevent DPN in both type 1 and type 2 diabetes.2 Thus, patients and clinicians must aim for stable glycemic control, avoiding swings in glycemia and
aiming for near-normoglycemia. Insulin is not always
needed in type 2 diabetes (normal glycated hemoglobin and blood glucose levels in the range of 70 to 140
mg/dL); such patients are not likely to benefit from
Table 1. Management of Diabetic Peripheral Neuropathy*
Symptomatic Relief
Influence Natural History
Medical
• Stable near-normoglycemia
• Tricyclics
• SSNRIs
• Antiepileptics
• Tramadol
•
•
•
•
•
Stable near-normoglycemia
ACE inhibitors
Aldose reductase inhibitors
α-lipoic acid†
Advanced glycation endproduct receptor blockers†
• PKC β inhibitors†
• PARP inhibitors†
• Benfotiamine†
• α-linolenic acid†
• Neurotrophic agents†
Physical
• Capsaicin
• Clonidine
• Acupuncture
• Electrical
SSNRIs = selective serotonin-norepinephrine reuptake inhibitors; ACE =
angiotensin-converting enzyme; PKC = protein kinase C; PARP = poly (ADPribose) polymerase.
*Data from Boulton et al. Diabetes Care. 2004;27:1458-14861; Boulton et
al. Diabetes Care. 2005;28:956-962.2
†Investigational agent.
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insulin therapy. It is important to explain to patients
that symptomatic improvement may be delayed after
stabilizing control.
In an early study, we treated outpatients with diabetic neuropathy with continuous subcutaneous
insulin infusion (CSII) for 4 months. Painful symptoms were scored on a 10-cm horizontal graphic rating
scale. Pain scores changed significantly (P < .1) from a
baseline of 7.2 to 2.2 by study end. In addition, motor
conduction velocity (MCV) was measured in the
median and peroneal nerves, and vibration perception
threshold (VPT) was recorded in the great toes.
Improved diabetic control was confirmed by significantly lower mean blood glucose levels, M-values
(baseline 85, study end 21.6; P < .1), and glycosylated
hemoglobin. In addition to the improvement in pain
scores, all patients noted symptom relief. Significant
improvement also was seen in VPT and MCV after 6
weeks of CSII, which was maintained throughout the
4-month period. However, sensory studies in the
median nerve showed no significant changes during
the study. The authors concluded that stable, nearnormoglycemic control is indicated in all cases of
symptomatic diabetic neuropathy.3
A later study that also utilized continuous glucose
monitoring demonstrated that patients with painful
neuropathy have very unstable control, with flux of
glycemia. Oyibo et al compared 2 matched groups of
patients (those with painful and those with painless
DPN) in terms of their mean glucose as well as the
mean amplitude of glucose excursions, concluding
that patients with painful neuropathy had greater glucose flux, and possibly poorer diabetes control. Thus,
it is hypothesized that blood sugar flux from low to
high brings on neuropathic pain, perhaps affecting less
receptive afferent fibers; however more investigation is
needed to support this conclusion.4 There is some evidence that certain nonsteroidal anti-inflammatory
medications (NSAIDs) might help, but extreme caution must be exercised when using nonsteroidal drugs
in patients with diabetic neuropathy, as these patients
also may have nephropathy and renal disease—both
contraindications to the use of NSAIDs.
MEDICATIONS USEFUL FOR TREATING SYMPTOMATIC
DIABETIC PERIPHERAL NEUROPATHY
The pathophysiology of the pain that accompanies
symptomatic diabetic neuropathy is not well under-
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stood, but undoubtedly involves complex pathways and
mechanisms that contribute to neuropathic pain signals.
