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EvaluatingtheEfficacyofDiaMetrix™inaRandomized,Double‐Blind

PlaceboControlledHumanClinicalTrial

KennethR.Hampshire1,StevenMiles1,RickMiles1,RobertT.Streeper2,JoelMichalek3,

ChristopherLouden3,ElzbietaIzbicka2&

1Syntratech™Corporation,Denver,Colorado,Colorado,USA,80237,800‐738‐0650,

www.syntratech.com,

2CPCLTD,SanAntonio,Texas,USA

3UniversityofTexasHealthScienceCenteratSanAntonio,SanAntonio,Texas,USA

&correspondingauthor

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ABSTRACT

Background:Peoplewithdiabetesareathighriskofcardiaccomplications,whichare

exacerbatedbyelevatedbloodpressureanddysfunctionalsugarandfatmetabolism.

Theaimofthisstudywastoevaluateeffectsofanherbalsupplement,DiaMetrix,on

bloodglucoselevels,triglycerides,cholesterol,andbloodpressureinsubjectswith

chronicuncontrolledbloodglucose.

Methods:Wedidarandomizedprospectivedouble‐blindedstudyin100subjects(47

menand53women)withfastingbloodglucoselevelsbetween160and240mg/dL.The

participantswererandomlyassignedtooralDiaMetrixat6tabletsdaily(n=50)or

placebo(n=50)for90days.Theendpointsincludedfastingbloodglucose,bodymass,

oralglucosetolerancetest,totalcholesterol,HDL,triglycerides,glycosylated

hemoglobinandbloodpressure.

Results:Allstudyparticipantscompletedthestudy.DiaMetrixreducedHbA1c,blood

glucose(fastingandafterchallenge),triglycerides,systolicanddiastolicbloodpressure,

totalcholesterol,andbodymassovertime.Meanfastingglucosewassignificantly

decreasedinsubjectstakingDiaMetrixat30,60and90daysafterbaselinerelativeto

thosetakingplacebo.HbA1cmeanchangefrombaselineto90dayswassignificantly

decreasedinsubjectstakingDiaMetrix.TheDiaMetrixmeanserumglucosewas

significantlydecreasedrelativetoplaceboat30,120and180minutesafterthe

challenge.Triglyceridesmeanchangesfrombaselineweresignificantlydecreasedby

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DiaMetrixat30,60and90days.Fortotalcholesterol,DiaMetrixmeanchangefrom

baselineto90dayswassignificantlydecreasedrelativetoplacebo.Highandlow

densitylipoproteinswerenotsignificantlyaffected.Systolicanddiastolicblood

pressurewassignificantlydecreasedat60‐90days,andmeanbodymasswas

significantlydecreasedrelativetoplaceboat90days.

Conclusions:Thisstudydemonstratedareductioninthemeanfastingbloodsugar,

bloodpressureandbodymassinsubjectsrandomizedtoDiaMetrix.Thesefindingsof

suggestthatDiaMetrix,anover‐thecounterpreparation,deservesfurtherevaluationof

itsactivityinlargerclinicalstudies.

