The Pharmacological The Pharmacological Management of Diabetic Management of Diabetic Peripheral Neuropathy:Peripheral Neuropathy:

Disease Modifying vs. Disease Modifying vs. Symptomatic StrategiesSymptomatic Strategies

Presentation ObjectivesPresentation Objectives

Understand the economic and social impact of DPNUnderstand the economic and social impact of DPN

Distinguish between positive and negative symptoms Distinguish between positive and negative symptoms of diabetic peripheral neuropathyof diabetic peripheral neuropathy

Describe disease modifying vs. symptomatic strategies Describe disease modifying vs. symptomatic strategies in the management of DPNin the management of DPN

Understand the potential MOA of MetanxUnderstand the potential MOA of Metanx®® in the in the management of positive and negative DPN symptomsmanagement of positive and negative DPN symptoms

““I marvel that societyI marvel that societywould pay a surgeonwould pay a surgeona large sum of moneya large sum of moneyto remove a person’sto remove a person’sleg – but nothing toleg – but nothing tosave it.”save it.”

– – George Bernard ShawGeorge Bernard Shaw

Diabetic Peripheral Neuropathy: Diabetic Peripheral Neuropathy: What is it?What is it?

Nerve damage and dysfunction secondary to diabetes Nerve damage and dysfunction secondary to diabetes mellitus type 1 or 2mellitus type 1 or 2– Consensus definition: “the presence of symptoms Consensus definition: “the presence of symptoms

and/or signs of peripheral nerve dysfunctionand/or signs of peripheral nerve dysfunctionin people with diabetes after exclusion ofin people with diabetes after exclusion ofother causes”other causes”

A leading cause of neuropathic painA leading cause of neuropathic pain– A very common complication of diabetesA very common complication of diabetes

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

DPN PrevalenceDPN Prevalence

Diabetic Neuropathy may occur inDiabetic Neuropathy may occur in50% to 90% of patients depending on50% to 90% of patients depending on

the criteria used for diagnosisthe criteria used for diagnosis

Impact of Diabetic NeuropathyImpact of Diabetic Neuropathy

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

85% of diabetes related85% of diabetes relatedlower limb amputations are lower limb amputations are preceded by a foot ulcerpreceded by a foot ulcer

3 out of 10 patients who 3 out of 10 patients who undergo lower limb undergo lower limb amputation will lose another amputation will lose another leg within 3 years and over leg within 3 years and over half of them will die within half of them will die within the first 5 years of thethe first 5 years of thefirst amputationfirst amputation

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

Impact of Diabetic NeuropathyImpact of Diabetic Neuropathy

Largest number of diabetesLargest number of diabetesrelated hospital bed-daysrelated hospital bed-days

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

Most Common Proximate,Most Common Proximate,Nontraumatic Cause of AmputationsNontraumatic Cause of Amputations

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 DPNClinical Unmet Needs in DPN

There are a wide range ofThere are a wide range oftreatments available fortreatments available forneuropathic painneuropathic pain

This prescribing pattern This prescribing pattern suggests that there is no one suggests that there is no one treatment that addressestreatment that addressesall the factorsall the factors

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

Datamonitor Research 2008.

IncreasingIncreasinglevel oflevel ofimportanceimportance

ImprovedImprovedefficacyefficacy

Improved sideImproved sideeffect profileeffect profile

Reduced time toReduced time toonset of actiononset of action

Fewer drug-drugFewer drug-druginteractionsinteractions

Reduced pillReduced pillburdenburden

Diabetic Neuropathy: Diabetic Neuropathy: The Forgotten ComplicationThe Forgotten Complication

Only one in four survey respondents who experience symptoms Only one in four survey respondents who experience symptoms of diabetic neuropathy have been diagnosed with the condition.of diabetic neuropathy have been diagnosed with the condition.

The majority of respondents who experience symptoms (56%) The majority of respondents who experience symptoms (56%) remain unaware of the term diabetic neuropathy.remain unaware of the term diabetic neuropathy.

62% believe that their symptoms are associated with their 62% believe that their symptoms are associated with their diabetes, but only 42% have been told by their physician that diabetes, but only 42% have been told by their physician that diabetes is the cause.diabetes is the cause.

Approximately one in seven people who said they talked to their Approximately one in seven people who said they talked to their doctor about their symptoms and pain reported that no cause doctor about their symptoms and pain reported that no cause was mentioned.was mentioned.

Results of the 2005 ADA National Survey

May 10, 2005 /PR Newswire via COMTEX.