For example, pain may result from hyperexcitability of
peripheral and central pain pathways mediated by sodium and calcium channels, by excitatory neurotransmitters such as glutamate, and/or reduced inhibition of
γ-aminobutyric acid (GABA). Antidepressants, anticonvulsants, and analgesics affect several of these mechanisms of pain signaling and therefore all may be useful
in the treatment of DPN (Table 2).
were examined. Twenty-one placebo-controlled treatments in 17 randomized-controlled trials were included, involving 10 antidepressants. In 6 of 13 diabetic
neuropathy studies, the odds ratios (ORs) showed significant benefit compared with placebo. The combined OR was 3.6 (95% confidence interval, 2.5–5.2),
with a number needed-to-treat for benefit of 3
(2.4–4). Comparisons of tricyclic antidepressants
failed to demonstrate any significant difference
between them; they were significantly more effective
than benzodiazepines in the 3 comparisons available.
Paroxetine and mianserin were less effective than
imipramine. In summary, the authors found that,
compared with placebo, 30 of 100 patients with neuropathic pain who are given antidepressants will
obtain more than 50% pain relief, 30 will have minor
adverse reactions, and 4 will have to stop treatment
because of major adverse effects.5 Early symptomatic
relief is typical and the efficacy is related to plasma
drug levels. Blockade of norepinephrine reuptake at
synapses of descending pain control systems is likely to
mediate the analgesic effect of these antidepressant
drugs.5,6 Furthermore, the pain relief effects are rapid
ANTIDEPRESSANTS
For the most part, the tricyclic antidepressant
drugs, such as imipramine (25 mg to 150 mg at night)
and amitriptyline (25 mg to 150 mg at night), remain
the first-line agents. This is because they are highly
effective, as demonstrated in randomized-controlled
trials. For example, in a meta-analysis by McQuay et
al, the effectiveness and safety of antidepressants in
neuropathic pain was examined via a review of randomized-controlled trials of such parameters as pain
relief or decrease in pain intensity (which approximated to more than 50% pain relief ); adverse effects also
Table 2. Drugs Used in the Treatment of Painful Diabetic Peripheral Neuropathy*
Drug Class
Drug†
Daily Dose
Side Effects
Tricyclics
Amitriptyline
Imipramine
25 to 150
25 to 150
++++
++++
SSRIs
Paroxetine
Citalopram
40
40
+++
+++
Anticonvulsants
Gabapentin
Lamotrigine
Carbamazepine
900 to 1800
200 to 400
Up to 800
++
++
+++
Antiarrhythmics
Mexiletine‡
Up to 450
+++
Opioids
Tramadol
Oxycodone CR§
50 to 400
10 to 60
+++
++++
SSRI = selective serotonin reuptake inhibitor.
*Reprinted from Boulton AJM, Malik RA, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27:1458-1486.1 Copyright © 2004 American
Diabetes Association. Reprinted with permission from the American Diabetes Association.
†All medications in the table have demonstrated efficacy in randomized-controlled studies.
‡Mexiletine should be used with caution and with regular electrocardiogram monitoring.
§Oxycodone CR may be useful as an add-on therapy in severe symptomatic neuropathy.
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and independent of mood changes (suggesting that
their efficacy is not related to treatment of depression).
These drugs also are inexpensive; however, the negative side to tricyclic antidepressants is the likelihood of
adverse effects—present in up to one third of all
patients. In particular, these drugs cause drowsiness
and anticholinergic side effects, especially dry mouth.
Thus, the clinician may need to consider other agents.