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Introduction

Basedonthedatafromthe2007NationalDiabetesFactSheetpublishedbythe

AmericanDiabetesAssociation,23.6millionchildrenandadultsintheUnitedStates

(7.8%ofthepopulation)havediabetesand1.6millionnewcasesofdiabetesare

diagnosedinpeopleaged20yearsandoldereachyear(1).In2003‐2004,therewerean

estimated5.7millionpeoplewithundiagnoseddiabetesand57millioninapre‐diabetes

stateintheUnitedStates(2).Inthelatter,bloodglucoselevelsknownasimpaired

fastingglucose(IFG)orimpairedglucosetolerance(IGT)areintherangeof100‐125

mg/dL,whilehigherlevelsareassociatedtype2diabetesmellitus,nowincreasingly

recognizedasanautoimmune‐inflammatorydisease(2).Notably,peoplewithpre‐

diabetesareatincreasedriskofdevelopingtype2diabetes,aconditioncharacterized

byimpairedinsulinsecretionfrompancreaticLangerhansislandscells,increasedhepatic

glucoseproductionandinconsequencehighbloodglucoselevels,anddecreaseduseof

glucoseinmuscletissue.Thesedefectsaremainlyresponsibleforthedevelopmentand

progressionoftype2diabetes(3).Furthermore,insulinresistanceisassociatedwith

decreasedratesofglycolysis,glycogenesis,lipogenesis,andproteinsynthesis.People

withtype2diabetesarealsoathighriskoffatalandnon‐fatalvascularevents.In

2003–2004,75%ofadultswithself‐reporteddiabeteshadelevatedbloodpressureof>

130/80mmHgorusedprescriptionmedicationsforhypertension.Intensivecontrolof

glycemiadecreasessomevascularcomplicationssuchasretinopathyandnephropathy

(4).

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DiaMetrix™isanherbaldietarysupplementcomposedofvitaminC(ascorbicacid),

biotinUSP,chromium(chelate),vanadium(chelate),garciniacambogiaextract(50%

hydroxycitricacid),gymnemasylvestreextract(25%),cinnamonextract(4:1),bitter

melonextract(10:1),betaineHCL,banabaextract(1%corosolicacid),fennugreek,

dicalciumphosphate,cellulose,croscarmellosesodium,stearicacid,silicondioxide,

magnesiumstearate,andhydroxypropylmethylcellulose.

AnotherrecentlycompletedstudycomparedtheactivityofDiaMetrixtothatofthree

anti‐diabeticdrugs;Metformin,Actos(pioglitazonehydrochloride),andByetta

(exenatide)inanobesediabeticmousemodelusingBKS.Cg‐m+/+Leprdb/BomTacfemale

micefedeithernormaldietorhighfatdiet(HFD)+/‐drugs.DiaMetrix’sprotection

againstorgandamagewascomparabletothatofByettaandbetterthanActosand

Metforminintheanimalsonnormaldiet.Themeanvaluesofmostinflammatory

plasmabiomarkerswereelevatedinhighfatdietrelativetonormaldiet.Biomarker

meansvariedsignificantlybytreatmentgroupanddiet.Onnormaldiet,DiaMetrix

decreasedlevelsofanumberofpro‐inflammatorycytokines,chemokinesandgrowth

factorssuchaseotaxin,MCP‐1,MCP‐3,M‐CSF,andincreasedanti‐inflammatory

cytokineIL‐4relativetountreated.DiaMetrixtreatmentdecreasedG‐CSF,GM‐CSF,and

TGFβrelativetountreatedinhighfatanimals.PyruvatekinaseandAGEincreased,

whileinsulinwasdecreasedinanimalstreatedwithDiaMetrixrelativetountreatedon

normaldiet.DiaMetrixdemonstratedsuperioranti‐inflammatoryactivityrelativetothe

commonlyusedanti‐diabeticdrugsagainstabackgroundofgeneticobesity,supporting

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thecontentionthatDiaMetrixmaybeaneffectiveinterventionfortype‐2diabetes

(Hampshireetal.,submitted).

ThegoalofthisclinicalstudywastoassesstheefficacyofDiaMetrixtreatmentin

diabeticsubjectswithfastingbloodglucoselevelsbetween160and240mg/dLandto

evaluateeffectsoforalDiaMetrixonclinicalendpointsusedintheroutineevaluationof

diabeticsubjects.Safetydatawasnotcollected.

METHODS

Subjects

SyntraTechcontractedtheclinicalstudywithacontractresearchorganization,Fenestra

ResearchLaboratories(Fenestra),LasVegas,NV.Fenestraalsoconductedthetestsas

describedbelow.In2006‐2007,Fenestrarecruited47menand53womenages23to50

(33Black,32Caucasian,25Asianand10Hispanic)usingparticipantsrecruitedfroma

largediversepopulationofpeoplelivinginorneartheLasVegas,NVarea,withchronic

uncontrolledbloodglucose(peoplewithfastingbloodglucoselevelsbetween160

mg/dLand240mg/dLwithameanof197mg/dL).

