Transcript Sample Title Slide - Virginia Osteopathic Medical Association

Diabetic Peripheral
Neuropathy
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
feet
Peripheral sensory neuropathy is the leading factor to diabetic foot ulcerations
Approximately 25% of those with diabetes will develop a foot
ulcer
More 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 dysfunction
in people with diabetes after exclusion of
other 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 related
lower limb amputations are
preceded by a foot ulcer
• Most Common Proximate,
Nontraumatic Cause of
Amputations
• Largest number of
diabetes related hospital
bed-days
Frykberg R, et al. Journ of Foot and Ankle Surgery 2006;45(5):S2-S8.
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.
Clinical Unmet Needs in DPN
Improved
efficacy
• There are a wide range of
treatments available for
neuropathic pain
Improved side
effect profile
Reduced time to
onset of action
Fewer drug-drug
interactions
Reduced pill
burden
Datamonitor Research 2008.
Increasing
level of
importance
• 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
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.
Diabetic Neuropathy:
A Small Fiber Disease
Normal Skin Biopsy
Normal innervation with small nerve fibers seen in the
epidermis (arrows). Skin biopsy specimens with protein
gene product 9.5 immunostaining.
TAVEE J , ZHOU L Cleveland Clinic Journal of Medicine
2009;76:297-305
Small Fiber Neuropathy Biopsy
A specimen from a patient with small fiber neuropathy
shows denervation with no small nerve fibers seen in
the epidermis
Symptoms and Signs of
Diabetic Peripheral Neuropathy
Symptoms
Signs
Small Fiber
Large 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
• 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 signs
progress from distal
to proximal over time
Boulton AJ, et al. Diabetes Care. 2005 April; 28(4):956-62.
Etiology of DPN
Hyperglycemia
Metabolic Abnormalities
AGEsOxidative StressPolyolsEFA
Endothelial Abnormalities
ETAIINOPGI2
Microvascular Insufficiency
Neuronal and Schwann Cell
Dysfunction
Vinik A. The Amer Journal of Med. August 1999
Endothelial Dysfunction in
DPN:
 Endothelium: a biologically
active organ
 Deranged nitric oxide
pathways
Endothelial Dysfunction in the
Diabetic Foot
A consequence of low nitric
oxide levels
poor microcirculation
loss of protective sensation
foot ulceration
DPN pain
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.
Putative Pathogenic Sequence
Hyperglycemia
Endoneurial Ischemia
Impaired Neuronal Regeneration
Neuronal Injury
Progressive Diabetic Peripheral Neuropathy
Clinical Impact of DPN TOTAL
Symptoms
DPN
Painful
Neuropathy
Sensory
Loss
Impairment
Disability
Handicap
Mortality
Foot
Ulcers
Quality of
Life
Infection
(skin, bone)
Charcot
Foot
Surgery,
Amputation
Boulton A. NCVH. Oral Presentations. 2007.
Cost
Microvascular Damage Leads to DPN
Normal nerve
Damaged nerve
Damage to myelinated
and unmyelinated
nerve fibers
Occluded vasa nervorum
•
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.
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
Clinical Markers of Neuropathy Severity
12
Neuropathy Severity
10
Neuropathy Impairment Score
10
8
6
P<0.001
4
4
2
0
Metformin
No Metformin
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
Wile DJ, et al. Diabetes Care 2009.
• 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)
DPN Treatment Options
Glucose Management
Pain Management
Amitryptiline, Duloxetine
Gabapentin / Pregabalin
Opioids
TOTAL Symptom Management
LMF MeCbl, PLP
Adapted 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.
LMF-MeCbl-PLP
L-Methylfolate
Methylcobalamin
Pyridoxal 5’ –phosphate
3 mg
2 mg
35 mg
Medical Food – Regulated by FDA
Nutritional support specifically modified for the management of the distinct
nutrient needs that result from the disease or condition, as determined by
medical evaluation.
• Dispensed by prescription under
supervision of a HCP
• Address the underlying condition such
as endothelial dysfunction / DPN
• Evidence in peer-reviewed literature
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.
The Role of LMF-MeCbl-PLP in DPN
Diabetes
Diabetes
LMF-MeCbl-PLP
Oxidative /
Nitrosative Stress
BH4 /
UNCOUPLED eNOS
Nerve Blood Flow
Symptomatic
Diabetic Neuropathy
Obrosova IF et al. Abstracts of the Experimental
Biology Meeting. Oral Presentations 2011.
LMF-MeCblPLP
Nerve Repair /
Regeneration
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 Overview
Type of Study (n)
Therapeutic Efficacy Evaluation
ZDF Rat Model (50)*
Endpoint
Bioanalytical Assays:
Nitrotyrosine; Nitrite/Nitrate
Nerve Conduction Velocity
IENFD
Thermal/Mechanical Algesia;
Tactile Allodynia
Duration
Results
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
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 Perception
Neuropathy TOTAL Symptoms
Quality of Life
6 months
No effect on VPT
Improved TOTAL Symptoms (p<0.03)
Improved QoL (p=0.03)
1 year
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.
Improved Sensory Perception at 6 months
(p=0.006); at 12 months (p<0.001)
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
sNCV Results
P<0.05
40
39
35.9
m/s
30
• ZDF controls developed
sensory NCV deficits
• After nutritional mgmt, LMFMeCbl-PLP Group
demonstrated a significant
increase in sensory NCV
compared
to controls
20
10
0
Control
Controls
LMF-MeCbl-PLP
®
Metanx Group
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
Controls experienced
26% loss of small fibers
ZDF + LMF-MeCbl-PLP
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
Clinical Endpoint Results:
Clinical Endpoint
P Value vs.