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

Signs and Symptoms ofSigns and Symptoms ofDiabetic Peripheral NeuropathyDiabetic Peripheral Neuropathy

SignsSigns Diminished vibratory Diminished vibratory

perceptionperception Decreased knee and ankle Decreased knee and ankle

reflexesreflexes Reduced protective Reduced protective

sensation, such as pressure, sensation, such as pressure, hot and cold, painhot and cold, pain

Diminished ability to sense Diminished ability to sense position of toes and feetposition of toes and feet

SymptomsSymptoms Numbness, loss of feeling, Numbness, loss of feeling,

prickling, tinglingprickling, tingling Aching painAching pain Burning painBurning pain Lancinating painLancinating pain Unusual sensitivity or Unusual sensitivity or

tenderness when feet are tenderness when feet are touched (allodynia)touched (allodynia)

Distal symmetrical sensorimotor polyneuropathy is the mostcommon form of DPN. Signs and symptoms may progress from

distal to proximal over time.

DPN Produces Positive andDPN Produces Positive andNegative SymptomsNegative Symptoms

Positive SymptomsPositive Symptoms Spontaneous PainSpontaneous Pain

DysesthesiasDysesthesias– C-FibersC-Fibers– UnpleasantUnpleasant

ParesthesiasParesthesias– A-FibersA-Fibers– Not UnpleasantNot Unpleasant

Negative SymptomsNegative Symptoms Loss/impairment ofLoss/impairment of

sensory qualitysensory quality

NumbnessNumbness

Dry skinDry skin

Erectile dysfunctionErectile dysfunction

IncontinenceIncontinence

Gait instability and fall riskGait instability and fall risk

Baron R. Clin J Pain. 2000;16(2 suppl):S12-S20.Argoff CE, et al. Mayo Clin Proc. 2006;81(4 Suppl):S3-S11.Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.

Neuropathic Symptoms and Neuropathic Symptoms and Quality of LifeQuality of Life

Positive and negative symptoms have an impact on functioning, activities of Positive and negative symptoms have an impact on functioning, activities of daily living (ADL) and QOLdaily living (ADL) and QOL

QOL is a unique, individual experience – how persons perceive and react to QOL is a unique, individual experience – how persons perceive and react to their health statustheir health status

Psychosocial MorbidityPsychosocial Morbidity– DepressionDepression– AnxietyAnxiety– AngerAnger– Loss of Self-EsteemLoss of Self-Esteem

Societal ConsequencesSocietal Consequences– Social isolation Social isolation – Strained relationships with family and friendsStrained relationships with family and friends– Effects upon intimacy/sexual activityEffects upon intimacy/sexual activity

Argoff CE, et al. Mayo Clin Proc. 2006;81(4 Suppl):S3-S11.

Diabetic Neuropathy: SymptomsDiabetic Neuropathy: Symptoms

Majority of symptomaticMajority of symptomaticDPN patients are insensateDPN patients are insensate

Argoff CE, et al. Mayo Clin Proc. 2006;81:(S4).Boulton AJM, et al. Diabetes Care. 2004;27.

Pain

Asymptomatic

SensoryLoss

Clinical Impact of Positive and Negative Clinical Impact of Positive and Negative DPN Symptoms DPN Symptoms

DPNDPN

Boulton A. NCVH. Oral Presentations. 2007.

MortalityMortality

CostCost

ImpairmentImpairmentDisabilityDisabilityHandicapHandicap

InfectionInfection(skin, bone)(skin, bone)

Charcot Charcot FootFoot

FootFootUlcersUlcers

Painful Painful NeuropathyNeuropathy

Quality ofQuality ofLifeLife

SensorySensoryLossLoss

Surgery, Surgery, AmputationAmputation

ADA Consensus StatementADA Consensus Statement

““The effort to optimize foot care for patients with The effort to optimize foot care for patients with diabetes led to the American Diabetes Association diabetes led to the American Diabetes Association

consensus statement on foot care, which consensus statement on foot care, which recommended that the recommended that the cutaneous pressure cutaneous pressure thresholdthreshold be measured at least once a year” be measured at least once a year”

““The goal of this recommendation is to reduceThe goal of this recommendation is to reducethe risk of ulceration, infection and amputationthe risk of ulceration, infection and amputation

due to due to sensory losssensory loss that can occur through that can occur through progressive neuropathy”progressive neuropathy”

Barber MA. Journ of APMA. 2001;91(10):508-514.

Vinik A. The Amer Journal of Med. August 1999.

