Kim Chong Hwa MD,PhD

Division of endocrinology & metabolism

Sejong general hospital

Conflict of interest disclosure

Committee of Scientific Affairs

None

Committee of Scientific Affairs

Diabetic peripheral neuropathy is Cinderella

Complication

Contents

Clinical impacts of diabetic peripheral

neuropathy

Comprehensive managements of diabetic

peripheral neuropathy

Glycemic control

Risk factor control

Symptomatic treatments

Pathogenetic treatments

Conclusion

Prevalence of Diabetic Peripheral

Neuropathy(DPN)

Prevalence (%) ranges of diabetic

neuropathy found in different studies

International Diabetes Federation. The diabetes atlas. 3rd ed. Brussels: International Diabetes Federation; 2006.

Prevalence of Diabetic peripheral

neuropathy in Korea

46.1% 53.9%

DSPN (-)

DSPN (+)

N = 875, (%)

Presence of DPN

Diabetic DSPN patient survey,2005

Prevalence of DPN

N = 3999, (%)

Kim CH et al. 8th IDF-WPR, 2010

66.5%

33.5%

Non-DPN DPN

Clinical Impact of Diabetic Distal Symmetric

Polyneuropathy (DSP)

DSP

Painful neuropathic symptoms

Neuropathic deficits

Impairment Disability Handicap

Foot ulcers

Infection (skin, bone)

Quality of life

Charcot foot

Surgery, Amputation

Cost

Mortality

Agent X Agent X

Job loss

Marital disha

rmony

Isolation

Loss of socia

l status

Anxiety

Depression

Anger

Fear

Loss of conf

idence

Vasculopathy PVD/IHD/CVA

Visual loss Obesity

Nephropathy

Autonomic neuropathy

Ulcers

Unsteadiness and Falls

Social Psychological

CVA = Cerebrovascular accident; IHD = Ischaemic heart disease; PVD = Peripheral vascular disease.

NICE guideline,2011

Multidimensionality of DPN

DPN: Impact on the quality of life

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Mood

Sleep

Walking

Daily activity

Occupational activity

Leisure

Personal Relationship

N = 472, (%) Diabetic DSPN patient survey,2005

Exercise

capability

Self -care

Daily activity

Pain /discomfort

Anxiety

/depression

[Unit: %] DPN (n=1338) Non-DPN (n=2661)

*3 score scale : 1= no infl., 2: mild affect, 3: mod to severe affect

** 3 score , 2, 3 rate of answer

(p<0.0001)

EQ-5D index – Korea scoring#

[ DPN: 0.70±0.20

Non-DPN: 0.78±0.11

(p <.0001)]

#: 0∼1 ; 1 welling being state

No

Yes

Kim CH et al. 8th IDF-WPR, 2010

Comprehensive managements of

diabetic peripheral neuropathy

Causal treatment aimed at near normoglycemia

Avoidance of risk factors and complications

Symptomatic treatment

Treatment based on pathogenetic mechanisms

*p=0.03; **p=0.001; ***p<0.001. BMI = Body mass index; CI = Confidence interval;

HbA1c = Glycated hemoglobin; PCS = Prospective complications study.

Data from Tesfaye S, et al. N Engl J Med. 2005;352:341–350.

Model 1: Without cardiovascular disease and retinopathy

N=1,101 with Type 1 DM;

Follow-up: 7.3±0.6 years

4 3 1 0 2

1.15 Total cholesterol

1.36 Change in HbA1c

1.48 HbA1c

1.38 History of Smoking

1.57 Hypertension

1.40 Diabetes duration

1.21 Triglycerides

1.27 BMI

Odds ratios (95% CI)

*

*

***

***

***

*

**

Risk Factors for Incident Neuropathy:

The EURODIAB PCS

Risk factors associated with the development of

peripheral sensory neuropathy in T2DM at 5 years

1426 patients from the Fremantle Diabetes Study (FDS) were recruited and 1294 patients had T2DM.

