Document Sample

                               EPIDEMIOLOGY AND ETIOLOGY OF
                              DIABETIC PERIPHERAL NEUROPATHIES*
                                                Solomon Tesfaye, MD, FRCP†

                       ABSTRACT                                     of reflexes and sensory responses to vibration,
                                                                    light touch, pinprick, and the 10-g monofilament.
        Although diabetic peripheral neuropathy                     Other tests to measure various thresholds are
    (DPN) affects up to 50% of patients with diabetes,              available as well.
    it has in some respects been considered the                          Several drugs and nonpharmacologic modal-
    “Cinderella” of microvascular complications of                  ities are available to treat painful DPN, but their
    diabetes, receiving less attention than it deserves             efficacy and tolerability vary. Recent evidence of
    with regard to screening, early detection, treat-               central nervous system involvement in DPN may
    ment, and prevention.                                           open new avenues of investigation for the devel-
        The clinical manifestations of DPN are pain                 opment of rational therapies.
    (often experienced as burning, tingling, or allody-                  The promise of the aldose reductase inhibitors
    nia) and insensitivity, which dramatically increases            in the treatment of DPN has not been fully real-
    the risk for burns, injuries, and foot ulceration.              ized. Newer aldose reductase inhibitors are
        Risk factors for DPN include poor glycemic                  undergoing clinical trials. Other interventions,
    control, duration of diabetes, hyperlipidemia,                  such as α-lipoic acid and ruboxistaurin, show
    elevated albumin excretion rate, and increased                  promise in reducing pain. In addition, according
    body mass index. DPN also is associated with                    to study results, ruboxistaurin appears to have
    cardiovascular disease and mortality and is sec-                beneficial effects on nerve impairment and pain
    ond only to macroangiopathy as an independent                   symptoms in patients with DPN.

    risk factor for mortality.                                      (Adv Stud Med. 2004;4(10G):S1014-S1021)
        The pathogenesis of DPN involves the progres-
    sion of diabetes and chronic hyperglycemia to
    endothelial dysfunction via increased activity in 4
    possible pathways: the protein kinase C pathway
    via diacylglycerol, advanced glycation end-product
    formation, the polyol pathway, and oxidative stress.                       iabetic peripheral neuropathy (DPN), a
    Endothelial dysfunction, influenced by cardiovascu-                        microvascular complication of diabetes, is
    lar and genetic factors, progresses to microan-                            associated with considerable morbidity,
    giopathy and then to nerve hypoxia.                                        mortality, and diminished quality of life.
        In clinical practice, detection of DPN begins             Characterized by pain, paresthesia, and sensory loss, it
    with a careful history of sensory and motor symp-             affects up to 50% of patients with diabetes,1 with new
    toms, an inspection of the feet, and an evaluation            cases occurring at an annual incidence of about 2%.2
                                                                  In absolute numbers, against the estimated global
                                                                  prevalence of 220 million cases of diabetes by 2010,1
    *Based on a presentation given by Dr Tesfaye at a sym-        DPN is likely to affect as many as 110 million persons
posium held in conjunction with the 12th International
Congress of Endocrinology.                                        worldwide—and at tremendous cost. In the United
    †Consultant Physician and Diabetologist, Sheffield            States alone, the total cost associated with DPN is
Teaching Hospitals, Sheffield, United Kingdom.                    $10.9 billion a year.3
    Address correspondence to: Solomon Tesfaye, MD,
Royal Hallamshire Hospital, Glossop Road, Sheffield, S10
                                                                      Diabetic peripheral neuropathy is the main predis-
2 JF, UK. E-mail: Solomon.Tesfaye@sth.nhs.uk.                     posing factor for foot ulceration and infection. Foot

S1014                                                                                         Vol. 4 (10G)   I   December 2004