Excludedweresubjectswithahistoryofheadtrauma,seriousdiseasesorillness

diagnosedatthistime,knownmoderatetosevererenalinsufficiency,recenthistory(<6

monthspriortoVisit1)ofmyocardialinfarction.Alsoexcludedwerethosewho

regularlyusedoxygentherapy,thosewithknownactivetuberculosis,withtreatedbasal

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cellcarcinoma,historyofcancerwithinthelast5years,thoracotomywithpulmonary

resectionwithin1yearpriortothetrial,thoseinapulmonaryrehabilitationprogramor

whocompletedapulmonaryrehabilitationprograminthe6weekspriortothe

screeningvisit(Visit1),takingprescribeddiureticmedications,cardiacstimulants,or

anyotherprescribedornon‐prescribedmedicationthatmightaltertestingresults,

thosetakingopiateanalgesicsprescribedorotherwiseobtainedforanytreatment

reasonincludingmigrainetreatment,orforrecreationandhistoryofdrugaddictionor

alcoholaddictionwithinsix(5)monthsofthisstudyperiod,femaleswhowerepregnant,

lactating,ornursingorwhomaybecomepregnantduringthecourseofthestudy,and

thosediagnosedasHIV‐positive,diagnosedwithAIDS,orwithanyneuromuscular

conditionincludingCP,MS,ALS,orHuntington'sChorea.Alsoexcludedwerepeople

withuncontrolledhypertension(e.g.BP>140/90),oranyconditionnotpreviously

namedthat,intheopinionofFenestrainvestigatorsorintakestaff,wouldjeopardize

safetyoraffectthevalidityoftheresultscollectedinthisstudy.

Thestudyincludedfemalesormales18yearsofageorolder,whosignedawritten

informedconsent.Tobeeligibleforinclusion,potentialsubjectswererequiredto

documentbloodsugarimbalanceforaminimumofthepreviousconsecutive6months

ofthescreeningvisitatafrequencyofatleasttwenty(20)timeseachmonthbasedon

dailyglucometerreadings.Eligibleparticipantswererandomizedintotwogroupsof50

participants.Thestudywasdoubleblinded.

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Compliancetoinclusionandexclusioncriteriawasmonitoredandmaintainedthrough

bi‐weeklyphonecallswithFenestrapersonnelandin‐personofficevisits.All

participantswereinstructedtocontacttheirregularhealthcareprofessionaliftheyhad

anyunusualoruncomfortablesymptomsduringthecourseofthisstudy.All

participantswereinstructedtomakenochangestotheirdailyactivityorconsumption

offoodorliquidrelatingtotheamount,volume,ortypeconsumed.

Procedures

Participantsinbothtreatmentgroups,DiaMetrixandplacebo(vegetariantablet,

magnesiumcitrate,silicondioxide),wereinstructedtotaketwotabletsthreetimes

daily,orthreetabletstwotimesdailyifonlytwomeals,approximately15minutes

beforemeals.Participantswereinstructedtotakeproductonlyiftheyateameal.

Participantswhometallinclusioncriteriaandnoneoftheexclusioncriteriaatthefirst

visit(day0)andgavesignedinformedconsentwerethenprovidedeithertheplaceboor

DiaMetrix™alongwithinstructionsdescribingdailydosingtofollowforthedurationof

thestudy.Baselinemeasurementsweremadeatday1(visit2).Followingscreening

(day0),randomization,andsignedinformedconsent,participantsentereda1‐week

baselineperiod.Inthattime,participantswereaskedtorefrainfromtakingany

unnecessaryover‐the‐counterorprescriptionmedications,ornaturalproductsthatthey

werenotalreadytakingfortheremainderofthestudy.Ibuprofen,acetaminophen,and

aspirinwereallowed.Atthethirdandfourthvisits(days14and30)evaluationswere

performedfollowingstandardproceduresandtheinclusionandexclusioncriteriawere

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againreviewedwitheachparticipantonanindividualbasis.Thefifthvisittookplaceon

day60andthesixthandfinalvisitonday90.

