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Diabetic Peripheral Neuropathy Optimal Assessment and Management.

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1 Diabetic Peripheral Neuropathy Optimal Assessment and Management

2 Presentation Objectives Understand the clinical impact of DPNUnderstand the clinical impact of DPN Distinguish between symptoms and signs DPNDistinguish between symptoms and signs DPN Describe the proposed etiology of diabetic neuropathyDescribe the proposed etiology of diabetic neuropathy Understand the potential MOA of currently used medications in the management of DPN SymptomsUnderstand the potential MOA of currently used medications in the management of DPN Symptoms

3 Chronic Diabetes Complications 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:

4 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.

5 Diabetic Peripheral Neuropathy: What is it? Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2Nerve 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 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:

6 Impact of Diabetic Neuropathy 60-70% of foot ulcers are preceded by neuropathy60-70% of foot ulcers are preceded by neuropathy 85% of diabetes related lower limb amputations are preceded by a foot ulcer85% of diabetes related lower limb amputations are preceded by a foot ulcer Most Common Proximate, Nontraumatic Cause of AmputationsMost Common Proximate, Nontraumatic Cause of Amputations Largest number of diabetes related hospital bed-daysLargest number of diabetes related hospital bed-days Gordois et al. Diabetes Care. 2003;26: Reiber G, et al. Diabetes in America. 1995; 2nd ed: 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.

7 Clinical Unmet Needs in DPN There are a wide range of treatments available for neuropathic painThere are a wide range of treatments available for neuropathic pain This prescribing pattern suggests that there is no one treatment that addresses all the factorsThis 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 diseaseDespite a spectrum of drugs available with different modes of action, many patients remain inadequately treated in several aspects of the disease Datamonitor Research Increasing level of importance Improved efficacy Improved side effect profile Reduced time to onset of action Fewer drug-drug interactions Reduced pill burden

8 Peripheral Nervous System Vinik et al. Nature Clinical Practice Endocrinology & Metabolism 2006.

9 Diagnostic Tools for DPN: Large Fiber 5.07 Semmes-Weinstein Monofilament5.07 Semmes-Weinstein Monofilament Biosthesiometer ®Biosthesiometer ® Calibrated Tuning ForkCalibrated Tuning Fork Nerve Conduction VelocityNerve Conduction Velocity Quatrini C, Boulton A, et al. Diabetologia. 2008;51(6): Boulton AJ, et al. Diabetes Care. 2004;27(6): Boulton AJ, et al. Prev and Treatment of Diab and its Compli. 1998;82(4): Barber MA, et al. J Am Podiatr Med Assoc. 2001;91(10): Kiso T, et al. Journ of Pharmaco and Experi Therap. 2001;297(1):

10 TAVEE J, ZHOU L Cleveland Clinic Journal of Medicine 2009;76: 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

11 Symptoms and Signs of Diabetic Peripheral Neuropathy Symptoms Small Fiber Numbness or loss of feeling (asleep or bunched up sock under toes sensation)Numbness or loss of feeling (asleep or bunched up sock under toes sensation) Prickling/TinglingPrickling/Tingling Aching PainAching Pain Burning PainBurning Pain Lancinating PainLancinating Pain AllodyniaAllodynia Defective Thermal SensationDefective Thermal Sensation Decreased SweatingDecreased Sweating Signs Large Fiber Diminished vibratory perceptionDiminished vibratory perception Decreased knee and ankle reflexesDecreased knee and ankle reflexes Reduced protective sensation such as pressure, hot and cold, painReduced protective sensation such as pressure, hot and cold, pain Diminished ability to sense position of toes and feetDiminished ability to sense position of toes and feet Pain is deep, aching or crampingPain is deep, aching or cramping Symptoms and signs progress from distal to proximal over time Boulton AJ, et al. Diabetes Care April; 28(4):

12 Hyperglycemi a Metabolic Abnormalities AGEs Oxidative Stress Polyols EFA Endothelial Abnormalities ET A II NO PGI 2 Microvascular Insufficiency Neuronal and Schwann Cell Dysfunction Endothelial Dysfunction in DPN: Endothelium: a biologically active organ Endothelium: a biologically active organ Deranged nitric oxide pathways Deranged nitric oxide pathways Vinik A. The Amer Journal of Med. August 1999 Etiology of DPN

13 A consequence of low nitric oxide levels Endothelial Dysfunction in the Diabetic Foot Moncada S., Higgs A.N Engl J Med 1993; 329: Schäffer M, et al. Nitric Oxide Regulates Wound Healing. J Surg Res 1996; 63: Schwentker A, et al. Nitric Oxide and Wound Repair. Surg Clin N Am 2003; 83: poor microcirculation loss of protective sensation foot ulceration DPN pain