ORs of risk factors associated with the presence

of DPN using logistic-regression analysis

Variables OR (95% CI) P value

Age (yr) 1.01 (1.00, 1.02) 0.01

Duration of diabetes (yrs) 1.03 (1.01, 1.04) < 0.01

Current smoker (%) 1.41 (1.08, 1.85) 0.01

Hypertension (%) 1.48 (1.21, 1.79) < 0.01

Dyslipidemia (%) 1.28 (1.07, 1.55) < 0.01

Any retinopathy (%) 1.88 (1.50, 2.35) < 0.01

History of CVDs (%) 1.45 (1.07, 1.94) 0.01

History of PADs (%) 5.53 (3.17, 9.64) < 0.01

Foot ulcer or amputation (%) 3.82 (1.03, 14.16) < 0.01

MNSI scores (≥ 2.0) 4.66 (3.49, 5.14) < 0.01

Diabetic Medicine .vol29(9) e290–e296, September 2012

Odds ratios of risk factors associated with

the presence of Painful DPN

CH Kim et al. DRCP. 2014; 103(3):522-529

DCCT: Effect of intensive vs conventional glycemic control on

neuropathy in type 1 diabetes

Data from

Effect of long-term intensive insulin vs conventional

control on peripheral neuropathy in T2DM (cont)

Data from

ACCORD

Data from Esmail-Beigi F et al. Lancet. 2010 ; 376(9739) : 419-30.

Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy.

Elevated triglycerides correlate with

progression of diabetic neuropathy

Data from Wiggin TD Diabetes. 2009;58(7):1634-40.

The indirect evidence in treating TG for

reducing DPNP Effect of fenofibrate on amputation events in people with

type 2 diabetes mellitus (FIELD study) - Lancet 2009

Data from Rajamani K et al Lancet. 2009 ;373(9677):1780-8.

DSPN: Treatment

Yes, 47%

No, 52%

Unkown, 1%

0% 10% 20% 30% 40% 50%

Alpha lipoic acid

Antidepressant

Anticonvulsant

γ-linoleic acid

Opiod analgesics

Others

N = 472, (%)

N = 222, (%)

Diabetic DSPN patient survey,2005

N = 1338, (%)

Kim CH et al. 8th IDF-WPR, 2010

Pain matrix

Spinal dorsal horn

Neuropathic Pain

1. Treede et al. Neurology 2008;70(18):1630–5. 2. Scholz et al. Nat Neurosci 2002;5 (Suppl):1062-67.

Pain arising as a direct consequence

of a lesion or disease affecting the

somatosensory system1

Peripheral nerve damage

− Action potentials are

generated ectopically

− Threshold is lowered

Various Na+ channels and

TRPV seem to be involved2

TRPV = Transient receptor potential vanilloid.

Slide courtesy of Walter Zieglgänsberger, Max Planck Institute of Psychiatry, Munich, Germany.

Nociceptive Versus Neuropathic Pain1–2

Nociceptive pain

Adaptive

Identifiable stimuli that normally produce tissue damage

Usually self-limiting

Transmitted by structurally and functionally intact pain pathways

Examples: post-operative pain, burns, ischemic pain

Neuropathic pain

Maladaptive

Often spontaneous (occurring without identifiable stimuli)

Often chronic

May involve structural and functional changes in pain pathways

Examples: polyneuropathy (e.g., diabetic, HIV), trigeminal neuralgia, central post-stroke pain

1. Portenoy RK and Kanner RM. Pain Management: Theory and Practice. Philadelphia, PA: FA Davis; 1996:4. 2. Galer BS and Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000:8–9.

– Clinical pain syndromes occur along a spectrum from nociceptive to neuropathic

– Nociceptive and neuropathic pain may coexist in the same patient

Multiple Mechanisms of Pain Dysfunction

Peripheral nervous

system input:

Peripheral sensitization

Ectopic excitability

Central nervous

system processing:

Central sensitization

Structural

reorganization

Disinhibition

Woolf CJ. Ann Intern Med. 2004;140:441–451.

Mechanisms of pain and possible

treatments

Treatment of DPNP

Tricyclic compounds/SSRIs1

SNRIs

Duloxetine — indicated for painful DPN (KFDA)

Venlafaxine

Anticonvulsants

Pregabalin — indicated for painful DPN (KFDA)

Topiramate, Oxcarbazepine, Lamotrigine, Sodium

Valproate,Lacosamide

Tramadol, oxycodone1,3,4

Capsaicin1

TENS, acupuncture, ESCS etc.1,5

α-lipoic acid, GLA

ESCS = Epidural spinal cord stimulation; TENS = Transcutaneous electrical nerve stimulation. GLA: gamma linoleic acid

1. Tesfaye S, Kempler P. Diabetologia. 2005;48:805–807; 2. Backonja M, et al. JAMA. 1998;280:

1831–1836; 3. Gimbel JS, et al. Neurology. 2003;60:927–934; 4. Watson CP, et al. Pain. 2003;

105:71–78; 5. Tesfaye S, et al. Lancet. 1996;348:1696–1701.