(Among other tricyclic antidepressants, desipramine
may be better tolerated than amitriptyline.6)
Certain selective serotonin reuptake inhibitors, for
example, paroxetine but not fluoxetine, also may produce significant pain relief with fewer side effects.6,7 In
addition, duloxetine, which is a serotonin and norepinephrine reuptake inhibitor (SNRI) newly approved
(September 2004) for treatment of painful diabetic
neuropathy, also has demonstrated efficacy. Goldstein
et al found it to be effective in a 12-week double-blind,
randomized clinical trial in 457 patients with painful
diabetic neuropathy. In all 3 active treatment groups a
greater number of patients achieved 50% reduction in
pain scores compared with placebo, and there were no
issues with safety or adverse effects.8
ANTICONVULSANTS
Anticonvulsants have been used in the management of neuropathic pain for many years. For example, carbamazepine may be useful, but adverse effects
are common. Gabapentin, although originally introduced as an anticonvulsant for complex partial
seizures, is now widely used for neuropathic symptoms. Its efficacy in diabetic neuropathy was proven in
a randomized, double-blind, controlled trial of 165
patients with symptomatic neuropathy; significant
pain relief together with reduced sleep disturbance
were reported using dosages of 300 to 3600 mg daily.9
Furthermore, in a meta-analysis published in 2003 of
all the trials of gabapentin for neuropathic pain, it was
concluded that dosages of 1800 to 3600 mg/day of
this agent were effective, with fewer side effects than
tricyclic medications.10 To avoid side effects, however,
it is advisable to begin with a low dose, such as 300 mg
at bedtime, and gradually titrate up to the effective
dose, which generally is 1800 mg daily.
Pregabalin is an analog of GABA. Like gabapentin,
it is an antiepileptic for complex partial seizures, but also
useful as an analgesic. Its efficacy in diabetic neuropathy
was demonstrated in a randomized double-blind trial of
146 patients given pregabalin at doses of 150 to 600
Advanced Studies in Medicine
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mg/day. Compared with placebo, daily pain scores were
lower and sleep disturbances fewer in patients who took
pregabalin. Furthermore, it has convenient twice-daily
dosage of 150 or 300 mg as compared with gabapentin’s
dosing schedule of 3 times per day.11
Lamotrigine and topiramate are 2 other new
antiepileptic medications with antinociceptive properties. In a randomized placebo-controlled study,
Eisenberg et al confirmed the efficacy of lamotrigine
in patients with neuropathic pain. Specifically, the
authors noted that pain scores in the lamotriginetreated group were reduced from 6.4 ± 0.1 to 4.2 ±
0.1 and in the control group from 6.5 ± 0.1 to 5.3 ±
0.1 (P < .001 for lamotrigine doses of 200, 300, and
400 mg).12 Topiramate also has been utilized effectively in the management of neuropathic pain.
Raskin et al conducted a 12-week, randomized, double-blind trial including 323 subjects with painful
DPN comparing topiramate (titrated to 400 mg
daily) with placebo. The investigators found that topiramate treatment reduced pain scores more effectively than did placebo (P = .038). Fifty percent of
topiramate-treated subjects and 34% of placebotreated subjects responded to treatment, defined as
>30% reduction in pain visual analog scale score
(P = .004). Topiramate monotherapy also reduced
worst pain intensity (P = .003 vs placebo) and sleep
disruption (P = .020 vs placebo).13
ANALGESIC MEDICATIONS
Tramadol, an opioid-like drug with fewer side
effects than opioids, was shown to be effective in a
randomized trial by Harati (and also in a 6-month
follow-up study) of 117 patients comparing tramadol
with placebo.14,15 Unfortunately, the predictable side
effects that accompany opioid and opioid-like medications were present, including nausea, somnolence,
and constipation.
Whereas there are limited data on the use of opioids in painful diabetic neuropathy, 2 recent randomized clinical trials of oxycodone controlled
release (CR) demonstrated significant improvement
in symptoms and quality of life. The first, a multicenter study by Gimbel et al, examined 159 subjects
given 10 to 60 mg per day of oxycodone vs placebo.
The mean dose necessary to demonstrate significant
relief of symptoms was 37 mg; however, at this range
of therapeutic dosages, side effects were exhibited in
96% of patients.16 In another single-center study by
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PROCEEDINGS
Watson et al, 36 subjects ingested oxycodone CR at
dosages of 10 to 80 mg/day vs active placebo (benztropine). As with the previous study, significant
improvement in symptoms and quality of life were
demonstrated in patients taking oxycodone (mean
dose 40 mg/day) and typical opioid adverse effects
were present in >90% of patients.17 Thus, oxycodone
CR may be useful in resistant cases of painful diabetic neuropathy, but other agents with less adverse
effects should be implemented first.
