The Role of Neurotrophic in

Management Diabetic Neuropathy

Dr. Nanang Miftah Fajari,SpPD-KEMD

Divisi Endokrin Metabolik dan Diabetes
RS ULIN/ FK ULM
Neuropathy Nerve Damage

European Journal of Neurology, Volume: 28, Issue: 6, Pages: 2054-2064, First published: 22 February 2021, DOI: (10.1111/ene.14786)
 Neuropathic Pain

Disebabkan kerusakan myelin sheet,

yang berakibat :
1. impuls yang lewat akan
menyebar ke sel saraf lainnya,
sehingga timbul nyeri
2. penghantaran implus ke sel
saraf berikutnya menjadi
terhambat
 timbul gangguan sensorik.
What is Neuropathic Pain?
Characterized by:
Pain often described as shooting, electric shock-like
or burning.
The painful region may not necessarily be the same
as the site of injury.
Almost always a chronic condition (e.g. postherpetic
neuralgia, poststroke pain)
Responds poorly to conventional analgesics
Example: PHN, DPN
 Diabetic Neuropathy
At the time of diagnosis of diabetes, 10–18% of patients present with
nerve damage, but neuropathy has also been shown to occur even in
prediabetes
Diabetic Autonomic Prevalence : 7% of type 2 DM
Neuropathy. Incidence >> by 4.6- 6% / yrs

independent predictor of
Cardiovascular Autonomic
Neuropathy cardiovascular
mortality, it is often
underdiagnose

Diabetic Peripheral
Neuropathy
Painfull Diabetic Neuropathy
Didangelos et al.Nutrients 2021, 13, 395.
• DPN  50% of patients
• Sensory symptoms
• Associated with foot
infections, ulcers, Charcot
arthropathy, fractures, and
amputations
Diabetic Neuropati : Ruang Lingkup dan Risiko

• 60%-70% Individu dengan Diabetes

• Risiko meningkat dg usia dan

lamanya penyakit:
• Rerata tertinggi: diabetes >25 tahun
• Kadar HbA1C yang tak terkendali
• Hiperkolesterolemia (LDL)
• Obesitas
• Hipertensi
 Neuropati Diabeticum : Definisi
Kerusakan syaraf yg simtomatik dan asimtomatik
akibat diabetes:

• Simtomatik:
• Rasa nyeri
• Rasa kesemutan atau tebal di ujung-ujung ekstremitas.

• Asimtomatik:

Kerusakan Saraf Yang terlibat :

• Sistem Saraf Tepi ( Sensorik, Motorik )
• Sistem Saraf Otonom : sistem pencernaan, reproduksi,
jantung.
Indonesia: Epidemiologi Komplikasi Diabetes

Mikrovaskular >> Makrovaskular

IDMPS Indonesia 2011

 DiabCare Indonesia 2016
Chronic Complication Profile
100%
90%
80%
70% 59,1%
60%
50%
40% 29,1% 32,4%
30% 22,8%
20% 14,5% 12,4%
10%
0%

n s ns ns ns h y
tio
n
tio io it o it o at
a at a a p n c
ic lic lic lic ro u
pl p p p u sf
om o m o m om l ne dy
c c a e
r alc e tc er ctil
la n ey oo h
re
scu re ed d
f
erip E
a d de P
ov de rd
i r co or
r d co re re
c
ca r e
ny
ed ny A ny
A
rd A
co
re
ny
A

n = 1967
Peripheral neuropathy, erectile dysfunction, eye complications, and cardiovascular complications
were most common.
Interaksi Beberapa Faktor Resiko
Timbulnya Diabetic Neuropathy
Pathophysiology Diabetic Neuropathy
Pathogenesis of Diabetic Neuropathy

Gonçalves, N. P. et al. (2017) Schwann cell interactions with axons and microvessels in diabetic neuropathy
Nat. Rev. Neurol. doi:10.1038/nrneurol.2016.201
Clinical Manifestation of Diabetic
Neuropathy
 Neuropati: Gejala - gejala
• Baal, tebal, kesemutan, atau nyeri di jari kaki, telapak
kaki, betis, lengan, tangan dan jari tangan.
• Berkurangnya massa kaki dan tangan.
• Gangguan pencernaan, mual dan muntah.
• Diare atau konstipasi
• Pusing atau kunang2 setelah bangkit dari posisi duduk
ke berdiri.
• Gangguan berkemih
• Disfungsi ereksi pd pria, vagina yang kering pd wanita.
• Kelemahan
Classification of Diabetic Neuropathy

Watkins et al. In: Diabetes and Its Management 2003. Pickup & Williams. In: Slide Atlas of Diabetes 2004
Diagnostic Test
 Standar Pengobatan DPN
• DPN adalah diagnosis yg bersifat pereksklusionam.

• Kendali glikemik yg optimal adalah satu-satunya upaya

pencegahan yg sudah terbukti.

• Skrining:
• DMT1: Setiap tahun setelah 5 tahun dengan diabetes.
• DMT2: Saat Diagnosis dan selanjutnya setahun sekali

• Obat-obatan untuk mengurangi keluhan direkomendasikan

untuk meningkatkan kualitas hidup pasien.

ADA. Standards of Medical Care in Diabetes-2012 Diabetes Care 35 (Suppl 1).