DIABETESDIABETES

HyperglycemiaHyperglycemia

DAGDAGPKCPKC

Impaired n-6 fattyImpaired n-6 fattyacid metabolismacid metabolism

PolyolPolyolpathwaypathway

Sugar Sugar autoxidationautoxidation

Advanced Advanced glycationglycation

OXIDATIVE STRESSOXIDATIVE STRESS

ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION

capillary blood flow capillary blood flow endoneurial hypoxiaendoneurial hypoxia

NERVE DYSFUNCTIONNERVE DYSFUNCTIONNCV, NCV, Regeneration, Structural damageRegeneration, Structural damage

TriglyceridesTriglyceridesLDLLDL

Etiology of Diabetic NeuropathyEtiology of Diabetic Neuropathy

Endothelial Dysfunction inEndothelial Dysfunction inDiabetic NeuropathyDiabetic Neuropathy

EndotheliumEndothelium: a biologically active organ: a biologically active organ

Deranged nitric oxide pathwaysDeranged nitric oxide pathways

MultifactorialMultifactorial– HyperglycemiaHyperglycemia– Insulin resistanceInsulin resistance– FFA production / metabolismFFA production / metabolism

Minami M, et al. Journ of Cardiovas Pharmacol. 1998;31(Suppl 1):S467-S469.Wu G and Meininger CJ. Biofactors. 2009;35(1):21-27.Veves A, et al. Diabetes. 1998;47:457-463.

ADA Statement Diabetic Neuropathies ADA Statement Diabetic Neuropathies Classification of NeuropathiesClassification of Neuropathies

Generalized symmetric polyneuropathiesGeneralized symmetric polyneuropathies– Acute sensorimotorAcute sensorimotor– Chronic sensorimotorChronic sensorimotor– AutonomicAutonomic

Focal and multifocal neuropathiesFocal and multifocal neuropathies– CranialCranial– TruncalTruncal– Focal limbFocal limb– Proximal (Amyotrophy)Proximal (Amyotrophy)– Co-existing CIDPCo-existing CIDP

Boulton AJ, et al. Diabetes Care. 2005;28(4):956-962.

Sensorimotor NeuropathySensorimotor Neuropathy

Most common type of diabetic neuropathyMost common type of diabetic neuropathy

Affects 30-50% of all diabetic populationAffects 30-50% of all diabetic population

Most commonly involved in diabetic foot problemsMost commonly involved in diabetic foot problems

Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.

Sensorimotor NeuropathySensorimotor Neuropathy

Development progressive, initially involving more Development progressive, initially involving more distal partsdistal parts

Main symptoms are numbness of the legs andMain symptoms are numbness of the legs andfeet, muscular cramps, pins and needles, shooting, feet, muscular cramps, pins and needles, shooting, deep aching and burning pain. Nocturnaldeep aching and burning pain. Nocturnalexacerbation characteristicexacerbation characteristic

Symptoms may be absent or present either in theSymptoms may be absent or present either in theearly or late stagesearly or late stages

Symptoms

Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.

Acute Sensory and ChronicAcute Sensory and ChronicSensory NeuropathiesSensory Neuropathies

Acute SensoryAcute Sensory Chronic SensorimotorChronic Sensorimotor

Mode of onsetMode of onset Relatively rapidRelatively rapid Gradual, insidiousGradual, insidious

SymptomsSymptoms Severe burning pain, aching: Severe burning pain, aching: weight loss usualweight loss usual

Burning pain, paresthesia, Burning pain, paresthesia, numbness: weight loss usualnumbness: weight loss usual

Symptom severitySymptom severity ++++++ 0 to ++0 to ++

SignsSigns Mild sensory in some:Mild sensory in some:motor unusualmotor unusual

Stocking and glove sensory Stocking and glove sensory loss: absent ankle reflexesloss: absent ankle reflexes

Other diabetic Other diabetic complicationscomplications UnusualUnusual Increased prevalenceIncreased prevalence

Electrophysiological Electrophysiological investigationsinvestigations

May be normal or minor May be normal or minor abnormalitiesabnormalities

Abnormalities unusual in Abnormalities unusual in motor and sensory nervesmotor and sensory nerves

Natural historyNatural history Complete recovery withinComplete recovery within12 months12 months

Symptoms may persist Symptoms may persist intermittently for years: at risk intermittently for years: at risk of foot ulcerationof foot ulceration

Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.

Autonomic NeuropathyAutonomic Neuropathy

Heart rate abnormalitiesHeart rate abnormalities

Postural hypotensionPostural hypotension

Abnormal sweatingAbnormal sweating

GastroparesisGastroparesis

Neuropathic diarrheaNeuropathic diarrhea

ImpotenceImpotence

Retrograde ejaculationRetrograde ejaculation

Diabetic Neuropathies: A Statement by the ADA. Diabetes Care. 2005;28(4):956-962.

Predictors of Foot UlcerationPredictors of Foot Ulceration

Rich J, Veves A. Wounds. 2000;12(4):82-87.