Atthescreenandpriortorandomization,14oftheparticipantsreportedmild

headachesand"notfeelingwell".All100studyparticipantswereattemptingtocontrol

theirglucoselevelswithdietandexercise.Dietandexercisewerenotmonitoredduring

thestudy,butallparticipantswereinstructedtomakenochangesintheirdiet,

activities,orwaterintakeduringthedurationofthestudyatthescreeningandat

subsequentvisits.

Tests

ThetestsbrieflydescribedbelowwereperformedbyFenestrausingstandardclinical

procedures.

FastingBloodGlucose:Approximately7mLofvenousbloodwascollectedfromeach

participantateachblooddrawandfastingbloodglucosewasmeasured.

BodyMass:Bodymass(lbs)wasrecordedonallparticipantsatall6visitsusinga

monthlycalibratedweightscale.

GlucoseChallenge:Eachparticipant'sfastingbloodglucose(FBG)levelwasmeasured

atbaseline(day2).Fortheoralglucosetolerancetest(OGTT),allparticipantswere

givenatesttablet(halfoftheparticipantsweregivenactiveproductandhalfofthe

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participantsweregivenplacebo),followedbyastandard75gcarbohydrateloaddrink.

Bloodplasmareadingsweretakenat30minute,120minute,and180minuteintervals.

TotalCholesterol:Participant’sbloodwastakenaftera12‐14hourfastingperiod.

Participantswereaskedtoabstainfromalcoholforatleast24hoursbefore5‐19mlof

arterialbloodwasdrawn.

Lipoproteins:LDLlevelswerecalculatedbysubtractingHDLreadingsplusonefifthof

thetriglyceridesfromthetotalcholesterol.LDL=Totalcholesterol‐(HDL+Triglycerides/5).

Triglycerides:Thebloodtestwasperformedonfasting(12‐14hour)participants.

Participantswereaskedtoabstainfromanyalcoholfor24hoursbeforethetest.Fiveto

10mLofvenousbloodwasdrawnfromeachparticipantateachtestinterval.

BloodPressure:Bloodpressurewastakenbymedicalprofessionalswithaminimumof

20yearsexperienceusingasphygmomanometerandstethoscope.Bloodpressure

measurementsweretakenanaverageofthreetimesafteraminimumrestofatleast15

minutes.

HemoglobinA1c(HbA1c,Glycohemoglobin,Glycatedhemoglobin,Glycosylated

hemoglobin):BloodwasdrawnonDay1andDay90.Anarterialbloodsamplewas

obtainedbyinsertinganeedleintoanarteryoftheparticipant’sarmandastandard

HbA1cvialofbloodwascollectedbyahealthcareprofessional.

Statisticalmethods

Continuouslydistributedoutcomesweresummarizedwiththemean±onestandard

deviation.Treatmentgroups(DiaMetrix,Placebo)werecontrastedonthemeanof

continuouslydistributedoutcomesusingrepeatedmeasureslinearmodelsofthe

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outcomeintermsoftime,treatmentgroup,andthetimebytreatmentgroup

interactionwithanautoregressiveorder1autocorrelationmatrix.Allstatisticaltesting

was2‐sidedwithasignificancelevelof5%.RVersion2.11.1(RFoundation)wasused

throughout;tableswerecreatedusingSASVersion9.2forWindows(SASInstitute,Cary,

NC).

RESULTS

Allparticipantscompletedthestudy;therewerenomissingdata.

DemographicCharacteristics:Treatmentgroupsweresimilarwithregardtothe

proportionmale[DiaMetrix22(44%),Placebo25(50%)]andmeanage(DiaMetrix

43.5±12.7,Placebo45.8±10.8,p=0.32)andthepercentageofsubjectsofthewhiterace

wassignificantlydecreasedamongthoserandomizedtoDiaMetrix(DiaMetrix24(48%),

Placebo37(74%),p=0.01);seeTable1.

FastingSerumGlucose:Treatmentgroupfastingglucosemeans(ng/dL),showninTable

2andFigure2,weresimilaratbaseline(DiaMetrix196.6±17.5,Placebo196.9±17.4,

p=0.93)whereastheDiaMetrixmean(14days:DiaMetrix96.6±10.3,Placebo

205.5±30.7,p<0.001;30days:DiaMetrix96.5±11.0,Placebo204.9±21.6,p<0.001;60

days:DiaMetrix94.8±10.1,Placebo209.4±22.5,p<0.001;90days:DiaMetrix89.4±9.2,

Placebo205.2±20.2,p<0.001)andmeanchangesfrombaseline(DiaMetrix‐107.2±14.5,

Placebo8.3±14.8,p<0.001)weresignificantlydecreasedat90days.

