Diabetic PeripheralNeuropathy Optimal Assessment and Management

Presentation Objectives

• Understand the clinical impact of DPN

• Distinguish between “symptoms” and “signs” DPN

• Describe the proposed etiology of diabetic neuropathy

• Understand the potential MOA of currently used medications in the management of DPN Symptoms

Chronic Diabetes Complications

Stroke

Retinopathy

Cardiovascular Disease (CVD)

Hypertension

Nephropathy

Peripheral Vascular Disease (PVD)

Peripheral Neuropathy

most common complication 50% to 90% of diabetes patients depending upon criteria used for diagnosis

Tavakoli M, et al. Current Pain and Headache Reports. 2008;12:192-197.

Diabetes Statistics…Did you know…?

Up to 70% of those with diabetes will lose sensation in their feetPeripheral sensory neuropathy is the leading factor to diabetic foot ulcerations

Approximately 25% of those with diabetes will develop a foot ulcerMore than half of all foot ulcers will become infected, requiring hospitalization and 1 in 5 will require an amputation

After a major amputation, 30% of patients will have their other limb amputated within 3 years 5-year mortality rate after limb amputation is reported as high as 74%, when compared to cancer- it is greater than colorectal, breast, and prostate cancer

Dyck et al. Diabetic Neuropathy 1999; Singh et al. J Amer Med Assoc 2005; Robbins, et al. J Am Podiatr Med Assoc 2008.

Diabetic Peripheral Neuropathy: What is it?

• Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2

‒ Consensus definition: “the presence of symptoms and/or signs of peripheral nerve dysfunctionin people with diabetes after exclusion ofother causes”

Tavakoli M, et al. Current Pain and Headache Reports. 2008;12:192-197.

Impact of Diabetic Neuropathy

• 60-70% of foot ulcers are preceded by neuropathy

• 85% of diabetes relatedlower limb amputations are preceded by a foot ulcer

• Most Common Proximate,Nontraumatic Cause of Amputations

• Largest number of diabetes related hospital bed-days

Gordois et al. Diabetes Care. 2003;26:1790-1795.Reiber G, et al. Diabetes in America. 1995; 2nd ed:409-428.

Reiber GE, Vilekyte L, Bokyo EJ et al. Diabetes Care.1999;22.Pecoraro RE, Reiber GE, Burgess EM. Diabetes Care. 1990;13.

Frykberg R, et al. Journ of Foot and Ankle Surgery 2006;45(5):S2-S8.

Clinical Unmet Needs in DPN

• There are a wide range of treatments available forneuropathic pain

• This prescribing pattern suggests that there is no one treatment that addresses all the factors

• Despite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the disease

Datamonitor Research 2008.

Increasinglevel ofimportance

Improvedefficacy

Improved sideeffect profile

Reduced time toonset of action

Fewer drug-druginteractions

Reduced pillburden

Peripheral Nervous System

Vinik et al. Nature Clinical Practice Endocrinology & Metabolism 2006.

Diagnostic Tools for DPN: Large Fiber

• 5.07 Semmes-Weinstein Monofilament

• Biosthesiometer®

• Calibrated Tuning Fork• Nerve Conduction Velocity

Quatrini C, Boulton A, et al. Diabetologia. 2008;51(6):1046-1050.Boulton AJ, et al. Diabetes Care. 2004;27(6):1458-1486.Boulton AJ, et al. Prev and Treatment of Diab and its Compli. 1998;82(4):909-919.Barber MA, et al. J Am Podiatr Med Assoc. 2001;91(10):508-514.Kiso T, et al. Journ of Pharmaco and Experi Therap. 2001;297(1):352-356.

TAVEE J , ZHOU L Cleveland Clinic Journal of Medicine 2009;76:297-305

Normal Skin Biopsy Small Fiber Neuropathy Biopsy

Normal innervation with small nerve fibers seen in the epidermis (arrows). Skin biopsy specimens with protein gene product 9.5 immunostaining.