VariableVariable No Ulcer (127)No Ulcer (127) Ulcer (53)Ulcer (53) P-valueP-value

NSSNSS 2.1 + 2.42.1 + 2.4 2.7 + 2.82.7 + 2.8 0.2970.297

NDSNDS 13 + 813 + 8 18 + 518 + 5 0.00010.0001

VPT (volts)VPT (volts) 38 + 1538 + 15 46 + 646 + 6 0.00010.0001

SWFSWF 5.90 + 1.205.90 + 1.20 6.63 + 0.746.63 + 0.74 0.00010.0001

NP Pedal PulseNP Pedal Pulse 28 (22%)28 (22%) 20 (38%)20 (38%) 0.0350.035

STJ mobilitySTJ mobility 22 + 722 + 7 22 + 1122 + 11 0.7840.784

1st MTP mobility1st MTP mobility 71 + 1871 + 18 61 + 2061 + 20 0.0020.002

Forefoot PPForefoot PP 6.6 + 2.86.6 + 2.8 8.2 + 4.38.2 + 4.3 0.0050.005

Rearfoot PPRearfoot PP 3.1 + 1.53.1 + 1.5 3.4 + 1.83.4 + 1.8 0.370.37

Other Diagnostic Tools forOther Diagnostic Tools forDetection of DPNDetection of DPN

5.07 Semmes-Weinstein Monofilament 5.07 Semmes-Weinstein Monofilament BiosthesiometerBiosthesiometer®®

Calibrated Tuning ForkCalibrated Tuning Fork Diskcriminator for 2 Point SpacingDiskcriminator for 2 Point Spacing Neurometer CPTNeurometer CPT®® (A-beta,A-delta,C fibers) (A-beta,A-delta,C fibers) PSSDPSSD®® (Earliest detection of pathology of A-beta skin surface/touch fibers (Earliest detection of pathology of A-beta skin surface/touch fibers Neuropad (correlates with IENFD, p=0.04)Neuropad (correlates with IENFD, p=0.04)

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.

Diagnostic Tests for DPNPDiagnostic Tests for DPNP

Nerve Conduction Studies/ElectromyogramNerve Conduction Studies/Electromyogram– Measures the speed and amplitude of sensory and motor conductionMeasures the speed and amplitude of sensory and motor conduction– Objective, parametric, non-invasiveObjective, parametric, non-invasive– Insensitive in acute and small-fiber neuropathyInsensitive in acute and small-fiber neuropathy– > 50% False Negative for Tarsal Tunnel Syndrome> 50% False Negative for Tarsal Tunnel Syndrome

Quantitative Sensory TestQuantitative Sensory Test– Detects sensory thresholds for vibration, heat and painDetects sensory thresholds for vibration, heat and pain– Useful in tracking the progression of neuropathy in large cohorts and the efficacy Useful in tracking the progression of neuropathy in large cohorts and the efficacy

of treatment end points in multicenter clinical trialsof treatment end points in multicenter clinical trials

Skin Biopsy (IENFD)Skin Biopsy (IENFD)– Measures density of intraepidermal nerve fibers at various sites in the legMeasures density of intraepidermal nerve fibers at various sites in the leg– Loss of nerve fibers is associated with increased neuropathic painLoss of nerve fibers is associated with increased neuropathic pain– Although the test is invasive, it requires a 3mm skin biopsy specimen and enables Although the test is invasive, it requires a 3mm skin biopsy specimen and enables

a direct study of small nerve fibersa direct study of small nerve fibers

Pathways: Perspectives in Modern Neurology and Pain Management. Vol 3. July 2007; Page 6.

Diagnosing Small Fiber Neuropathy with Diagnosing Small Fiber Neuropathy with Skin Punch BiopsySkin Punch Biopsy

Small Fiber Neuropathy (SFN) is a major cause of painful Small Fiber Neuropathy (SFN) is a major cause of painful burning, numbness and tingling in feet/handsburning, numbness and tingling in feet/hands

SFN often precedes diagnosis of diabetes a.k.a. “impaired SFN often precedes diagnosis of diabetes a.k.a. “impaired glucose tolerance neuropathy”glucose tolerance neuropathy”

Diagnostic efficiency of skin punch biopsy is ≈ 88% Diagnostic efficiency of skin punch biopsy is ≈ 88%

Findings on routine nerve conduction studies and Findings on routine nerve conduction studies and electromyography are typically normal (large fiber only)electromyography are typically normal (large fiber only)

Management of SFN should involve controllingManagement of SFN should involve controllingthe symptoms and aggressively treating thethe symptoms and aggressively treating theunderlying causeunderlying cause

Tavee et al. Cleveland Clinic Journal of Medicine. May 2009.

Skin BiopsySkin Biopsy

Normal nerve fiber density. Arrow pointsNormal nerve fiber density. Arrow pointsto the small nerve fiber in the epidermalto the small nerve fiber in the epidermallayer of skin, arrowhead points to thelayer of skin, arrowhead points to thebasement membrane that separates thebasement membrane that separates thedermis from the epidermis. dermis from the epidermis.

Low normal nerve fibers, consistent withLow normal nerve fibers, consistent withsmall fiber neuropathy. The arrow pointssmall fiber neuropathy. The arrow pointsto the basement membrane of the epidermis. to the basement membrane of the epidermis.

Images Courtesy of Therapath, LLC.