HbA1c(%):TreatmentgroupHbA1c(%)means(Table2)weresimilaratbaseline

(DiaMetrix7.7±0.5,Placebo7.7±0.5;p=0.93)whereasthemeanat90days(DiaMetrix

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4.7±0.3,Placebo8±0.6,p<0.001)andthemeanchangefrombaselineto90days

(DiaMetrix‐3.0±0.5,Placebo0.3±0.4,p<0.001)weresignificantlydecreasedinsubjects

takingDiaMetrix.At90days,nosubjectwhoreceivedDiaMetrixhadanHbA1cabove

5%.Incontrast,at90daysnosubjectwhoreceivedPlacebohadanHbA1cbelow6.9%.

GlucoseChallengeTest(ng/dL):TheDiaMetrixmeanserumglucose(Table2)was

significantlydecreasedrelativetoplaceboat30,120and180minutesafterthe

challenge(30minutes:DiaMetrix110.1±24.1,Placebo205.1±18.5,p<0.001;120

minutes:DiaMetrix110.0±23.0,Placebo221.9±14.6,p<0.001;180minutes:DiaMetrix

109.5±23.3,Placebo225.8±12.6,p<0.001).

Triglycerides:Treatmentgrouptriglyceridesmeans(mg/dl),seeTable2andFigure1,

weresimilaratbaseline(DiaMetrix255.2±48.1,Placebo254.5±46.5,p=0.95)whereas

theDiaMetrixmean(30days:DiaMetrix234.6±50.2,Placebo259.3±45.4,p=0.01;60

days:DiaMetrix213.9±44.4,Placebo269.6±48.1,p<0.001;90days:DiaMetrix

203.2±42.4,Placebo271.3±48.3,p<0.001)andmeanchangesfrombaseline(90days:

DiaMetrix‐52.0±23.7,Placebo16.8±28.6,p<0.001)weresignificantlydecreasedat90

days.

TotalCholesterol:TheDiaMetrixmeanCholesterol(µg/dL),seeTable2,was

significantlyincreasedatbaselinerelativetoplacebo(DiaMetrix:338.5±96.9,Placebo:

301.3±89.4,p=0.01).ThetreatmentgroupCholesterolmeansdidnotdiffersignificantly

at90days(90days:DiaMetrix240.0±32.8,Placebo261.2±29.2,p=0.13)whereasthe

DiaMetrixmeanchangefrombaselinewassignificantlydecreasedrelativetoplacebo

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(changesfrombaselineto90days:DiaMetrix‐98.5±110.0,Placebo‐40.1±99.6,

p=0.004).

HighDensityLipoproteins(HDL):TheDiaMetrixmeanHLDL(µg/dL),seeTable2,did

notdiffersignificantlyfromtheplacebomeanatbaseline(DiaMetrix:56.8±29.8,

Placebo:57.3±29.8,p=0.93)orat90days(90days:DiaMetrix47.7±9.3,Placebo

52.6±10.5,p=0.28;changesfrombaselineto90days:DiaMetrix‐9.0±33.6,Placebo‐

4.7±35.0,p=0.45).

LowDensityLipoproteins(LDL):TheDiaMetrixmeanLDL(mg/dL),showninTable2,

wassignificantlyincreasedatbaselinerelativetoplacebo(DiaMetrix:230.7±106.9,

Placebo:193.2±87.2,p=0.01)whereasthetreatmentgroupLDLmeansandmean

changesinLDLdidnotdiffersignificantlyat90days(90days:DiaMetrix151.7±33.5,

Placebo154.4±30.3,p=0.86;changesfrombaselineto90days:DiaMetrix‐79.0±120.8,

Placebo‐38±94.9,p=0.11).