 ulceration alone occurs in 15% of patients with dia-             completely numb feet, putting them at extremely high
 betes during their lifetime4 and is the most common              risk for foot ulceration.
 cause of hospital bed occupancy in the United States                 Pain and insensitivity are the 2 clinical conse-
 and abroad. With an annual incidence that ranges                 quences of DPN. Pain symptoms, including burning,
 from 1% to 3%,5,6 diabetic foot ulceration accounts for          paresthesia (“pins and needles”), hyperesthesia, and
 a 15-fold increase in the likelihood of lower limb               allodynia (contact pain), can be extremely distressing
 amputation in patients with diabetes versus nondia-              and are typically worse at night.10 Pain can range from
 betic people,7 and a 2-fold increase in mortality.8 Of           tingling in one or more toes to severe and persistent
 those patients with diabetes who have had a lower                neuropathic pain. Patients commonly describe their
 limb amputated, more than 50% required amputation                symptoms as “sharp electric shocks that shoot up my
 of the contralateral limb within 1 year.4                        legs” or “stepping on broken glass.” Others complain
     From these epidemiologic data, DPN and diabetic              of disrupted sleep and pacing the floor during the
 foot ulceration clearly are far from rare, far from              night to distract themselves from the pain. Still, others
 benign, and pose a major healthcare challenge to the             voice frustration and depression because of the pain.11
 medical profession and to society. However, in some              Some patients, in fact, have committed suicide because
 respects, DPN is the “Cinderella” of diabetic microvas-          of intractable and persistent neuropathic pain.
 cular complications, receiving less attention than it                Insensitivity, or loss of pain, can lead to foot ulcer-
 deserves in terms of screening, early detection, treat-          ation and a host of unintentional, but serious injuries.
 ment, and prevention. New and emerging treatments                Patients who have lost sensation in their hands cannot
 for DPN, in addition to early detection and better               detect temperature and often burn themselves while
 control of hyperglycemia and other risk factors, soon            cooking or ironing, for example, and also have diffi-
 may bring more attention to DPN.                                 culty handling small objects. Those patients who have
                                                                  lost sensation in their feet often sustain puncture
 CLINICAL FEATURES OF                                             wounds, friction wounds, and burns that can become
 DIABETIC PERIPHERAL NEUROPATHY                                   infected and/or ulcerated and lead to amputation.
                                                                  However, with appropriate foot care, at least 50% of
     Diabetic peripheral neuropathy, which is also                ulcerations can be prevented.10
 referred to as distal symmetrical polyneuropathy, is the
 most common neuropathic syndrome seen in patients                RISK FACTORS FOR DIABETIC PERIPHERAL NEUROPATHY
 with diabetes. Less common neuropathic syndromes
 include cranial mononeuropathies and focal neu-                      Studies in patients with type 1 or type 2 diabetes
 ropathies such as proximal motor neuropathy.                     mellitus have shown that poor glycemic control is one
     Diabetic peripheral neuropathy starts in the toes            risk factor for DPN.
 and gradually moves upward. Once it is well estab-                   The EURODIAB IDDM Complications Study,
 lished in the lower limbs, DPN affects the upper                 which involved 3250 patients with type 1 diabetes
 limbs, with sensory loss following the typical “glove            mellitus from 31 centers in 16 European countries,
 and stocking” pattern of distribution.9 Significant              found that DPN was related to both glycemic control
 motor deficits are not common in the early stages of             and duration of disease.12 Although the 30% baseline
 DPN,9 although magnetic resonance imaging (MRI)                  prevalence of DPN was significantly related to glyco-
 examination of the lower limbs reveals atrophy of                sylated hemoglobin (HbA1c; P <.001), the prevalence
 the small muscles of the foot as an early feature.               varied from 17% to 41% after data were adjusted for
 Symptomatic muscle weakness, however, tends to                   duration of diabetes mellitus, with lower HbA1c levels
 develop later in the disease course.                             associated with lower prevalence rates and higher lev-
     Painful symptoms such as burning, tingling, and              els associated with higher prevalence rates. However,
 paresthesias are present early on in 30% of patients.9           even those with good glycemic control (HbA1c <5.4%,
 Importantly, symptoms are not a reliable indicator of            equivalent to HbA1c of 7% in the Diabetes Control
 the severity of nerve damage.9 Some patients with                and Complications Trial) still developed microvascular
 severe pain symptoms have little sensory deficit,                disease, suggesting that factors other than glycemic
 whereas other patients with no painful symptoms have             control and disease duration are involved.