Diabetic Neuropathy: Diabetic Neuropathy: Current TreatmentsCurrent Treatments

25% NO TREATMENT25% NO TREATMENT

53.9% OPIOIDS53.9% OPIOIDS

39.7% NSAIDS39.7% NSAIDS

21.1% SSRIs21.1% SSRIs

11.3% TCAs11.3% TCAs

11.1% ANTICONVULSANTS11.1% ANTICONVULSANTS

Berger A, Dukes EM, Oster G. J Pain. 2004;5.

Only Target PositiveOnly Target Positive(Painful) Symptoms(Painful) Symptoms

Treatment Options for DPNP: Treatment Options for DPNP: Palliative AgentsPalliative Agents

ClassClass TherapyTherapy Dose (mg/day)Dose (mg/day)

Aldose reductase inhibitorsAldose reductase inhibitors EpalrestatEpalrestat Only licensed in JapanOnly licensed in Japan

Angiotensin-convertingAngiotensin-convertingenzyme inhibitorsenzyme inhibitors

TrandaloprilTrandalopril More studies neededMore studies needed

Tricyclic antidepressantsTricyclic antidepressants AmitriptylineAmitriptylineImipramineImipramine

20-15020-15025-15025-150

SNRIsSNRIs Duloxetine*Duloxetine* 60-12060-120

AnticonvulsantsAnticonvulsants GabapentinGabapentinLamotrigineLamotrigineCarbamazepineCarbamazepinePregabalin*Pregabalin*

900-3600900-3600200-400200-400200-600200-600300-600300-600

AntiarrhythmicsAntiarrhythmics MexiliteneMexilitene Up to 900Up to 900

OpioidsOpioids TramadolTramadol 50-40050-400

*FDA Approved.Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008.

Current Palliative TreatmentsCurrent Palliative Treatments

Chen H, Lamer TH, Rho RH, et al. Mayo Clin Proceed. 2004;79.

Distal NeuropathyDistal Neuropathy

C-fibers (dysesthesias,C-fibers (dysesthesias,allodynia, burning)allodynia, burning)

A-fibers (paresthesias,A-fibers (paresthesias,radiating, night cramps)radiating, night cramps)

Capsaicin creamCapsaicin creamClonidineClonidineLidocaineLidocaine

Insulin InfusionInsulin InfusionCarbamazepineCarbamazepine

LidocaineLidocaineMuscle relaxantMuscle relaxant

NSAIDsNSAIDs

TramadolTramadolTCATCA

GabapentinGabapentinPregabalinPregabalinDuloxetineDuloxetine

Treatment Options for DPN: Treatment Options for DPN: Disease Modifying AgentsDisease Modifying Agents

ClassClass TherapyTherapy Dose (mg/day)Dose (mg/day)

Glucose ControlGlucose Control –– ––

Pancreas transplantationPancreas transplantation –– ––

AntioxidantAntioxidant Alpha Lipoic AcidAlpha Lipoic Acid600 mg intravenously600 mg intravenously1200-1800 mg orally1200-1800 mg orally

Neurotrophic SupportNeurotrophic Support L-methylfolate, P5P, Me-CblL-methylfolate, P5P, Me-Cbl 2.8 mg, 25 mg, 2 mg, BID2.8 mg, 25 mg, 2 mg, BID

Adapted from Tavakoli M and Malik R. Expert Opin Pharmacother. 2008.

L-MethylfolateL-Methylfolate 2.8 mg2.8 mgMethylcobalaminMethylcobalamin 2 mg 2 mgPyridoxal 5’ –phosphate 25 mgPyridoxal 5’ –phosphate 25 mgMETANXMETANX®®

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.Verhaar, et al. Circulation. 1998.Yaqub, et al. Clin Neurol and Neuros. 1992.Beck W. New Eng Journ Med. 1988.Goh S and Cooper M. Clin Endocrin & Metabol. 2008.Wantanabe, et al. Journ of Neurolog Scien. 1994.

L-methylfolateL-methylfolate Active form of folate necessary for neural functionActive form of folate necessary for neural function Works with Methyl BWorks with Methyl B1212 to activate protein, DNA / RNA synthesis to activate protein, DNA / RNA synthesis Increase nitric oxide synthesisIncrease nitric oxide synthesis

MethylcobalaminMethylcobalamin Neurologically active form of BNeurologically active form of B1212

Methyl donor in DNA metabolism, Up-regulate gene transcription for Methyl donor in DNA metabolism, Up-regulate gene transcription for peripheral nerve repair & regenerationperipheral nerve repair & regeneration

Enhance protein metabolism in Schwann CellsEnhance protein metabolism in Schwann Cells

Pyridoxal 5’-phosphatePyridoxal 5’-phosphate Active form of BActive form of B66, Necessary for neural function, Necessary for neural function May inhibit effects of advanced glycation end productsMay inhibit effects of advanced glycation end products