CARDIAC AGENTS: MEXILETINE AND NITRATE SPRAY
Mexiletine is a class 1B antiarrhythmic agent that
has been used short term for DPN in dosages of up
to 450 mg/day, which is lower than the usual dosage
for cardiac use. Its efficacy has been confirmed in
controlled trials1; however, like oxycodone, it is not a
first-line therapy nor can it be recommended for
long-term use because of potential adverse effects.
During use of mexiletine, regular electrocardiogram
monitoring is necessary.1
Another traditional cardiac medication that has been
studied for use in DPN is isosorbide dinitrate (ISDN)
spray. The basis for its use is the theory that impaired
nitric oxide (NO) generation is involved in the pathogenesis of diabetic neuropathic pain. ISDN is an NO
donor with local vasodilating properties, and in a study
by Yuen, it was applied locally to the feet to ascertain
what effect, if any, it would have on pain. The study was
double-blind, randomized, and placebo-controlled with
22 subjects either using ISDN or placebo sprays for 4
weeks, or then exchanging their treatment for a further 4
weeks after a 2-week washout period. ISDN spray
reduced overall neuropathic pain (P = .02) and burning
sensation (P = .006). No treatment difference was
observed with other sensory modalities (eg, hot/cold sensation, tingling, numbness, hyperesthesia, and jabbinglike sensation). At study completion, 11 patients (50%)
reported benefit and wished to continue using the ISDN
spray, 4 (18%) preferred the placebo, and the remaining
7 (32%) were undecided. Thus, ISDN spray may represent a new therapeutic approach to neuropathic pain
management. (Nitrate patches also may be efficacious.18)
Other local treatments that have been used with success
in some patients include acupuncture and electrical therapy. However, all of these target symptoms rather than
altering the natural history of microvascular complications, which is the aim of the therapies considered in the
sections that follow.
S1042
TREATMENTS THAT INFLUENCE DISEASE
NATURAL HISTORY
GLYCEMIC CONTROL
Hyperglycemia plays a role in both the symptomatology and natural history of DPN. The Rochester
Diabetic Neuropathy Study Group conducted a longitudinal study of 264 individuals with diabetes over a
span of 7 years. In multivariate analysis, the severity
level of neuropathy was associated with the severity level
of retinopathy, nephropathy (as measured by 24-hour
proteinuria multiplied by duration of diabetes), and
mean glycated hemoglobin.19 This and other studies
point to the fact that achieving near-normoglycemia is a
vital step in both the prevention and treatment of DPN.
However, a number of other pathogenetic treatments are emerging. These include the use of
angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARBs) (Table 3). Of the
latter group, only irbesartan and losartan are Food and
Drug Administration (FDA) approved for the treatment of diabetic complications.
ANGIOTENSIN-CONVERTING ENZYME INHIBITION
Clinical trials have demonstrated that ACE
inhibitors delay progression of other microvascular
complications of diabetes mellitus (DM)—specifically,
both diabetic nephropathy and retinopathy—in type 1
and type 2 diabetes.21,22 Building upon that concept,
Mallik et al investigated the effect of ACE inhibition
on diabetic neuropathy. The authors conducted a
small, randomized, double-blind, placebo-controlled
study over 1 year of 41 normotensive patients with
type 1 or type 2 DM and mild neuropathy.
Neuropathy symptoms and deficits were evaluated
based on VPT, peripheral-nerve electrophysiology, and
cardiovascular autonomic function. Peroneal nerve
motor function improved after 12 months in the
group using ACE inhibitors compared with placebo,
regardless of diabetes type.20 Thus, given the benefit
that these drugs provide, it is prudent to administer
them to all patients with diabetes, unless they are otherwise contraindicated.