General considerations in the

pharmacotherapy of neuropathic pain

The appropriate and effective drug has to be tried and

identified in each patient by carefully titrating the dose

based on efficacy and side effects.

Lack of efficacy should be judged only after 2–4 weeks

of treatment using an adequate dose.

Because the evidence from clinical trials suggests only

a maximum response of ≈50% for any monotherapy,

analgesic combinations may be useful.

Potential drug interactions have to be considered, given

the frequent use of polypharmacy in diabetic patients.

Summary of American Academy of

Neurology recommendations

Neurology. 2011;76:1758–1765.15

Efficacy analysis of drugs used for

painful diabetic neuropathy

Endotext.org [homepage on the internet]. Darmouth: Chapter 31 – Diabetic Neuropathies

Tailoring treatment to the patient (Toronto

Consensus Panel on Diabetic Neuropathy)

Diabetes Metab Res Rev. 2011;27:629–638.

PDN = Peripheral diabetic neuropathy; SNRI = Serotonin-norepinephrine reuptake inhibitor;

TCA = Tricyclic antidepressants.

Treatment Algorithm for PDN

Painful diabetic neuropathy

Add opioid agonist as combination therapy

Consideration of contraindications and comorbidities

2- agonist

(pregabalin or gabapentin) TCA

SNRI

(duloxetine)

If pain control is inadequate and considering contraindications

TCA or SNRI SNRI or 2- agonist

(pregabalin or gabapentin)

TCA or 2- agonist

(pregabalin or gabapentin)

If pain control is still inadequate

Data from Tesfaye et al. Diabetes Care 2013; 36: 2456-2465

Pathogenesis of Diabetic Neuropathy

Hyperglycemia

Free transition metal ions

Autoxidation

AGE formation

Endogenous scavengers

Reactive Oxygen Species

Diabetes

Polyol pathway flux

Dyslipidemia EFA dysmetabolism

NEUROPATHY

DAG

PKC ß

AII

ET

NO

PGI2

EDHF

Vascular dysfunction Nerve and ganglion

blood flow

Endoneurial hypoxia

Ischemia/ reperfusion A - V shunting

ONOO-

Modified from Cameron et al., Diabetologia, 2001

PKCß Inhibitor

ARIs

Antioxidants

- Lipoic acid

Linoleic acid

GLA

DGLA

AA

GLA

AGE Inhibitors

ACE-I., ARB

C-Peptide

-Lipoic Acid in Diabetic Neuropathy:

Randomized Placebo-Controlled Trials

ALADIN* ALADIN 2* ALADIN 3* ORPIL* DEKAN* SYDNEY* SYDNEY 2* NATHAN 1 NATHAN 2

R(+) S(-)

*published i.v. oral

Days

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Rela

tive d

iffe

rence

s in

TS

S b

etw

een

ALA

and

pla

ce

bo

(%

)

-10

0

10

20

30

40

Favors placebo

LV

Favors alpha-lipoic acid

Total Symptom Score (TSS): Relative Daily Differences Between -Lipoic Acid i.v. and

Placebo i.v.

LV=Last value

Meta-Analysis

Ziegler et al., Diabetic Med 2004; 21: 114-121

Comprehensive management of diabetic

peripheral neuropathy.

KCH. Korean J Med 2015;89:277-281

Conclusions Patients With DPN have high rates of cormobidities anxiety,

mood and sleep difficulties.

Management of DPN consists of glycemic control, modifiy

risk factors, symptomatic and pathogenic oriented therapy.

Symptomatic treatments only relieve

pain without targeting the underlying neuropathy, which is

associated with a poor prognosis (ulcers, amputations).

Pathogenic treatments may be added, given its safety and

potential for improving neuropathic symptoms

Therefore, treatment based on the combination of

symptomatic and pathogenetic mechanisms of DPN, which

would be effective despite persisting hyperglycemia, is

preferred.

As Winston Churchill said,

“We need to go from failure to

failure without losing our

enthusiasm and ultimately we

will succeed.”