Institute for Clinical Diabetology

German Diabetes Center at the Heinrich Heine University

Leibniz Center for Diabetes Research

Department of Endocrinology and Diabetology

University Hospital, Düsseldorf, Germany

Diabetic Neuropathy: New Developments

in Early Diagnosis and Treatment

Dan Ziegler, MD, FRCPE

painful painless

?

Prevalence: ≈30%

Diabetic sensorimotorpolyneuropathy (DSPN)

PROTECT Study: Percentages of previously undiagnosed neuropathyin participants with distal sensory polyneuropathy (DSPN)

D S P N S ch m erz h af t e D S P N * S ch m erz lo se D S P N *

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

% (

95

%C

I)

Painful

DSPN

Painless

DSPN

Total

DSPN

■ No DM (n=167)

■ Type 1 DM (n=24)

■ Type 2 DM (n=242)

■ All (n=433)

Educational initiative “Diabetes! Do you listen to your feet?”

Shopping centers and diabetes/health care fairs in Germany (n=1,589)

Ziegler et al., EASD, 2016

Curr Diab Rep 2012;12: 376-383

Prevalence of polyneuropathy, neuropathic pain, and cardiacautonomic dysfunction in prediabetes and diabetes

Ziegler et al., Diabetes Care 2008; 31: 556-561

Ziegler et al., Pain Med 2009; 10: 393-400

Ziegler et al., Eur J Pain 2009; 13: 582-587

Bongaerts et al., Diabetes Care 2012; 35: 1891-1893

Ziegler et al., Diabetologia 2015; 58: 1118-1128

Survey Measure NGT

(%)

IFG

(%)

IGT

(%)

IFG+IGT

(%)

New DM

(%)

Known DM

(%)

S2+S3 MNSI>2 7.4 11.3 13.0 28.0

F4 VPT/MF bilat. 11.1 5.5 14.8 23.9 16.1 22.0

S2+S3 MNSI>2+pain 1.2 4.2 8.7 13.3

AMIR MNSI>2+pain 3.7 5.7 14.8 21.0

S4 Reduced HRV 4.5 8.1 5.9 11.4 11.7 17.5

NGT = normal glucose tolerance

IFG = isolated impaired fasting glucose

IGT = isolated impaired glucose tolerance

New DM = newly detected diabetes mellitus

Known DM = known diabetes mellitus

MNSI = Michigan Neuropathy Screening Instrument

VPT = vibration perception threshold

MF = monofilament

HRV = heart rate variability

AMIR = Augsburg Myocardial Infarction Registry

5 min

How to diagnose diabetic neuropathy?

Motor Sensory Autonomic

Myelinated Myelinated Thinlymyelinated

Un-myelinated

Thinlymyelinated

Un-myelinated

A A/ A C A C

Large

Motor,sensory

NCV

Touch,Vibration, Position

perception

Warm perc. Pain

IENFDCCM

HRV, AFTs, BRSSudomotor,

GIT, GUT function

Small

Modified after Vinik

Coldperception

Pain

Ziegler et al., Diabetes 2014; Diabetologia 2015

Control Type 2 DM

German Diabetes Study: Reduced epidermal nerve fiber density

and enhanced antioxidative defense in recent-onset type 2 DM

Intraepidermal nerve fiber density

PGP9.5

Control

Mean diabetes

duration: 1 year

0.16

Type 2 DM (n=69)

0.26

Increase in superoxide dismutase (SOD)2 area

Control (n=51)

Green: SOD2

Blue: nucleus

Control Type 2 DM

In vivo laser scanning

corneal confocal

microscopy (CCM)

Corneal Confocal Microscopy (CCM)

Diabetic neuropathyHealthy subject

Ziegler et al., Diabetes, 2014; 63: 2454-2463

CCM in recently diagnosed Type 2 diabetic patients

Ziegler et al., Diabetes, 2014; 63: 2454-2463

Key Messages I

Prevalence of neuropathy is increasedin prediabetes, particularly in combinedIFG-IGT.

An array of abnormalities in nerve functionand morphology are detected in conjunctionwith oxidative stress and inflammation asearly as in recent-onset DM.