Advanced Studies in Medicine   I                                                                                      S1015

    Follow-up data from the EURODIAB cohort of                        (PKC) activation. Increased activity in these path-
patients with type 1 diabetes mellitus revealed that tra-             ways leads to endothelial dysfunction, which in turn
ditional markers of macrovascular disease such as cho-                leads to microangiopathy and then to nerve hypoxia.
lesterol and fasting triglyceride levels, albumin                     The latter results in structural damage to the nerve
excretion rates, von Willebrand factor levels, and body               and irreversible neuropathy or reduced nerve con-
mass index also were associated with the development                  duction velocity.15
of DPN. After excluding all patients with DPN at
                                                                          Cardiovascular risk factors such as hyperlipidemia,
baseline and adjusting the data for HbA1c and dura-                   hypertension, smoking, and increased body mass
tion of diabetes mellitus, the investigators found that               index are major and independent contributors to
values for all of these factors were significantly elevat-            endothelial dysfunction. Genetic factors may play a
ed in all of the 276 patients who developed DPN after                 role as well, which may explain why some diabetic
7 years of follow-up compared with the values for the                 patients with good glycemic control develop microvas-
896 patients who did not develop DPN during the fol-                  cular complications while others with poor glycemic
low-up period.                                                        control do not. Similarly, cardiovascular risk factors
    There is also evidence that DPN, a microvascular                  contribute to microangiopathy, which is also influ-
complication of diabetes mellitus, is associated with                 enced by coagulation and hematologic factors.15
cardiovascular disease and mortality. In a study of 132                   Some of the vascular and metabolic interactions that
patients with type 2 diabetes mellitus, 38 died during                occur in the pathogenesis of DPN are described below to
the 9-year follow-up period.14 Macroangiopathy was                    help define the process further and to outline the ratio-
found to be the strongest independent risk factor for                 nale for new and emerging therapeutic interventions.
mortality, followed in descending order
by DPN, albumin excretion rate, and
HbA1c. In addition, postmortem stud-
ies conducted at King’s College
Hospital in London have demonstrated                Figure 1. Pathogenesis of Diabetic Peripheral Neuropathy
that patients with DPN die of coronary
artery disease (Personal communica-
tion, Michael Edmonds, MD, March
2003).                                                                                    (Duration)
                                                                                Diabetes (Duration)

                                                                                          Hyperglycemia                    DAG
                                                                                              HbA 1c
                                                     ↑ AGE - RAGE              ↑ Polyol             ↑ Free radical
                                                                                                                               ↑ PKC activity
                                                                           pathway activity           formation
    Until recently, there were 2 schools
of thought regarding the etiology and                             NO quenching
                                                                                                            ↓ NO generation
pathogenesis of DPN: metabolic versus
vascular. Recent studies, however, have                Genetics                 Endothelial dysfunction                DM ↑ Lipids, ↑ BP,
shown that vascular factors and meta-                                                                                   ↑ BMI, Smoking
bolic interactions are involved at all
                                                                Rigid RBC                    Micro-
stages of DPN.15                                              ↑ Coagulability              angiopathy                  DM ↑ Lipids, ↑ BP,
    Current thinking on the pathogene-                        ↑ Platelet reactivity                                         ↑ BMI
sis of DPN can be summarized by the
schematic shown in Figure 1. Diabetes
                                                                                        Nerve hypoxia
leads to chronic hyperglycemia, which
                                                      Structural damage                                           ↓ Nerve conduction
appears to stimulate 4 pathways directly              Irreversible neuropathy                                          velocity
or indirectly: advanced glycation end-
product (AGE-RAGE interaction) for-
                                                 AGE = advanced glycation end-products; BP = blood pressure; BMI = body mass index; DAG = dia-
mation, polyol pathway hyperactivity,            cylglycerol; DM = diabetes mellitus; HbA1c = glycosylated hemoglobin; NO = nitric oxide; PKC = pro-
oxidative stress, and protein kinase C           tein kinase C; RAGE = receptors for advanced glycation end-products; RBC = red blood cells.

S1016                                                                                                          Vol. 4 (10G)    I   December 2004