Management DN
Management Diabetic Neuropathy
Painful Diabetic Polyneuropathy

EFNS Canadian IASP

1st Line TCA TCA TCA, Gabapentin
Gabapentin Gabapentin Pregabalin
Pregabalin Pregabalin SNRIs

WHERE IS THE PLACE

2nd Line SNRI SNRI
Top. lidocaine
Opioids
Tramadol

OF Neurothropic drugs?
3rd Line Lamotrigine
Opioids
Tramadol
Tramadol
CR opioid
Antiepileptics
Mexiletine
NMDA antagonist
Top. capsaicin

4th Line Cannabinoid, methadone, lamotrigine,

topiramate, valproic acid
 Syndrome
Neuropathic pain Th/ Pain killer, eg :
gabapentin,
pregabalin
Symptoms
Stimulus- Stimulus
independent pain dependent pain

Patophysiology Mechanisms

Metabolic Traumatic Ischaemic Th/ Based on etiology

Etiology Ex : Oral Anti Diabetic,
Hereditary Compression Toxic
Steroid, Anti biotics,
Infectious Immune - mediated etc.

Th/ nerve repaired

Nerve damage
Nurotrophic drugs

Woolf CJ, Mannion RJ. Neuropathic Pain: Etiology, symptoms, mechanisms, and
management. Lancet, 1999;353:1959-64.
 • Cross-sectional study, Indonesia (4 centers, Dec 2008 - Feb 2009)
• 4 groups: Control, DM normoalbuminuria, microalbuminuria, albuminuria.
• 154 T2DM, 44 control, 2-month washout period for Vitamin B supplementation
• Result: disturbance of Vitamin B1, B6, and B12 metabolism:
• Vitamin B1, B6 : increased fractional excretion, decreased cellular concentration
• Vitamin B12 resistance: increased total plasma cobalamin, holotranscobalamin, homocysteine and folate
Conclusion:
• There was renal mishandling of thiamine, increased degradation of vitamin B6 and cytosolic metabolic
resistance to vitamin B12 in patients with type 2 diabetes in Indonesia
• Vitamin B1, B6, and B12 supplementation may be beneficial to diabetic patients – particularly in diabetic
nephropathy2)
 B12 Deficiency and DPN

Vitamin B12 deficiency in DM2 has

been mostly attributed to the use of
Prevalence of vitamin metformin
B12 deficiency in
DM2 > 50% of
patients

• Metformin reduces vitamin B12

uptake in terminal ileum in about
30% of patients.
At least half of patients with DM2 are
older than 60 years, an age group with Kim J, Ahn CW, Fang S, Lee HS, Park JS.
a prevalence of confirmed vitamin B12 Association between metformin dose and vitamin
B12 deficiency in patients with type 2 diabetes.
deficiency varying from 12% to 23% Medicine (Baltimore). 2019 Nov;98(46):e17918.
Conclusions:
• Vitamin B12 deficiency is highly
prevalent, especially in patients with
diabetic neuropathy.
• In this study an inverse correlation
was found between diabetic
neuropathy and the plasma level of
vitamin B12.
• Higher doses of metformin and male
sex were factors related to lower
levels of vitamin B12.
 Vitamin B
kombinasi (B1, B6
dan B12) lebih baik
dibandingkan
monoterapi
(tunggal) (vitamin
B12 saja)
Management of peripheral neuropathy with B1, B6 and B12
• NENOIN Study design Project name NENOIN = Neurobion non-interventional study

Study design Prospective, open label, non-interventional (observational), single arm

study
Study treatment Vitamin B1 = 100mg
Vitamin B6 = 100mg
Vitamin B12 = 5mg
Posology Once a day after meals

Visit schedule V1=baseline/day 0

V2=14 days; V3=30 days; V4=60 days; V5=90 days
Study duration 90 days

Patient profile Patients with mild to moderate peripheral neuropathy of different

etiology (diabetic, idiopathic, carpal tunnel, others).
Sample size 411 patients (Full Analysis Set = FAS)

Study parameters Total symptom score (TSS):

Stabbing pain, burning pain, paresthesia, numbness
Visual Analogue Scale (VAS):
Pain, burning, paresthesia, numbness, tingling
Quality of life (SF8); Safety (AEs, ADRs)
Study centers 8 centers in Indonesia
Management of peripheral neuropathy with B1, B6 and B12
• Patients are relieved of neuropathy symptoms significantly with progressive
improvement according to TSS (FAS)
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

TSS Score 5.451±2.0365 4.358±1.9148 3.551±1.6919 2.786±1.4801 2.020±1.2808

• Statistically significant
8
* reduction of the TSS
7 after 14 days
*
6

*
• Reduction of TSS is
TSS Score (0-14.64)**

5
statistically significant
*
4 at each following visit
*
3
• The TSS reduction is
2 progressive over time in
1 411 402 399 393 390 favor of long term
0 treatment
V1 V2 V3 V4 V5

** As patients with mild to moderate peripheral neuropathy have been recruited into the study, the maximal TSS at baseline has been lower than 8.
V1 = baseline; V2 = 14days; V3 = 30days; V4 = 60days; V5 = 90days; the numbers in bars represent the number of patients; p<0.05 vs. V1 (baseline)
VITAMIN NEUROTROPIK PADA PDN

Vitamin Neurotropik: Vitamin B1, B6 dan B12

Vitamin Neurotropik sangat diperlukan dalam

menjaga kesehatan saraf

Vitamin Neurotropik sangat dibutuhkan untuk dan

membantu perbaikan kerusakan sel saraf akibat
diabetes