MetanxMetanx®®: A Medical Food: A Medical Food

1988 via amendments to the Federal Food, Drug and Cosmetic Act:1988 via amendments to the Federal Food, Drug and Cosmetic Act: Active ingredient: present in / derived from a food (e.g. folate)Active ingredient: present in / derived from a food (e.g. folate)

Oral dosage formOral dosage form

Addresses distinct nutritional requirements of patients with Addresses distinct nutritional requirements of patients with specific diagnosed diseases or conditions (e.g. low plasma / specific diagnosed diseases or conditions (e.g. low plasma / RBC folate, hyperhomocysteinemia, endothelial dysfunction)RBC folate, hyperhomocysteinemia, endothelial dysfunction)

Efficacy/dosing must be proven in peer-reviewedEfficacy/dosing must be proven in peer-reviewedscientific literature scientific literature

Only under care of health care provider (Available by Only under care of health care provider (Available by prescription)prescription)

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.

Medical FoodsMedical Foods

PharmaceuticalPharmaceutical Medical FoodMedical FoodDietary SupplementDietary Supplement(Neutraceutical)(Neutraceutical)

Intended UseIntended Use To treat, prevent, or mitigate a To treat, prevent, or mitigate a disease or conditiondisease or condition

Nutritional or dietary management Nutritional or dietary management of a specific diseaseof a specific disease

To maintain the well-being of a To maintain the well-being of a particular function in the body particular function in the body (e.g. maintain healthy joints(e.g. maintain healthy joints

ConsumerConsumer Person suffering from a disease or Person suffering from a disease or abnormal conditionabnormal condition

Person suffering from a disease or Person suffering from a disease or abnormal conditionabnormal condition

Normal, relatively healthy personNormal, relatively healthy person

Evidence RequirementsEvidence Requirements Must have 2+ placebo controlled Must have 2+ placebo controlled trials (and a maintenance trial for trials (and a maintenance trial for certain disease states). Usually certain disease states). Usually involves animal testing: Phase 1, involves animal testing: Phase 1, 2, & 3 clinical trials2, & 3 clinical trials

The distinct nutritional The distinct nutritional requirement of the specific requirement of the specific disease and product performance disease and product performance must be supported by peer must be supported by peer reviewed literature, reviewed literature, clinical/scientific study, and clinical/scientific study, and medical determinationmedical determination

No specific requirements forNo specific requirements forpre-market testingpre-market testing

SafetySafety Pharmacology and toxicology Pharmacology and toxicology testing required. Must be deemed testing required. Must be deemed ‘safe & efficacious’ by the FDAs ‘safe & efficacious’ by the FDAs review of adverse events, drug review of adverse events, drug interactions, dosing and toxicityinteractions, dosing and toxicity

Ingredients must attain FDA GRAS Ingredients must attain FDA GRAS (Generally Regarded as Safe) (Generally Regarded as Safe) status. GRAS denotes broad scale, status. GRAS denotes broad scale, up-front safetyup-front safety

Ingredients have some Ingredients have some ‘expectations’ of safety as ‘expectations’ of safety as evidenced by having been sold in evidenced by having been sold in the U.S. market prior to October the U.S. market prior to October 19941994

Medical CareMedical Care Must be prescribed by a physician Must be prescribed by a physician or licensed NP/PAor licensed NP/PA

Must be used under a physician’s Must be used under a physician’s supervision (or licensed) by supervision (or licensed) by prescriptionprescription

None. Supplements are typically None. Supplements are typically self-administered by the consumer self-administered by the consumer and are sold over the counterand are sold over the counter

Regulatory Review Body of the Regulatory Review Body of the FDAFDA

Center for Drug Evaluation and Center for Drug Evaluation and Research (CDER)Research (CDER)

Center for Food Safety and Center for Food Safety and Applied Nutrition (CFSAN) Applied Nutrition (CFSAN)

DSHEA – Dietary Supplement DSHEA – Dietary Supplement Health Education Act (1994) under Health Education Act (1994) under the same center (CFSAN) as the same center (CFSAN) as medical foods.medical foods.

MetanxMetanx®® Indication and Dosage Indication and Dosage

The distinct nutritional requirements of patients withThe distinct nutritional requirements of patients withendothelial dysfunction:endothelial dysfunction: Who present with loss of protective sensation and neuropathic Who present with loss of protective sensation and neuropathic

pain associated with diabetic peripheral neuropathypain associated with diabetic peripheral neuropathy

and/or hyperhomocysteinemia who present with lower extremity and/or hyperhomocysteinemia who present with lower extremity ulceration(s)ulceration(s)

Identification StatementIdentification Statement MetanxMetanx®® is an orally administered prescription medical food for is an orally administered prescription medical food for

the dietary management of endothelial dysfunction in patients the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathywith diabetic peripheral neuropathy

DosageDosage 1 tablet twice daily1 tablet twice daily

Metanx Package Insert 2009.