A specimen from a patient with small fiber neuropathy shows denervation with no small nerve fibers seen in the epidermis

Diabetic Neuropathy:A Small Fiber Disease

Symptoms and Signs ofDiabetic Peripheral Neuropathy

SymptomsSmall Fiber

• Numbness or loss of feeling (asleep or “bunched up sock under toes” sensation)

• Prickling/Tingling• Aching Pain• Burning Pain• Lancinating Pain• Allodynia• Defective Thermal Sensation• Decreased Sweating

SignsLarge Fiber

• Diminished vibratory perception• Decreased knee and ankle reflexes• Reduced protective sensation such

as pressure, hot and cold, pain• Diminished ability to sense position

of toes and feet• Pain is deep, aching or cramping

Symptoms and signsprogress from distal to proximal over time

Boulton AJ, et al. Diabetes Care. 2005 April; 28(4):956-62.

Hyperglycemia

Metabolic AbnormalitiesAGEsOxidative StressPolyolsEFA

Endothelial AbnormalitiesETAIINOPGI2

Microvascular Insufficiency

Neuronal and Schwann Cell Dysfunction

NERVE DEGENERATION

Endothelial Dysfunction in DPN: Endothelium: a biologically

active organ

Deranged nitric oxide pathways

Vinik A. The Amer Journal of Med. August 1999

Etiology of DPN

A consequence of low nitric oxide levels

Endothelial Dysfunction in the Diabetic Foot

Moncada S., Higgs A.N Engl J Med 1993; 329:2002-2012. Schäffer M, et al. Nitric Oxide Regulates Wound Healing. J Surg Res 1996; 63:237-240.Schwentker A, et al. Nitric Oxide and Wound Repair. Surg Clin N Am 2003; 83:521-530.

poor microcirculation

loss of protective sensation

foot ulceration

DPN pain

HyperglycemiaHyperglycemia Endoneurial IschemiaEndoneurial Ischemia

Progressive Diabetic Peripheral Neuropathy Progressive Diabetic Peripheral Neuropathy

Neuronal InjuryNeuronal Injury

Putative Pathogenic Sequence

Impaired Neuronal RegenerationImpaired Neuronal Regeneration

Clinical Impact of DPN TOTAL Symptoms

DPN

Boulton A. NCVH. Oral Presentations. 2007.

Mortality

Cost

ImpairmentDisabilityHandicap

Infection(skin, bone)

Charcot Foot

FootUlcers

Painful Neuropathy

Quality ofLife

SensoryLoss

Surgery, Amputation

Microvascular Damage Leads to DPN

• Examination of tissues from patients with diabetes reveals capillary damage, including occlusion in the vasa nervorum

• Reduced blood supply to the neural tissue results in impairments in nerve signaling that affect both sensory and motor function

Dyck PJ, Giannini C. J Neuropathol Exp Neurol. 1996;55:1181-1193.Sheetz MJ, King GL. JAMA. 2002;288:2579-2588.

Normal nerve Damaged nerve

Occluded vasa nervorum

Damage to myelinated and unmyelinated

nerve fibers

Progression of Symptomatic DPN

 DPN patients are labor intensive and require multiple therapies to mask pain as disease continues progressing 

Tavakoli M, et al. Current Pain and Headache Reports 2008. Tavakoli M and Malik RA. Expert opin Pharmacother 2008. Argoff CE, et al. Mayo Clin Proc 2006.

Association of Metformin and Clinically Worsened DPN

• A prospective study of 122 symptomatic DPN patients compared those who had > 6 months of metformin to those without metformin

• Results demonstrate that metformin contributes to the severity of DPN (P<0.001) by inhibiting absorption of methlB12

• The severity of DPN positively correlates to increases in the cumulative metformin dose (P<0.001)

Wile DJ, et al. Diabetes Care 2009.

Neuropathy Impairment Score

10

4

0

2

4

6

8

10

12

Metformin No Metformin

P<0.001

The Neuropathy Impairment Scale has been designed in an effort to maximize the measurement of potential changes in all motor, sensory and reflex activity in the lower limbs. Total score ranges from normal = 0 to maximum of 16.n = 122

Clinical Markers of Neuropathy Severity

Ne

uro

pa

thy

Se

ve

rity

DPN Treatment Options

Amitryptiline, Duloxetine

Opioids

Gabapentin / Pregabalin

Pain Management

Glucose Management

TOTAL Symptom Management

LMF MeCbl, PLPAdapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008.Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress *These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

L-Methylfolate 3 mgMethylcobalamin 2 mgPyridoxal 5’ –phosphate 35 mg

• Dispensed by prescription under supervision of a HCP

• Address the underlying condition such as endothelial dysfunction / DPN

• Evidence in peer-reviewed literature

Nutritional support specifically modified for the management of the distinct nutrient needs that result from the disease or condition, as determined by medical evaluation.