INVESTIGATIONAL AGENTS FOR DIABETIC
MICROVASCULAR COMPLICATIONS
A number of non–FDA-approved investigational
agents also are being evaluated for use in averting or
delaying microvascular complications. These include
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Figure 1. Signaling Pathways Involved in Diabetic
Complications: Aldose Reductase Pathway Theory*
*Reprinted with permission from Sheetz MJ, King GL. JAMA .
2002;27:2579-2588.24
NAD = nicotinanide adenine dinucleotide; NADH = reduced NAD;
NADP+ = oxidized form of NAP phosphate; NADPH = reduced
NAD phosphate.
advanced glycation end-product (AGE) receptor
blockers, aldose reductase inhibitors (ARIs), benfotiamine, α-lipoic acid, poly (ADP-ribose) polymerase
(PARP) inhibitors, and protein kinase C (PKC)
β inhibitors.
ALDOSE REDUCTASE INHIBITORS
There are a number of signaling pathways
involved in glucose metabolism, and whereas chronic hyperglycemia is key at the beginning of all of
these pathways, sustained alteration in cell signaling
pathways (such as changes in phospholipids or
kinases) induced by the products of glucose metabolism may ultimately lead to microvascular complications. For example, animal models of diabetes
consistently demonstrate an association between the
alterations in the polyol pathway and nerve conduction velocity—both of which can be improved with
ARIs (Figure 1).24 However, it may not be as clearcut in human subjects. A meta-analysis of all randomized-controlled trials of ARIs identified 19
trials, testing 4 different ARIs for 4 to 208 weeks. It
demonstrated a small but statistically significant
reduction in decline of median and peroneal motor
nerve conduction velocity, but no benefit in sensory
nerves.25 This was unfortunate because it is mainly
loss of sensation—and not motor function—that is
cause for grave concern, as it is the latter that leads
to ulcer formation and amputation in patients with
DPN. Furthermore, trials of ARIs were either flawed
(too short-lived to demonstrate a benefit for a con-
Table 3. Angiotensin-Converting Enzyme and Angiotensin Receptor Blocker Therapy for Diabetic
Microvascular Complications
ACE inhibitor in mild DPN20
Peroneal motor nerve conduction velocity only improved after 12 months for type 1 and type 2
diabetes compared with placebo.
ACE inhibitor in diabetic retinopathy21
Over 5 years, fewer patients with type 2 diabetes randomized to intensive therapy vs placebo had
progression (13% vs 21%).
ACE inhibitor in diabetic nephropathy22
50% reduction in risk of the combined endpoints of death, dialysis, and transplantation.
ARB* in diabetic nephropathy23
Reduction in risk of ESRD (28%) and doubling of serum creatinine concentration (25%) in patients
with type 2 diabetes.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; DPN = diabetic peripheral neuropathy; ESRD = end-stage renal disease.
*Of the ARBs, only irbesartan and losartan are FDA approved for the treatment of diabetic complications.
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dition that takes years to impact; too few patients
under study; or intervention took place too late), or
the drugs themselves were toxic or ineffective.
Hence, there is only 1 drug (epalrestat) available in
this class for DPN, and it is marketed only in Japan.
ANTIOXIDANTS: α-LIPOIC ACID
Oxidative stress also may play an important role
in diabetic neuropathy—both from a symptom and
pathogenetic vantage point. There have been 2 large
German trials to date investigating this using the
antioxidant α-lipoic acid (ALA). The Alpha Lipoic
Acid in Diabetic Neuropathy (ALADIN) study
showed that intravenous ALA administered for 3
weeks resulted in significant symptom relief for
patients with diabetic neuropathy.26 Another, the
Deutsche Kardiale Autonome Neuropathie
(DEKAN) study, utilized oral ALA for 6 months
resulting in significant improvement in cardiac autonomic neuropathy tests.26 One additional investigation, the SYDNEY trial, randomized 120 patients to
receive either intravenous ALA or placebo, and
again, the patients receiving ALA demonstrated significant improvement in their neuropathic symptoms without side effects.27 As of this writing, there
are 2 large multinational studies in progress—one
using intravenous therapy and the other oral therapy; the results of these studies in terms of whether
this antioxidant reduces symptoms, or whether it
may slow the natural history of progression of loss of
nerve fibers, are forthcoming.