MetanxMetanx®® Safety Profile Safety Profile

Adverse Reactions: Adverse Reactions: While allergic sensitization has been reported following While allergic sensitization has been reported following

both oral and parenteral administration of folic acid, both oral and parenteral administration of folic acid, allergic sensitization has not been reported with the allergic sensitization has not been reported with the use of L-methylfolate. use of L-methylfolate.

Paresthesia, somnolence, nausea and headaches have Paresthesia, somnolence, nausea and headaches have been reported with P-5-P. Mild transient diarrhea, been reported with P-5-P. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been the feeling of swelling of the entire body has been associated with cobalamin.associated with cobalamin.

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Metanx Package Insert 2009.

MetanxMetanx®® Safety Profile Safety Profile

MetanxMetanx®® is well tolerated in short-term and chronic use: is well tolerated in short-term and chronic use: Side effects and/or discontinuation rates similar to placeboSide effects and/or discontinuation rates similar to placebo The Ingredients in MetanxThe Ingredients in Metanx®® are generally recognized as safe are generally recognized as safe

(GRAS) as designated by the FDA or independent review(GRAS) as designated by the FDA or independent review

Precautions:Precautions: Pyridoxal 5’-phosphate (P-5-P) should not be given in patients Pyridoxal 5’-phosphate (P-5-P) should not be given in patients

receiving levodopa, because the action of levodopa is receiving levodopa, because the action of levodopa is antagonized by P-5-P. However, P-5-P may be used concurrently antagonized by P-5-P. However, P-5-P may be used concurrently in patients receiving carbidopa/levodopain patients receiving carbidopa/levodopa

While the concurrent use of phenytoin and folic acid may result While the concurrent use of phenytoin and folic acid may result in decreased phenytoin effectiveness, no such decreased in decreased phenytoin effectiveness, no such decreased effectiveness has been reported with the use of L-methylfolateeffectiveness has been reported with the use of L-methylfolate

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients with diabeticperipheral neuropathy.Metanx Package Insert 2009.Abstracts of the 7th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology. Oral Presentations. Arterioscler Thromb Vasc Biol.2003;26:e43-e52.

Vitamin B for Peripheral Neuropathy: Vitamin B for Peripheral Neuropathy: Cochrane DatabaseCochrane Database

13 Studies / 741 Patients13 Studies / 741 Patients

2 Studies No Short-Term Pain Reduction2 Studies No Short-Term Pain Reduction

1 Study Vibration Detection Improved1 Study Vibration Detection Improved(Thiamine derivative)(Thiamine derivative)

Higher Doses Improved Short-Term Paresthesias, Pain, Higher Doses Improved Short-Term Paresthesias, Pain, Temperature, Vibration, NumbnessTemperature, Vibration, Numbness

Still Limited Data Still Limited Data

Ang, CD, Alviar, MJM, Dans, AL, Bautista-Velez, GGP, et al. Cochrane Database of Systemic Reviews. Issue 3, Article #CD004573, 2008.

(Metanx(Metanx®®)L-methylfolate, Me-Cbl, P-5-P:)L-methylfolate, Me-Cbl, P-5-P:Correlative DataCorrelative Data

Subjective VAS Study as isolated therapySubjective VAS Study as isolated therapy

Subjective VAS study combined with palliative agentSubjective VAS study combined with palliative agent

Quantitative Sensory Testing Quantitative Sensory Testing

Intraepidermal Nerve Fiber Density Testing Intraepidermal Nerve Fiber Density Testing

Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. Orally Administered L-methylfolate, Me-Cbl, P-5-P Reduces theSymptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008.Jacobs, AM. Abstracts of the New Cardiovascular Horizons Meeting. L-methylfolate, Me-Cbl, P-5-P supplementation to pregabalin partialresponders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.

Orally Administered L-methylfolate,Orally Administered L-methylfolate,Me-Cbl, and P-5-P Reduces DPNPMe-Cbl, and P-5-P Reduces DPNP

Results from a 20 week, randomized, Results from a 20 week, randomized, controlled study of 97 patients to evaluatecontrolled study of 97 patients to evaluateMetanxMetanx®® in patients with DPNP. in patients with DPNP.

After nutritional management with MetanxAfter nutritional management with Metanx®®:: The average absolute pain reduction after The average absolute pain reduction after

20 weeks in the study group was 1.73 20 weeks in the study group was 1.73 compared to .44 in the active group compared to .44 in the active group ((PP<0.008)<0.008)

Compared to baseline, after 10 weeks the Compared to baseline, after 10 weeks the study group demonstrated a reduction in study group demonstrated a reduction in VAS of 32.92% compared to the active VAS of 32.92% compared to the active control group of 11.57% reduction in VAS control group of 11.57% reduction in VAS ((PP<0.01)<0.01)

Compared to baseline, after 20 weeks the Compared to baseline, after 20 weeks the study group demonstrated a reduction in study group demonstrated a reduction in VAS of 35.28% compared to the active VAS of 35.28% compared to the active control group of 11.73% reduction in VAS control group of 11.73% reduction in VAS ((PP<0.01)<0.01)*L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 10 weeks.