Medical Food – Regulated by FDA

U.S. Food and Drug Administration. Guidance for Industry: Frequently Asked Questions About Medical Foods. Available at: http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/MedicalFoods/ucm054048.htm. Accessed August 3, 2011.

LMF-MeCbl-PLP

The Role of LMF-MeCbl-PLP in DPN

SymptomaticDiabetic Neuropathy

Diabetes

BH4 / UNCOUPLED eNOS

Oxidative /Nitrosative Stress Nerve Blood Flow Nerve Repair /

Regeneration

Diabetes

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

LMF-MeCbl-PLP

LMF-MeCbl-PLP

Clinical Evidence in DPN

Diabetic peripheral neuropathy can be caused by an imbalance in the metabolic processes that regulate blood vessel and nerve health.

LMF-MeCbl-PLP is designed to nutritionally manage these metabolic imbalances resulting in the following clinical benefits.

Clinical Evidence OverviewType of Study (n) Endpoint Duration Results

Therapeutic Efficacy EvaluationZDF Rat Model (50)*

Bioanalytical Assays:Nitrotyrosine; Nitrite/NitrateNerve Conduction VelocityIENFDThermal/Mechanical Algesia; Tactile Allodynia

1 month Significant improvements compared to control group:Nitrotyrosine (p<.005)Nitrite/Nitrate (p=.047)Sensory NCV (p<.05)IENFD (p<.02)Thermal/Mechanical Algesia (p<.0025)

Prospective, Open Label Trial (16)

Established sensory loss measured utilizing QST at 6 and 12 months 1 year Improved Sensory Perception at 6 months

(p=0.006); at 12 months (p<0.001)

Prospective, Open Label Trial (24)*

Neuropathic pain 5 months LMF-MeCbl-PLP group experienced a reduction of paresthesias compared to control group at 5 months. (P<0.001)

Prospective, Open Label Trial (11)

Epidermal nerve fiber density (ENFD) measured utilizing skin punch biopsy

6 months 97% increase IENFD (p=0.004)

Randomized-Controlled, Double-blind, Multicenter (214)*

Vibratory PerceptionNeuropathy TOTAL SymptomsQuality of Life

6 months No effect on VPTImproved TOTAL Symptoms (p<0.03)Improved QoL (p=0.03)

Jacobs AM and Cheng D Rev Neurol Dis. 2011. Walker MJ, et al. Rev Neurol Dis 2010. * These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

Evaluation of LMF-MeCbl-PLP on DPN in Zucker diabetic fatty (ZDF) rats

ZUCKER DIABETIC FATTY (ZDF) RAT: A commonly used animal model for type 2 diabetes with the potential to yield useful insights in the pathophysiology of disease.

STUDY DESIGN: To assess LMF-MeCbl-PLP on the disease and biomarkers of DPN versus ZDF controls.

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

Evaluation of LMF-MeCbl-PLP on diabetic peripheral neuropathy in Zucker diabetic fatty (ZDF) rats

FINDINGS:• ZDF Rats developed the following:

• Sensory and Motor nerve conduction velocity deficits

• ~ 26% loss of intraepidermal nerve fibers

• Abnormal Nitrotyrosine levels

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

Evaluation of LMF-MeCbl-PLP on Diabetic Peripheral Neuropathy in Zucker Diabetic Fatty (ZDF) Rats

• ZDF controls developed sensory NCV deficits

• After nutritional mgmt, LMF-MeCbl-PLP Group demonstrated a significant increase in sensory NCV compared to controls

Controls Metanx® Group

35.939

0

10

20

30

40 P<0.05

sNCV Results

m/s

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

Control LMF-MeCbl-PLP

Evaluation of LMF-MeCbl-PLP on diabetic peripheral neuropathy in Zucker diabetic fatty (ZDF) rats