POLY (ADP-RIBOSE) POLYMERASE (PARP) AND
GLYCATION INHIBITORS
PARP is a nuclear enzyme toxic to β cells and
involved in the development of brain dysfunction in
diabetic neuropathy. It has been discovered that PARP
inhibition reverses diabetic endothelial dysfunction in
diabetic mice, and in general seems to protect against β
cell destruction. Once again, a signaling pathway is
involved in this, and studies of aminoguanidine, which
inhibits the formation of AGEs, thus far has been
found to be useful in nephropathy. The usefulness of
these types of agents for DPN remains to be seen.
PROTEIN KINASE C (PKC) β INHIBITION: RUBOXISTAURIN
Intracellular hyperglycemia increases intracellular
1,2-diacylglycerol accumulation, and this leads to
activation of PKC that may ultimately lead to cellu-
S1044
lar dysfunction and damage in the nerves (Figure
2).24 This, in turn, results in numerous pathogenetic
consequences (eg, formation of NO and vascular
endothelial growth factor. Treatment with the PKC
β inhibitor ruboxistaurin might improve nerve function in patients with DPN. Vinik et al conducted a
phase 2, 1-year, randomized-controlled trial of
ruboxistaurin vs placebo. The authors noted symptomatic improvement at 6 and 12 months (Figure
3),28 and although phase 3 studies for neuropathy
have not been as encouraging, studies are ongoing,
and PKC β inhibitors appear to have an impact on
other microvascular complications, such as aspects
of diabetic retinopathy.
CONCLUSION
First-line treatment for diabetes complications
includes control of hyperglycemia, body weight, dyslipidemia, and high blood pressure. Treatments for
DPN can influence disease natural history and/or
provide symptom relief, although treatments that
influence pathogenesis are mainly experimental at
this point in time. Microvascular therapy may
include a range of drugs used off label, including tricyclic antidepressants; FDA-approved treatments for
painful DPN include the SNRI duloxetine and the
antiepileptic pregabalin. Emerging therapies differentially affect pathogenetic signaling through the
aldose reductase, AGE, and PKC β signaling pathways, and clinical trials are suggestive of some use of
these drugs in this area. Lastly, the American
Diabetes Association published a position statement
in 2005 that states that diabetic neuropathy is a
diagnosis of exclusion.
Tight glycemic control is the only proven preventative treatment. For patients with type 1 diabetes,
screening for DPN should commence after 5 years of
disease. For patients with type 2 diabetes, results
from the United Kingdom Prospective Diabetes
Study showed that 13% of patients at diagnosis have
neuropathy of significant enough severity to be at
risk of foot ulcers. Therefore, screening annually
from the date of diagnosis is advised for all patients
with type 2 diabetes.
Clinical history and physical examination of the
feet are essential to making an accurate diagnosis,
though quantitative sensory testing and electrophysiology should not be used routinely—but only in occa-
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Figure 2. Signaling Pathways Involved in Diabetic
Complications: Protein Kinase C Theory*
sional cases. Several evidence-based therapies are available for symptomatic neuropathy, and research is
ongoing to continue to develop treatment for this
potentially devastating complication of DM.
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ROI = region of interest; AGE = advanced glycation end-product; NADPH =
reduced NAD phosphate.
*Reprinted with permission from Sheetz MJ, King GL. JAMA. 2002;27:2579-2588.24
Figure 3. Ruboxistaurin Mesylate: Diabetic
Neuropathy Symptoms*
*Reprinted with permission from Vinik et al. Diabetes. 2002;51(suppl 2):
A79, 321-OR.28
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