RatioOfTotalCholesterolToHighDensityLipoproteins:TheDiaMetrixmeanratioof

totalcholesteroltohighdensitylipoproteins(Table2)didnotdiffersignificantlyfrom

theplacebomeanatbaseline(DiaMetrix:8.5±5.9,Placebo:7.2±5.1,p=0.10)orat90

days(90days:DiaMetrix5.3±1.5,Placebo5.1±1.1,p=0.88).

RatioOfLowDensityLipoproteinsToHighDensityLipoproteins:TheDiaMetrixmean

ratiooftotalcholesteroltohighdensitylipoproteins(Table2)didnotdiffersignificantly

fromtheplacebomeanatbaseline(DiaMetrix:6.2±5.2,Placebo:4.9±4.3,p=0.06)orat

90days(90days:DiaMetrix3.4±1.3,Placebo3.1±0.9,p=0.65).

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SystolicBloodPressure:TheDiaMetrixsystolicbloodpressuremean(Table2)was

significantlyincreasedrelativetoplaceboatbaseline(Baseline:DiaMetrix171.3±19.9,

Placebo155.2±25.1,p<0.001),whereasthetreatmentgroupmeanswerenot

significantlydifferentat30and60days(30days:DiaMetrix157.9±25.9,Placebo

154.2±21.4,p=0.37;60days:DiaMetrix149.7±16.3,Placebo155.4±19.4,p=0.16)and

theDiaMetrixmeanwassignificantlydecreasedat90days(90days:DiaMetrix

142.9±14.6,Placebo155.2±18.9,p=0.003).Analysesonchangesfrombaselineshowed

significantlydecreasedmeanchangesfrombaselineto90(p<0.001)daysinsubjects

randomizedtoDiaMetrix.

DiastolicBloodPressure:Treatmentgroupdiastolicbloodpressuremeans(mmHg),see

Table2andFigure3,weresimilaratbaselineandat30days(Baseline:DiaMetrix

75.2±9.9,Placebo76.0±8.7,p=0.55;30days:DiaMetrix74.5±6.4,Placebo75.5±6.9,

p=0.44),whereastheDiaMetrixmeanwassignificantlydecreaseat60and90days(60

days:DiaMetrix71.9±4.3,Placebo76.7±5.7,p=0.001;90days:DiaMetrix70.3±3.2,

Placebo76.6±5.2,p<0.001).Themeanchangefrombaselineto90dayswas

significantlydecreasedinsubjectsrandomizedtoDiaMetrix(p<0.001).

BodyMass:TheDiaMetrixmeanbodymass(lb),seeTable2,wasnotsignificantly

differentfromtheplacebomeanatbaseline(DiaMetrix:211.4±54.7,Placebo:

211.6±53.6,p=0.99).Thetreatmentgroupweightmeansdidnotdiffersignificantlyat

90days(90days:DiaMetrix202.1±54.0,Placebo211.6±52.8,p=0.38)whereasthe

DiaMetrixmeanchangefrombaselinewassignificantlydecreasedrelativetoplacebo

(changesfrombaselineto90days:DiaMetrix‐9.3±3.1,Placebo0.0±2.9,p<0.001).

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Discussion

Thisstudyinsubjectswithpre‐diabetesanddiabetesdemonstratedstatistically

significanteffectsofDiaMetrixonfastingglucoselevelandtheglucosechallengetest,

HbA1c,andbloodpressure.TotalcholesterolwasdecreasedbutLDLandHDLwerenot

significantlyaffected.Withrespecttobodymass,DiaMetrixtreatmentgroupmean

changefrombaselinewassignificantlydecreasedrelativetoplacebo.