     In 1966, Gabbay et al proposed that sorbitol accu-             blood vessels on the nerve surface—similar to the net-
 mulation was a cause of DPN.16 In the polyol pathway,              work of new blood vessels seen on the surface of the
 glucose is converted to sorbitol by the enzyme aldose              retina in patients with diabetes.
 reductase, and sorbitol to fructose by the enzyme sor-                 A recent study examining epineurial blood flow in
 bitol dehydrogenase. The key enzyme is aldose reduc-               patients with painful and painless DPN found that
 tase. Later studies showed that aldose reductase                   fluorescein levels rose more rapidly and epineurial
 inhibitors were able to increase nerve conduction                  intravascular oxygen saturation was significantly high-
 velocity in animals,17 and to a lesser extent in                   er in patients with painful DPN compared to patients
 humans,18 and that these agents produced some                      with painless DPN.26 These findings may reflect
 increase in nerve fiber counts in patients with                    shunting from the endoneurium to the epineurium in
 DPN.19,20 However, there was no unequivocal improve-               patients with painful DPN and also support the
 ment in terms of lessening signs and symptoms. Newer               premise that hemodynamic factors play a role in the
 aldose reductase inhibitors are currently undergoing               pathogenesis of neuropathic pain.
 clinical trials.
     Nerve fiber loss is the cause of insensitivity in
 DPN. As revealed by fascicular biopsy of the sural
 nerve, nerve fibers in patients with diabetes but no                   Figure 2. Nerve Fiber Loss in Diabetes and
 DPN are more numerous than in those patients with                      Diabetes with Diabetic Peripheral Neuropathy
 diabetes with DPN (Figure 2).21 Sural nerve biopsies
 also reveal microvascular defects in the endoneurial
 vessels, such as gross basement membrane thickening,
 endothelial cell proliferation, and hypertrophy (Figure
 3),15 in addition to reduced oxygen tension22 in
 patients with DPN, as compared with patients who
 have diabetes but do not have DPN. Similarly, pho-
 tography of surgically isolated sural nerve reveals
 microvascular abnormalities in the epineurial arteries                     Normal diabetic                           Neuropathy
 and veins (Figure 4),23 whereas fluorescein angiography            Biopsy of the sural nerve demonstrates that nerve fibers are less numerous
 reveals arteriosclerosis on the surface of the nerve and           in diabetic peripheral neuropathy.
                                                                    Reproduced with permission from Malik et al. Diabetologia.
 impaired blood flow23 in patients with DPN compared                1993;36:454-459.21
 to patients with diabetes without DPN.
     Impaired blood flow adversely affects nerve con-
 duction velocity, as demonstrated in exercise studies.24
 Exercise to 80% maximal heart rate will increase sural                 Figure 3. Microvascular Defects in Endoneurial
 sensory nerve conduction velocity by about 5 m per                     Vessels in Diabetes and Diabetes with Diabetic
 second in healthy people and 4 m per second in                         Peripheral Neuropathy
 patients with diabetes without DPN. The same exer-
 cise will not increase conduction velocity in those
 patients with DPN because the neuropathic nerve that
 is also arteriosclerotic is unable to increase blood flow
 in response to exercise.
     A more recent study of changes in sural nerve
 blood vessels in acute diabetic neuropathies such as
 acute insulin neuritis has shown that rapid improve-
 ment in blood glucose control can produce severe                           Normal diabetic                     Diabetic neuropathy
 painful neuropathic symptoms.25 Acute insulin neuri-               Photomicrographs of capillaries from sural nerve biopsies show an open ves-
 tis, once thought to be a metabolic condition, is, in              sel in the normal diabetic nerve and gross basement membrane thickening,
                                                                    endothelial cell proliferation, and a closed vessel in the neuropathic nerve.
 fact, associated with proliferative changes that result in         Reproduced with permission from Cameron et al. Diabetologia.
 the development of a fine network of “neural new”                  2001;44:1973-1988.15

Advanced Studies in Medicine   I                                                                                                      S1017

Figure 4. Microvascular Abnormalities in Epineurial                                   because inappropriate or ill-fitting shoes are the most
Vessels in Diabetes and Diabetes with Diabetic                                        common form of trauma to the diabetic foot.
Peripheral Neuropathy                                                                     Some authorities advocate the additional use of a
                                                                                      clinical scoring system that grades the degree of neu-
                                                                                      ropathy on the basis of symptom, reflex, and sensory
                                                                                      scores, such as the Toronto Clinical Scoring System
                                                                                      that is weighted to emphasize sensory symptoms
                                                                                      (Table).28 The scoring system has been validated and
                                                                                      correlates well with electrophysiology findings and
                                                                                      glycemic control.
                                                                                          The 10-g monofilament test is now standard for
                                                                                      examination of the diabetic foot, is inexpensive and
             Normal                              Neuropathy
                                                                                      easy to use, and produces rapid and reproducible
                                                                                      results.29 The test also predicts foot ulceration; those
Photographs of surgically isolated sural nerve show increased arterial tortu-
osity in diabetic peripheral neuropathy. In the area where the artery joins
                                                                                      patients who cannot feel the monofilament are 15
the vein, the vein is distended because of increased pressure and also                times more likely to develop ulceration within 3 years
becomes tortuous.                                                                     than are those patients who have foot sensation.30
Reproduced with permission from Tesfaye et al. Diabetologia.
1993;36:1266-1274.23                                                                      However, there is some controversy regarding which
                                                                                      and how many areas of the foot should be tested. Some
                                                                                      groups suggest testing as many as 10 areas of the foot,
     In studying the effect of revascularization on                                   but the group in Toronto that developed the scoring sys-
 nerve function in patients with DPN, Young et al                                     tem advocates testing only the dorsum of the first toe in
 examined groups of patients who had and had not                                      both feet.31 Within the 0 to 8 reference range, a com-
 undergone femoral popliteal bypass. 27 The                                           bined score of 5 or above for both feet predicts DPN.
 researchers found that both foot transcutaneous oxy-                                     Another important test is the vibration percep-
 gen saturation and peroneal nerve multiconduction                                    tion threshold that detects subclinical neuropathy.
 velocity increased significantly 6 weeks after surgery.                              It, too, is easy to use and predicts foot ulceration,
 However, in the control group of patients, there was                                 with 0 to 5 volts indicating low risk, 16 to 25 volts
 no increase in either variable, demonstrating that                                   indicating intermediate risk, and more than 25 volts
 improving blood flow to the limbs improves nerve                                     indicating high risk.32,33 And, as demonstrated by
 conduction velocity.