14 HyperglycemiaHyperglycemia Endoneurial Ischemia Progressive Diabetic Peripheral Neuropathy Progressive Diabetic Peripheral Neuropathy Neuronal Injury Putative Pathogenic Sequence Impaired Neuronal Regeneration

15 Clinical Impact of DPN TOTAL Symptoms DPN Boulton A. NCVH. Oral Presentations Mortality Cost ImpairmentDisabilityHandicap Infection (skin, bone) CharcotFoot Foot Ulcers PainfulNeuropathy Quality of Life Sensory Loss Surgery,Amputation

16 Microvascular Damage Leads to DPN Examination of tissues from patients with diabetes reveals capillary damage, including occlusion in the vasa nervorumExamination 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 functionReduced 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: Sheetz MJ, King GL. JAMA. 2002;288: Normal nerve Damaged nerve Occluded vasa nervorum Damage to myelinated and unmyelinated nerve fibers

17 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 Tavakoli M and Malik RA. Expert opin Pharmacother Argoff CE, et al. Mayo Clin Proc 2006.

18 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 metforminA 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 methlB 12Results demonstrate that metformin contributes to the severity of DPN (P<0.001) by inhibiting absorption of methlB 12 The severity of DPN positively correlates to increases in the cumulative metformin dose (P<0.001)The severity of DPN positively correlates to increases in the cumulative metformin dose (P<0.001) Wile DJ, et al. Diabetes Care P< 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 Neuropathy Severity

19 DPN Treatment Options Amitryptiline, Duloxetine Opioids Gabapentin / Pregabalin Pain Management Glucose Management TOTAL Symptom Management LMF MeCbl, PLP Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother Fonseca V. et al. Poster presented at the 20 th 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.

20 L-Methylfolate 3 mg Methylcobalamin 2 mg Pyridoxal 5 –phosphate 35 mg Dispensed by prescription under supervision of a HCPDispensed by prescription under supervision of a HCP Address the underlying condition such as endothelial dysfunction / DPNAddress the underlying condition such as endothelial dysfunction / DPN Evidence in peer-reviewed literatureEvidence 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: Accessed August 3, LMF-MeCbl-PLP

21 The Role of LMF-MeCbl-PLP in DPN Symptomatic Diabetic Neuropathy Diabetes BH 4 / UNCOUPLED eNOS BH 4 / UNCOUPLED eNOS Oxidative / Nitrosative Stress Oxidative / Nitrosative Stress Nerve Blood Flow Nerve Blood Flow Nerve Repair / Regeneration Nerve Repair / Regeneration Diabetes Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations LMF-MeCbl- PLP

22 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.

23 Clinical Evidence Overview Type of Study (n) EndpointDurationResults Therapeutic Efficacy Evaluation ZDF Rat Model (50)* Bioanalytical Assays: Nitrotyrosine; Nitrite/Nitrate Nerve Conduction Velocity IENFD Thermal/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 Perception Neuropathy TOTAL Symptoms Quality of Life 6 months No effect on VPT Improved TOTAL Symptoms (p<0.03) Improved QoL (p=0.03) Jacobs AM and Cheng D Rev Neurol Dis Walker MJ, et al. Rev Neurol Dis * These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

24 Evaluation of LMF-MeCbl-PLP on DPN in Zucker diabetic fatty (ZDF) rats Z UCKER D IABETIC F ATTY (ZDF) R AT : A commonly used animal model for type 2 diabetes with the potential to yield useful insights in the pathophysiology of disease. S TUDY D ESIGN : 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.

25 Evaluation of LMF-MeCbl-PLP on diabetic peripheral neuropathy in Zucker diabetic fatty (ZDF) rats FINDINGS: ZDF Rats developed the following:ZDF Rats developed the following: Sensory and Motor nerve conduction velocity deficitsSensory and Motor nerve conduction velocity deficits ~ 26% loss of intraepidermal nerve fibers~ 26% loss of intraepidermal nerve fibers Abnormal Nitrotyrosine levelsAbnormal Nitrotyrosine levels Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations 2011.

26 Evaluation of LMF-MeCbl-PLP on Diabetic Peripheral Neuropathy in Zucker Diabetic Fatty (ZDF) Rats ZDF controls developed sensory NCV deficitsZDF controls developed sensory NCV deficits After nutritional mgmt, LMF- MeCbl-PLP Group demonstrated a significant increase in sensory NCV compared to controlsAfter nutritional mgmt, LMF- MeCbl-PLP Group demonstrated a significant increase in sensory NCV compared to controls ControlsMetanx ® Group P< 0.05 sNCV Results m/s Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations Control LMF-MeCbl-PLP

27 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.