Basedonthemagnitudeofclinicalresponses,DiaMetrixcomparedfavorablyto

standardtherapeuticsusedintreatmentofdiabetes.Metforminisoneoftheoldest

anti‐diabetesdrugsandwasclaimedto"lowerthebloodsugartominimum

physiologicallimit"intreatedpatients.Basedonitsfavorabletoxicityprofileitwas

widelyusedbutwasapprovedbytheU.S.FoodandDrugAdministrationfortype2

diabetesin1994(6).MedianHbA1cwas7.4%intheMetformingroupcomparedwith

8.0%intheconventionalgroup,andintensiveglucosecontrolwithMetformin

decreasedtheriskofdiabetesrelatedendpointsinoverweightdiabeticpatients,and

wasassociatedwithlessweightgain(6).Pioglitazone(Actos),adruginthe

thiazolidinedionefamily,selectivelystimulatesthenuclearreceptorperoxisome

proliferator‐activatedreceptorgamma(PPAR‐γ)andmodulatesthetranscriptionof

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insulin‐responsivegenesinvolvedinthecontrolofglucoseandlipidmetabolism(7).

Actossignificantlydecreasedfastingplasmaglucoselevelfrom11.0+/‐2.0mmol/literto

8.9+/‐1.1mmol/literwithasignificantimprovementinthehemoglobinHbA1clevel

from9.2+/‐1.8%to8.3+/‐1.5%(11).Rosiglitazone,anotherthiazolidinedioneoral

antidiabeticagent,hasbeenshowntosignificantlyreduceHbA1candfastingplasma

glucoseunderdifferentdosingregimens(8).Exenatideisasyntheticversionof

exendin‐4,ahormonefoundinthesalivaoftheGilamonster.Itdisplaysbiological

propertiessimilartohumanglucagon‐likepeptide‐1throughregulationofglucose

metabolismandinsulinsecretionbutitsmechanismofactionisstillunderstudy[2].A

52‐weektreatmentwithexenatidereducedHBA1Cby−0.8±0.1%(9).

Atpresent,themanagementoftype2diabetesfocusesonglucosecontrolthrough

loweringofbloodglucoseandbyextensionHbA1candotheradvancedglycationend

products(3).Inouropinion,theseclinicalendpointsaresymptomsofdisease,not

diseasemechanisms.Persistenthighbloodsugarinpeopleisaproblem;however,even

withperfectglucosecontrolpeoplestillsufferfromsignificantorganpathologies,

morbidityandmortality.Drugsthataredesignedtocontrolbloodsugarhavemany

liabilitiessuchasinductionofhypoglycemia.Thusthecommonlyacceptedemphasison

controllingbloodsugarasasoleendpointmaybesomewhatmisguidedinthatblood

sugarlevelisonlyoneofthemultiplefacetsofdiabetes.Wefeelthatmoreemphasis

shouldbeplacedoncontroloftheimmunedysfunctionthatisamajorbiochemical

driverofthepathologyofdiabetes.Therefore,understandinghowdrugsimpact

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inflammatorybiomarkerprofileswillbeextremelyimportantinunderstandingand

treatingdiabetes.Weproposethattheoptimaltherapeuticstrategyfordiabetesshould

addressnotonlybloodsugarcontrol,butalsobedirectedtocontrolofimmunesystem

imbalanceinaefforttodelaydiseaseprogression(3).

Giventhattype2diabetesisfundamentallyaninflammatorydisease(2),inourrecentin

vivostudyinamodelofhumantype2diabetesinobesemice,weselectedabroad

rangeofendpointstoevaluatemechanismofactionofDiaMetrix.Inadditionto

commonlytestedmetabolites(glucose,advancedglycationendproduct,insulin,

cholesterol,triglycerides),weincludedpyruvatekinase,hexokinaseII,andcitrateas

potentiallyrelevantendpointsalongwithalargepanelofcytokines,chemokines,

endocrinemarkersandgrowthfactorsandhaveshownthatofDiaMetrixsignificantly

downregulatedseveralpro‐inflammatorychemokines,cytokines,andgrowthfactors

andupregulatedlevelsoftheanti‐inflammatorycytokineIL‐4.Wespeculatethat

DiaMetrixmaybreaktheselfreinforcinginflammatorycycleandthusslowdownthe

naturalcourseofthedisease(Hampshireetal.,submitted).

Inconclusion,thisstudydemonstratedareductioninthemeanfastingbloodsugar,

bloodpressureandbodymassinsubjectsrandomizedtoDiaMetrix.Thesefindings

suggestthatDiaMetrix,anover‐thecounterpreparation,deservesfurtherevaluationof

itsactivityinlargerclinicalstudies.