†L-methylfolate, Me-Cbl, P-5-P vs. Acetaminophen at 20 weeks.Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Jacobs AM. NCVH Oral Presentations 2008.

0

-0.2

-0.4

-0.6

-0.8

-1

-1.2

-1.4

-1.6

-1.8

-20 10 20

Weeks

Pain

Red

uctio

n

*P<0.01 †P=0.008

Acetaminophen

L-methylfolate,Me-CBl, P-5-P

Mean Pain Reduction From Baseline

L-Methylfolate, Me-Cbl, and P-5-P Administration to L-Methylfolate, Me-Cbl, and P-5-P Administration to Pregabalin Partial-Responders for Management of DPNPPregabalin Partial-Responders for Management of DPNP

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

After nutritional management with Metanx:After nutritional management with Metanx: The average absolute pain reduction The average absolute pain reduction

after 20 weeks in the study group was after 20 weeks in the study group was 3.0 compared to .25 in the active3.0 compared to .25 in the activecontrol group (control group (PP<0.001)<0.001)

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

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.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

L-methylfolate,Me-CBl, P-S-P/Pregabalin

Mean Pain Reduction From Baseline

Restoration of Cutaneous Sensorum Restoration of Cutaneous Sensorum

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

Study outcomes were measured at Study outcomes were measured at baseline, 6 months baseline, 6 months and 1 yearand 1 year after L-methylfolate, Me-Cbl, P-5-P for all after L-methylfolate, Me-Cbl, P-5-P for all8 measurements8 measurements

FootFoot Medial HeelMedial Heel Great Toe PulpGreat Toe Pulp

Left / RightLeft / Right 1 & 2 point static touch1 & 2 point static touch 1 & 2 point static touch1 & 2 point static touch

Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

Eight Outcome MeasurementsEight Outcome Measurements

Restoration of Cutaneous Sensorum Restoration of Cutaneous Sensorum

Improved sensory perception at theImproved sensory perception at themedial heel and great toemedial heel and great toe

Walker MJ, et al. Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

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

The Pharmacological Management of Diabetic Small Fiber The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing MetanxNeuropathy Utilizing Metanx®® as a Neurotrophic Agent as a Neurotrophic Agent

11 patients symptomatic DPN 11 patients symptomatic DPN patients patients

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

MetanxMetanx®® B.I.D. for 6 months B.I.D. for 6 months demonstrated 97% ↑ ENFDdemonstrated 97% ↑ ENFD

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

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

Clinical Case Outcome IClinical Case Outcome I

BaselineBaseline 6 months6 months

Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl, P-5-P (Metanx ®) 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

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

Clinical Case Outcome IIClinical Case Outcome II

Patient received baseline skin punch biopsy and given L-methylfolate, Me-Cbl , P-5-P (Metanx ®) 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.

BaselineBaseline 6 months6 months

Metanx® is an orally administered prescription medical food for the dietary management of endothelial dysfunction in patients withdiabetic peripheral neuropathy.Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

The Pharmacological Management of Diabetic Small Fiber The Pharmacological Management of Diabetic Small Fiber Neuropathy Utilizing L-Methylfolate, Me-Cbl, P-5-P as a Neuropathy Utilizing L-Methylfolate, Me-Cbl, P-5-P as a Neurotrophic AgentNeurotrophic Agent

This preliminary study suggests that the administration ofThis preliminary study suggests that the administration of2.8 mg L-Methylfolate, 2 mg Me-Cbl, 25 mg P-5-P appears to be 2.8 mg L-Methylfolate, 2 mg Me-Cbl, 25 mg P-5-P appears to be associated with increased ENFD in patients with DPN. associated with increased ENFD in patients with DPN.

The increased epidermal nerve fiber density may beThe increased epidermal nerve fiber density may beassociated with diminished symptoms of anesthesia, associated with diminished symptoms of anesthesia, paresthesia, or dysesthesia. paresthesia, or dysesthesia.

Abstracts of the Diabetic Foot Global Conference. Oral Presentations 2009.

SummarySummary

Distal symmetrical sensorimotor polyneuropathy is the Distal symmetrical sensorimotor polyneuropathy is the most common form of DPN most common form of DPN

Etiology of DPN may primarily be microvascular Etiology of DPN may primarily be microvascular insufficiency insufficiency

Treatment should be based upon individualTreatment should be based upon individualpatient factors patient factors

Focus on disease modifying agents to manipulate Focus on disease modifying agents to manipulate underlying pathophysiology of DPN underlying pathophysiology of DPN