Glycemiccontrol

Lifestyle/multi-factorial riskintervention

Analgesics

Pathogenetic

treatment

Treatment

of Diabetic

Neuropathy

DCCT/EDIC: Reduced incidence of DPN following previousintensive vs standard insulin therapy in type 1 diabetic

patients at year 13-14 („metabolic memory“)

Albers et al., Diabetes Care, 2010

0

5

10

15

20

25

30

35

40Intensive

Standard

DCCTBaseline

DCCTEnd

EDICYear 13-14

% w

ith

DP

N **p<0.05

*

+ = benefit; = no effect; #higher mortality on IT.

ST = standard therapy; IT = intensive therapy

NCV = nerve conduction velocity; VPT = vibration perception threshold

Trial

n Duration

(years)

HbA1c(%)

ST vs IT

DSPN endpoints

Clinical NCV VPT

UKPDS 3,867 up to 15 7.9 vs 7.0 ? ? ?

Kumamoto 110 up to 10 9.4 vs 7.1 ? ? ?

VADT 1,791 5.6 8.4 vs 6.9 ? ? ?

ADVANCE 11,140 5 7.3 vs 6.5 ? ? ?

ACCORD 10,251 3.7 / 1.3 7.6 vs 6.3#/7.2 ? ? ?

HOME 390 4.3 7.9 vs 7.5 ? ? ?

BARI 2D 2,159 4 7.6 vs 7.1 (IP/IS) ? ? ?

ADDITION 1,161 6 6.4 vs 6.3 ? ? ?

Steno Type 2 160 8 / 5 9.0 vs 7.7 ? ? ?

Effects of intensive diabetes therapy on

development/progression of DSPN in type 2 DM

+ = benefit; = no effect; #higher mortality on IT.

ST = standard therapy; IT = intensive therapy

NCV = nerve conduction velocity; VPT = vibration perception threshold

Trial

n Duration

(years)

HbA1c(%)

ST vs IT

DSPN endpoints

Clinical NCV VPT

UKPDS 3,867 up to 15 7.9 vs 7.0 +

Kumamoto 110 up to 10 9.4 vs 7.1 +

VADT 1,791 5.6 8.4 vs 6.9

ADVANCE 11,140 5 7.3 vs 6.5

ACCORD 10,251 3.7 / 1.3 7.6 vs 6.3#/7.2 +

HOME 390 4.3 7.9 vs 7.5

BARI 2D 2,159 4 7.6 vs 7.1 (IP/IS) +

ADDITION 1,161 6 6.4 vs 6.3

Steno Type 2 160 8 / 5 9.0 vs 7.7

Effects of intensive diabetes therapy on

development/progression of DSPN in type 2 DM

Gibbons & Freeman, Brain, 2015; 138: 43-52

HbA1c ↓ 4–7% (n=52)HbA1c ↓ 2–3.9% (n=27) HbA1c ↓ >7% (n=25)

Treatment-induced neuropathy of diabetes (TIND)

All patients with pain

Many patients with pain

Treatment-induced neuropathy of diabetes (TIND)

HbA1c ↓ 2–3% points over 3 months: 20% risk of TIND

HbA1c ↓ >4% points over 3 months: >80% risk of TIND

Risk of developing TIND

TIND was present in 10.9% of all individuals seen in a

tertiary referral diabetic neuropathy clinic over a 5-year period

Gibbons & Freeman, Brain, 2015; 138: 43-52

X

Hyperglycemia-induced micro- and macrovascular

endothelial cell damage

Glucose

ROS

Insulin resistance

Insulin

Ox-FFA-k

PARP

FFA-k

Polyol pathway

AGE pathway

PKC activation

Hexosamine pathway

Mitochondrium

Adipocyte

Endothelial cell

Brownlee M. Diabetes 2005;54:1615–1625.