                                                                                          Table. Toronto Clinical Scoring System
     Early detection of DPN is extremely important as
 it may result in earlier treatment and in prevention of
                                                                                      Symptom Scores              Reflex Scores            Sensory Scores
 further damage. In clinical practice, early detection
                                                                                           0–6                         0–8                      0–5
 begins with a careful history and an evaluation of sen-
 sory and motor symptoms, an assessment of disability                                 Foot pain                   Knee reflexes               Pinprick
 resulting from the neuropathy, and the exclusion of                                  Numbness                    Ankle reflexes           Temperature
 conditions other than diabetes mellitus that may be                                  Tingling                     (both sides)             Light touch
 causing the neuropathy.                                                              Weakness                                               Vibration
     The clinical examination should include a careful                                Ataxia                                               Position sense
 inspection of the feet; evaluation of ankle and knee
                                                                                      Upper limb symptoms
 reflexes; a sensory examination that includes testing
 for vibration, light touch, and pinprick sensations; the                             Maximum score = 19.
                                                                                      0–6 = no neuropathy; 6–8 = mild neuropathy; 9–11 = moderate neuropa-
 10-g monofilament test to assess sensation in the foot;                              thy; ≥12 = severe neuropathy.
 and an assessment of footwear, which is important                                    Modified from Bril V, Perkins BA. Diabetes Care. 2002;25:2048-2052.28

S1018                                                                                                                   Vol. 4 (10G)   I   December 2004