Controls
Sensory NCV
.05
Motor NCV
ns
Nerve Fiber Density
.02
Nitrotyrosine
.005
• After nutritional mgmt with LMFMeCbl-PLP, the dose currently
employed in clinical practice,
alleviated multiple manifestations
of DPN, including:
‒ SNCV deficit
‒ Small fiber regeneration
‒ Nitrosative/Oxidative stress
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
Eight Outcome Measurements
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.
Restoration of Cutaneous Sensorum
Baseline, 6 month, & 1 year follow up
2 Point Static Medial Heel
Left/Right Combined
60
60
50
50
40
P=0.006†
30
Normal*
20
P<0.001‡
gm/mm2
gm/mm2
2 Point Static Great Toe
Left/Right Combined
40
30
20
10
10
0
Baseline
0
Baseline
6 months
1 year
*<25.7 gm/mm2 represents normal pressure thresholds for Pressure Specified Sensory
Device™ (PSSD) 99% Confidence level.
†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16
P<0.001†
Normal*
P<0.001‡
6 months
1 year
*<30.0 gm/mm2 represents normal pressure thresholds for Pressure Specified Sensory
Device™ (PSSD) 99% Confidence level.
†Baseline vs. 6 month. ‡Baseline vs. 1 year. n = 16
Improved sensory perception at the
medial heel and great toe following nutritional mgmt with LMF-MeCbl-PLP
Walker MJ, et al. Rev Neurol Dis 2010.
LMF-MeCbl-PLP Administration to Pregabalin
Partial-Responders for Management of DPNP
Mean Pain Reduction From Baseline
0
Pain Reduction
-0.5
-1
-1.5
Pregabalin
-2.5
LMF, MeCbl, PLP/
Pregabalin
-3
-3.5
After nutritional management with
LMF-MeCbl-PLP:
• The average absolute pain
reduction after 20 weeks in the
study group was 3.0 compared
to .25 in the active
control group (P<0.001)
P<0.001
-2
0
20
Weeks
Jacobs AM. NCVH Oral Presentations 2008.
• Results from a 20 week, open
trial of 24 patients to evaluate
LMF-MeCbl-PLP with ≤ 50%
response to pregabalin (VAS
score).
• 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)
The Pharmacological Management of
Diabetic Small Fiber Neuropathy Utilizing
LMF-MeCbl-PLP as a Neurotrophic Agent
Epidermal Nerve Fiber Density
4
3.5
P=0.004
ENFD/mm
3
3.07
2.5
• Baseline / 6 month skin
biopsies (n=22)
2
1.5
• 11 patients symptomatic
DPN patients
1.56
• LMF-MeCbl-PLP B.I.D. for
6 months demonstrated 97%
↑ ENFD
1
0.5
0
Baseline
Jacobs AM and Cheng D. Rev Neurol Dis. 2011.
6 months
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
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 averaged an increase of .76
nerve fibers per mm. Skin Punch Biopsy Analysis and Images Performed by Therapath, LLC.
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, MPH
Professor of Medicine & Pharmacology
Tulane University Health Sciences Center
2012 Incoming President, ADA
New Orleans, LA
Professor of Surgery
Texas A&M University College of Medicine
Round Rock, TX
Cyrus DeSouza, MD
Julio Rosenstock, MD
Associate Professor
Omaha VA Medical Center
Omaha, NE
Dallas Diabetes and Endocrine Center
Dallas, TX
Fernando Ovalle, MD
Douglas Denham, MD
Division of Endocrinology
University of Alabama at Birmingham,
School of Medicine
Birmingham, AL
DGD Research, Inc.
San Antonio, TX
“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
Study Findings:
Neuropathy Total Symptom Score-6 (NTSS-6)*
0
Mean scores in the
LMF-MeCbl-PLP group
improved more at 16
and 24 weeks
compared to placebo
NTSS-6
-0.2
Mean Change
-0.4
NTSS-6:
-0.6
• Numbness
p=0.01
-0.8
p=0.03
-1
-1.2
LMF-MeCbl-PLP
METANX
PLACEBO
PLACEBO
Baseline
Visit 3 (Week 8)
Visit 4 (Week 16)
00
-0.54
-0.54
-0.9
-0.9
0
0
-0.33
-0.33
-0.4
-0.4
Visit 5 (Week 24)
• Tingling
• Aching pain
• Burning pain
• Lancinating pain
• Allodynia
-0.96
-0.96
-0.53
-0.53
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.
Findings: Quality of Life
SF-36 Health Survey Summary Mental Component Scale (MCS)*
Change in SF-36 MCS at 24 Weeks
3
Mean Change
2
LMF-Me-Cbl-PLP
P=0.031
Placebo
1.99
-1
Role Emotional
No problems with work or other
daily activities
Social Function
Performs normal social activities
without interference due to physical
or emotional problems
1
0
Mental Health
Feels peaceful, happy and calm all
of the time
-0.29
Vitality
Feel full of pep and energy all of
the time
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*
100%
Percent of Patients Reporting
Total Adverse Events
% of Patients
75%
• LMF-MeCbl-PLP safety profile
is NO DIFFERENT
than placebo
50%
• Individual AEs reported were
< 2%
25%
• No patient discontinued trial
due to AEs in either group
0%
LMF-MeCbl-PLP
Placebo
Treatment Group
• Most common AE with LMFMeCbl-PLP was rash (1)
mild GI upset (1)
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
LMF-MeCbl-PLP2-4
• 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.