ZDF Controls

ZDF + LMF-MeCbl-PLP

Controls experienced 26% loss of small fibers

After nutritional mgmt with LMF-MeCbl-PLP, ENFD was 15% higher in the LMF-MeCbl-PLP group compared to controls

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

Evaluation of LMF-MeCbl-PLP on Diabetic Peripheral Neuropathy in Zucker Diabetic Fatty (ZDF) Rats

• After nutritional mgmt with LMF-MeCbl-PLP, the dose currently employed in clinical practice, alleviated multiple manifestations of DPN, including:

‒ SNCV deficit‒ Small fiber regeneration‒ Nitrosative/Oxidative stress

Clinical Endpoint Results:

Clinical Endpoint P Value vs.

Controls

Sensory NCV .05

Motor NCV ns

Nerve Fiber Density .02

Nitrotyrosine .005

Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

• 16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSD

• Outcomes measured at baseline, 6 months & 1 year after LMF-MeCbl-PLP

Foot Medial Heel Great Toe Pulp

Left / Right 1 & 2 point static touch 1 & 2 point static touch

Walker MJ, et al. Rev Neurol Dis.2010;132-139.

Eight Outcome Measurements

Restoration of Cutaneous Sensorum

Improved sensory perception at themedial heel and great toe following nutritional mgmt with LMF-MeCbl-PLP

Walker MJ, et al. Rev Neurol Dis 2010.

Baseline, 6 month, & 1 year follow up

60

50

40

30

20

10

0

gm/m

m2

Baseline 6 months 1 year

P=0.006†

P<0.001‡

Normal*

2 Point Static Great ToeLeft/Right Combined

*<25.7 gm/mm2 represents normal pressure thresholds for Pressure Specified SensoryDevice™ (PSSD) 99% Confidence level.†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16

60

50

40

30

20

10

0gm

/mm

2Baseline 6 months 1 year

P<0.001†

P<0.001‡

Normal*

2 Point Static Medial HeelLeft/Right Combined

*<30.0 gm/mm2 represents normal pressure thresholds for Pressure Specified SensoryDevice™ (PSSD) 99% Confidence level.†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16

LMF-MeCbl-PLP Administration to Pregabalin Partial-Responders for Management of DPNP

• Results from a 20 week, open trial of 24 patients to evaluate LMF-MeCbl-PLP with ≤ 50% response to pregabalin (VAS score).

After nutritional management withLMF-MeCbl-PLP:• The average absolute pain reduction after 20 weeks in the study group

was 3.0 compared to .25 in the activecontrol group (P<0.001)

• After 20 weeks, the study group experienced greater pain relief compared to the active control group, 87.5% vs. 25.0% reduction in NPS respectively (P=0.005)

Jacobs AM. NCVH Oral Presentations 2008.

0

-0.5

-1

-1.5

-2

-2.5

-3

-3.50 20

Weeks

Pain

Red

uctio

n

P<0.001

Pregabalin

LMF, MeCbl, PLP/Pregabalin

Mean Pain Reduction From Baseline

The Pharmacological Management ofDiabetic Small Fiber Neuropathy Utilizing LMF-MeCbl-PLP as a Neurotrophic Agent

• 11 patients symptomatic DPN patients

• Baseline / 6 month skin biopsies (n=22)

• LMF-MeCbl-PLP B.I.D. for 6 months demonstrated 97% ↑ ENFD

P=0.004

Epidermal Nerve Fiber Density

1.56

3.07

0

0.5

1

1.5

2

2.5

3

3.5

4

Baseline 6 months

ENFD

/mm

Jacobs AM and Cheng D. Rev Neurol Dis. 2011.

Clinical Case Outcome I

Baseline 6 months

Patient received baseline skin punch biopsy and given LMF, MeCbl, PLP twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient average increase of 3.02 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC

Jacobs AM and Cheng D. Rev Neurol Dis. 2011.

Clinical Case Outcome II

Patient received baseline skin punch biopsy and given LMF, MeCbl , PLP twice daily and followed for six months. Left image represents baseline skin punch biopsy at right calf. Right image represents six month follow up skin punch biopsy at right calf. Patient averaged an increase of .76 nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC.