 Coppini et al, the vibration perception threshold                   low-up in one study, patients reported that the stimula-
 also predicts mortality, with higher death rates in                 tor markedly reduced both background pain and peak
 diabetic patients with neuropathy than in diabetic                  pain when it was turned on compared to when it was
 patients without neuropathy.34                                      turned off.38 Over all, about 80% of patients responded
     Other devices to measure the vibration perception               to spinal cord stimulation; 20% did not respond, leading
 threshold include the biothesiometer, the vibrameter,               the investigators to explore whether abnormalities in the
 and the neuroasthesiometer. Efforts to standardize the              spinal cord itself could explain the lack of response.
 equipment used for threshold measurement are cur-                       Using MRI examination, the investigators found
 rently under way.                                                   that the cross-sectional area of the cord was much
     More sophisticated equipment also is available to               smaller in patients with DPN than in control subjects
 assess DPN and to detect thresholds for vibration, cool-            and slightly smaller in those with DPN compared to
 ing, heat, and pain.35 However, to characterize DPN                 patients with diabetes who did not have DPN.39
 most accurately, nerve conduction velocity tests and stag-          Although there was no statistically significant differ-
 ing the severity of neuropathy also are necessary.                  ence between the diabetic patients with DPN and
                                                                     without DPN, the study findings demonstrated spinal
 TREATMENT OF PAINFUL DIABETIC PERIPHERAL                            cord involvement in DPN. More recently, a large MRI
 NEUROPATHY                                                          study found significant spinal cord atrophy not only in
                                                                     patients with established DPN but also in those patients
     The current approach to management of painful                   with subclinical DPN compared to patients with dia-
 DPN centers on achieving and maintaining near-nor-                  betes who did not have DPN.40 This study provides fur-
 mal glycemia (HbA1c) levels. However, many patients                 ther evidence of spinal cord involvement in DPN.
 with diabetes, particularly those with type 2 diabetes                  More recent research provides evidence of neuronal
 mellitus, find this difficult.                                      dysfunction in the thalamus as a source of severe painful
     Several drugs and nonpharmacologic modalities                   neuropathic symptoms (Unpublished observations).
 are available for pain relief, but efficacy and tolerabili-         Clearly, a deeper understanding of the origins of these
 ty of adverse effects vary. For example, tricyclic antide-          symptoms is needed to develop more effective therapies.
 pressants are effective in many patients but are
 associated with numerous adverse effects. Therefore,                NEW INTERVENTIONS FOR
 the starting dose, to be given at bedtime, should be                DIABETIC PERIPHERAL NEUROPATHY
 low and can then be increased gradually or discontin-
 ued, depending on how effectively pain is relieved and                  Although aldose reductase inhibitors, which
 whether the patient is tolerating the side effects.                 reduce activity in the polyol pathway, generated con-
     Anticonvulsants such as gabapentin are also help-               siderable optimism about the treatment of DPN
 ful,36 as is the opiate derivative tramadol.37 Although             when first introduced in the 1980s, they have not
 there may be a risk of addiction with tramadol, it is a             demonstrated consistent efficacy or safety. Two of the
 useful drug to have in the armamentarium. Similarly,                inhibitors have been withdrawn from the market
 intravenous lidocaine and oral mexiletine, which are                because of lack of efficacy, and 3 have been with-
 usually used to control cardiac arrhythmias, are often              drawn because of allergic reactions, hepatotoxicity, or
 helpful in refractory patients.                                     renal toxicity. Only one of this class of agents, epal-
     Other drugs and nonpharmacologic approaches that                restat, is still on the market (in Japan), although
 are helpful in some patients include capsaicin cream,               newer agents, including fidarestat, are being investi-
 isosorbide dinitrate nasal spray, amantadine, acupunc-              gated in ongoing clinical trials.
 ture, and transcutaneous electrical nerve stimulation.                  Antioxidants have been used to treat DPN on the
     However, treatment of painful DPN is less than                  premise that they reduce free radical formation. In the
 satisfactory, with some patients having severe adverse              SYDNEY trial, α-lipoic acid 600 mg per day signifi-
 effects to therapy and others failing to respond at all to          cantly lowered pain scores at 4 weeks compared to
 any of the above therapies.                                         intravenous riboflavin.41 Thus far, α-lipoic acid, which
     A last resort for the treatment of refractory pain in           is marketed in Germany, appears to be effective in
 DPN is spinal cord stimulation. After 3 years of fol-               reducing pain.

Advanced Studies in Medicine   I                                                                                       S1019

    Ruboxistaurin, an inhibitor of the β isoform of
                                                                 Figure 5. Effect of Treatment with Ruboxistaurin on
PKC, is being studied in clinical trials involving
                                                                 Neurologic Impairment Scores and Composite Score
patients with DPN and other microvascular compli-
cations of diabetes mellitus. In a phase II study of
205 patients with DPN and significant nerve
                                                                                            Entire patient population, n = 205
impairment, preliminary results showed that rubox-
istaurin 32 mg administered every day for 1 year                                       P = .049        P = .033          P = .046

markedly improved the composite score of 3 mea-
sures of nerve function from baseline compared to a

                                                                  Change from
placebo (Figure 5).42 The measures were the nerve

impairment score of the lower limbs (representing
the clinical examination), the nerve impairment                                   0

score for the reflex examination, and the nerve                                                                                         Pl acebo
impairment score of the lower limbs plus 4.                                                                                             32 mg QD

    A preliminary subgroup analysis of 83 patients                                     NIS (LL)        NIS reflex        NIS (LL) + 4
with clinically significant pain symptoms at baseline
revealed marked improvement in pain scores after 6
months of treatment with ruboxistaurin 64 mg                     NIS = neurologic impairment score; NIS(LL) = neurologic impairment score of
administered every day and after 1 year of treatment             the lower limbs; QD = every day.
                                                                 Reproduced with permission from Litchy et al. Diabetes. 2002;51(suppl 2):A197.42
with ruboxistaurin 32 mg administered every day.43
    As the study results indicate, ruboxistaurin appears
to have beneficial effects on nerve impairment and
pain symptoms in patients with DPN. Two large mul-                                                REFERENCES
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