GAPDH

1

2

3

4

5

Glucose toxicity(oxidative stress)

FFA = free fatty acids

PKC = proteinkinase C

PARP = Poly(ADP-Ribose)

polymerase

GAPDH = Glyceraldehyde 3-phosphate

dehydrogenase

α-Lipoic acid

Actovegin

Benfotiamine

Courtesy P. Kempler (modified)

-Lipoic Acid in Diabetic Neuropathy:

Randomized Placebo-Controlled Trials

ALADINALADIN 2ALADIN 3ORPILDEKANSYDNEYSYDNEY 2NATHAN 1NATHAN 2

R(+) S(-)

• Intravenous• Oral

Meta-Analysis of Individual Neuropathic SymptomsRelative Differences between -Lipoic Acid (600 mg/day i.v.) and Placebo after 3 Weeks

Numbness

Paresthesias

Burning

Pain

TSS

GM with 95% CI

n=1258

Favors -lipoic acid; p<0.05

% -10 0 10 20 30 40 50Ziegler et al., Diabetic Med, 2004;21:114-21

-Lipoic acid (i.v. and oral): Meta-analysis of RCTs in symptomatic DSPN

Çakici et al., Diabet Med 2016 Jan 29. doi: 10.1111/dme.13083. [Epub ahead of print]

Total Symptom Score (TSS)

20

25

30

35

40

45

%

-Lipoic acid (n=219)

Placebo (n=210)

NATHAN 1 Study: NIS-LL Responders vs NIS-LL Progressors

RespondersNIS-LL -2 pts

UnchangedNIS-LL > -2 to < +2

Progressors NIS-LL +2 pts

P=0.025

35.6

29.0

36.2 34.8

40.2

24.2

After4 years:

Ziegler et al., Diabetes Care, 2011; 34: 2054-60

NIS-LL = Neuropathy Impaiment Score- Lower Limbs

NATHAN 1 Trial: Predictors of NIS-LL Improvement

Baseline variables: diabetes-related, DSPN, and analgesic treatment

ATC codes: N02: analgesics, N03: antiepileptics, N06: psychoanaleptics

F Favors placebo Favors α-lipoic acid

Ziegler et al., J Diabetes Complications 2016; 30: 350-6

Measures of treatment effect in

neuropathic pain

Pain relief Mood Functionality

Chronic pain treatementrequires assessment of

Pain intensity Sleep

0 321 4 5 6 7 108 9No pain Intolerable pain

Numeric Analog Scale (NAS = Likert Scale)

Finnerup et al., Lancet Neurol 2015; 14: 162-73

GRADE = Grading of Recommendations Assessment, Development, and Evaluation

Pharmacotherapy of neuropathic pain

GRADE Recommendations (I)

Finnerup et al., Lancet Neurol 2015; 14: 162-73

Pharmacotherapy of neuropathic pain

GRADE Recommendations (II)

Treatment of Painful Diabetic Neuropathy

under Consideration of Comorbidities

Duloxetine(SNRI)

Amitriptyline(TCA)

Pregabalin/Gabapentin

Opioids α-Lipoicacid

Depression + + ↔ ↔ ↔Obesity ↔ ↔ ↔Coronary heart

disease↔ ↔ ↔ ↔

Autonomic

neuropathy? (+) +

Pathogenetic

treatmentNo No No No Yes

+ favorable, unfavorable, ↔ neutral

Holbech et al., Pain. 2015; 156: 958-966

Analgesic combination therapy

in painful neuropathy

●Placebo

▲Pregabalin

300 mg/Tag

Imipramine

75 mg/Tag

Combination

*P<0,05 vs Placebo†P<0,05 vs either

monotherapy

n=50, 22% DM

Cross-over

NRS: Numerical

Rating Scale

Non-pharmacological pain treatment

AcupunctureNerve

stimulationMuscle

stimulation

Psychologicalsupport

TENS

Protective effects of near-normoglycemiaon nerve function are proven in type 1 but not in type 2 diabetes.

Key Messages II

Antioxidant treatment with -lipoic acid for up to 4 years is safe and improves neuropathic symptoms and signs.

Since analgesic monotherapy of neuropathicpain is effective in 50% of the patients,drug combinations are often required.

German Diabetes Center (DDZ)

Leibniz Center for Diabetes Research

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