28 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:After nutritional mgmt with LMF- MeCbl-PLP, the dose currently employed in clinical practice, alleviated multiple manifestations of DPN, including: SNCV deficit SNCV deficit Small fiber regeneration Small fiber regeneration Nitrosative/Oxidative stress Nitrosative/Oxidative stress Clinical Endpoint Results: Clinical Endpoint P Value vs. Controls 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.

29 16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSD16 consecutive DPN patients with established sensory loss were quantified utilizing the PSSD Outcomes measured at baseline, 6 months & 1 year after LMF-MeCbl-PLPOutcomes measured at baseline, 6 months & 1 year after LMF-MeCbl-PLP Foot Medial Heel Great Toe Pulp Left / Right 1 & 2 point static touch Walker MJ, et al. Rev Neurol Dis.2010; Eight Outcome Measurements

30 Restoration of Cutaneous Sensorum Improved sensory perception at the medial heel and great toe following nutritional mgmt with Improved sensory perception at the medial heel and great toe following nutritional mgmt with LMF-MeCbl-PLP Walker MJ, et al. Rev Neurol Dis Baseline, 6 month, & 1 year follow up gm/mm 2 Baseline6 months1 year P =0.006 P <0.001 Normal* 2 Point Static Great Toe Left/Right Combined *<25.7 gm/mm 2 represents normal pressure thresholds for Pressure Specified Sensory Device (PSSD) 99% Confidence level. Baseline vs. 6 month. Baseline vs. 1 year. n = gm/mm 2 Baseline6 months1 year P <0.001 Normal* 2 Point Static Medial Heel Left/Right Combined *<30.0 gm/mm 2 represents normal pressure thresholds for Pressure Specified Sensory Device (PSSD) 99% Confidence level. Baseline vs. 6 month. Baseline vs. 1 year. n = 16

31 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).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 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)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) 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)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 Weeks Pain Reduction P <0.001 Pregabalin LMF, MeCbl, PLP/ Pregabalin Mean Pain Reduction From Baseline

32 The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing LMF-MeCbl-PLP as a Neurotrophic Agent 11 patients symptomatic DPN patients11 patients symptomatic DPN patients Baseline / 6 month skin biopsies (n=22)Baseline / 6 month skin biopsies (n=22) LMF-MeCbl-PLP B.I.D. for 6 months demonstrated 97% ENFDLMF-MeCbl-PLP B.I.D. for 6 months demonstrated 97% ENFD P =0.004 Jacobs AM and Cheng D. Rev Neurol Dis

33 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

34 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

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

36 Study Objective: LMF-MeCbl-PLP 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 20 th Anniversary 2011 American Academy of Clinical Endocrinology Annual Meeting and Clinical Congress

37 Primary Endpoint: Vibration Perception Threshold (VPT) STUDY FINDINGS: Change in VPT with LMF-MeCbl-PLP was no different than with placeboChange in VPT with LMF-MeCbl-PLP was no different than with placebo

38 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 20 th 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

39 Findings: Quality of Life Mental Health Feels peaceful, happy and calm all of the time Role Emotional No problems with work or other daily activities Social Function Performs normal social activities without interference due to physical or emotional problems Vitality Feel full of pep and energy all of the time 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 20 th 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.

40 Safety Profile Similar to Placebo* LMF-MeCbl-PLP safety profile is NO DIFFERENT than placeboLMF-MeCbl-PLP safety profile is NO DIFFERENT than placebo Individual AEs reported were < 2%Individual AEs reported were < 2% No patient discontinued trial due to AEs in either groupNo patient discontinued trial due to AEs in either group Most common AE with LMF- MeCbl-PLP was rash (1) mild GI upset (1)Most common AE with LMF- MeCbl-PLP was rash (1) mild GI upset (1) 100% 75% 50% 25% 0% LMF-MeCbl-PLP Treatment Group % of Patients Percent of Patients Reporting Total Adverse Events Placebo Fonseca V. et al. Poster presented at the 20 th 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.

41 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 patients well being. Fonseca V. et al. Poster presented at the 20 th 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.

42 Summary Patients with DPN experience TOTAL SymptomsPatients with DPN experience TOTAL Symptoms Current therapies may have a quick onset, but are palliative onlyCurrent therapies may have a quick onset, but are palliative only LMF-MeCbl-PLP has a nutritional effect on peripheral nervesLMF-MeCbl-PLP has a nutritional effect on peripheral nerves Ware JE et al. SF-36 Health Survey: Manual & Interpretation Guide Obrosova IF et al. Abstracts of the Experimental Biology Meeting. Oral Presentations Jacobs AM and Cheng D Rev Neurol Dis Tanenberg RJ. Hospital Physician LMF-MeCbl-PLP 2-4


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