Baseline 6 months

Jacobs AM and Cheng D. Rev Neurol Dis. 2011.

“A 24 week, double-blind, placebo-controlled, multisite study of LMF-MeCbl-PLP in subjects with diabetic peripheral neuropathy (DPN).”

Vivian A. Fonseca (PI) Lawrence Lavery, DPM, MPHProfessor of Medicine & Pharmacology Professor of Surgery

Tulane University Health Sciences Center Texas A&M University College of Medicine

2012 Incoming President, ADA Round Rock, TX

New Orleans, LA

Cyrus DeSouza, MD Julio Rosenstock, MDAssociate Professor Dallas Diabetes and Endocrine CenterOmaha VA Medical Center Dallas, TXOmaha, NE

Fernando Ovalle, MD Douglas Denham, MDDivision of Endocrinology DGD Research, Inc.University of Alabama at Birmingham, San Antonio, TX School of MedicineBirmingham, AL

“A 24 week, double-blind, placebo-controlled, multisite study of LMF-MeCbl-PLP in subjects with diabetic peripheral neuropathy (DPN).”

Study Objective:

To assess LMF-MeCbl-PLP (compared to placebo) twice daily in 214 persons with established diabetic peripheral neuropathy

Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress

Primary Endpoint: Vibration Perception Threshold (VPT)

STUDY FINDINGS:• Change in VPT with LMF-MeCbl-PLP was no different

than with placebo

Baseline Visit 3 (Week 8) Visit 4 (Week 16) Visit 5 (Week 24)

METANX 0 -0.54 -0.9 -0.960000000000001

PLACEBO 0 -0.330000000000005 -0.4 -0.53

-1.1

-0.9

-0.7

-0.5

-0.3

-0.1

Mea

n C

han

ge

NTSS-6

p=0.03

p=0.01

Study Findings:Neuropathy Total Symptom Score-6 (NTSS-6)*

Mean scores in the LMF-MeCbl-PLP group improved more at 16 and 24 weeks compared to placebo

NTSS-6:• Numbness• Tingling • Aching pain• Burning pain• Lancinating pain• Allodynia

Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress *These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

LMF-MeCbl-PLP

PLACEBO

0

0

-0.54

-0.33

-0.9

-0.4

-0.96

-0.53

Findings: Quality of Life

Mental HealthFeels peaceful, happy and calm all of the time

Role EmotionalNo problems with work or other daily activities

Social FunctionPerforms normal social activities without interference due to physical or emotional problems

VitalityFeel full of pep and energy all of the time

Change in SF-36 MCS at 24 Weeks

1.99

-0.29

-1

0

1

2

3

Mea

n C

hang

e

P=0.031

LMF-Me-Cbl-PLP

Placebo

SF-36 Health Survey Summary Mental Component Scale (MCS)*

Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress *These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

Safety Profile Similar to Placebo*

• LMF-MeCbl-PLP safety profile is NO DIFFERENT than placebo

• Individual AEs reported were < 2%

• No patient discontinued trial due to AEs in either group

• Most common AE with LMF-MeCbl-PLP was rash (1) mild GI upset (1)

100%

75%

50%

25%

0%LMF-MeCbl-PLP

Treatment Group

% o

f Pat

ient

s

Percent of Patients Reporting Total Adverse Events

Placebo

Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress *These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

“A 24 week, double-blind, placebo-controlled, multisite study of LMF-MeCbl-PLP in subjects with diabetic peripheral neuropathy (DPN).”*

CONCLUSION OF STUDY:These findings suggest that LMF-MeCbl-PLP may be a safe and effective therapy nutritional management for patients with DPN.

Significant benefits with LMF-MeCbl-PLP were observed in parameters that may have a greater impact on patient’s well being.

Fonseca V. et al. Poster presented at the 20th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress *These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

Summary

• Patients with DPN experience TOTAL Symptoms

• Current therapies may have a quick onset, but are palliative only

• LMF-MeCbl-PLP has a nutritional effect on peripheral nerves

Ware JE et al. SF-36 Health Survey: Manual & Interpretation Guide 2000. Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011. Jacobs AM and Cheng D Rev Neurol Dis. 2011. Tanenberg RJ. Hospital Physician 2009.

LMF-MeCbl-PLP2-4