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Competinginterests

KRH,SM,andRMareownersofSyntraTech.

EI,RTS,JM,andCLareconsultantsforSyntraTech.

Authors'contributions

KRH,SM,andRMfundedthestudyandanalysisoftheclinicaldata.

JMandCLperformedstatisticalanalysisoftheclinicaldata.

EI,JMandRTSreviewedtheresultsandwrotethemanuscript.

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CL - Page 1 of 3

DiaMetrix Human Study (14 October 2010)

Table 1. Demographics

Syntra-5 (N=50) Placebo (N=50) Total P-Value

Male [N (%)] 22 (44) 25 (50) 47 (47) 0.691

White [N (%)] 24 (48) 37 (74) 61 (61) 0.011

Age (Mean ± SD) 43.48±12.68 45.82±10.77 44.65±12 0.322

1Pearson's Chi Square Test 2F Test for treatment

CL - Page 3 of 3

Human Study (14 October 2010)

Table 2. Blood Chemistry

Outcome (Mean ± SD) Time - (N=50) Placebo (N=50) Total P-Value

High Density Lipoprotein (?g/?L) Baseline 56.8±29.8 57.3±29.8 57±30 0.931

Day 90 47.7±9.3 52.6±10.5 50.1±10 0.282

Change from Baseline to Day 90 -9±33.6 -4.7±35 -6.9±34 0.452

Low Density Lipoprotein (?g/?L) Baseline 230.7±106.9 193.2±87.2 212±99 0.011

Day 90 151.7±33.5 154.4±30.3 153±32 0.862

Change from Baseline to Day 90 -79±120.8 -38.8±94.9 -58.9±110 0.112

Ratio of Low Density Lipoprotein to High Density Lipoproteins

Baseline 6.2±5.2 4.9±4.3 5.6±5 0.061

Day 90 3.4±1.3 3.1±0.9 3.2±1 0.652

Systolic Blood Pressure (mm Hg) Baseline 171.3±19.9 155.2±25.1 163.2±24 < 0.0011

Day 30 157.9±25.9 154.2±21.4 156±24 0.372

Day 60 149.7±16.3 155.4±19.4 152.6±18 0.162

Day 90 142.9±14.6 155.2±18.9 149±18 0.0032

Change from Baseline to Day 90 -28.4±17.1 0±10.5 -14.2±20 < 0.0012

Diastolic Blood Pressure (mm Hg) Baseline 75.2±9.9 76±8.7 75.6±9 0.551

Day 30 74.5±6.4 75.5±6.9 75±7 0.442

Day 60 71.9±4.3 76.7±5.7 74.3±6 0.0012

Day 90 70.3±3.2 76.6±5.2 73.5±5 < 0.0012

Change from Baseline to Day 90 -4.9±9 0.7±6.5 -2.1±8 < 0.0012

Weight (lbs) Baseline 211.4±54.7 211.6±53.6 211.5±54 0.991

Day 90 202.1±54 211.6±52.8 206.8±53 0.382

Change from Baseline to Day 90 -9.3±3.1 0±2.9 -4.6±6 < 0.0012

1F Test for treatment 2F Test for treatment based on a repeated measures ANOVA in terms of treatment, time and treatment by time and an AR(1) correlation structure (treatment by time interaction: p-value < 0.001).

DiaMetrix

DiaMetrix

CL - Page 2 of 3

Table 2. Blood Chemistry

Outcome (Mean ± SD) Time Placebo (N=50) Total P-Value

Fasting Serum Glucose (mg/dL) Baseline 196.6±17.5 196.9±17.4 196.8±17 0.931

Day 14 96.6±10.3 205.5±30.7 151.1±59 < 0.0012

Day 30 96.5±11 204.9±21.6 150.7±57 < 0.0012

Day 60 94.8±10.1 209.4±22.5 152.1±60 < 0.0012

Day 90 89.4±9.2 205.2±20.2 147.3±60 < 0.0012

Change from Baseline to Day 90 -107.2±14.5 8.3±14.8 -49.5±60 < 0.0012

A1c (%) Baseline 7.7±0.5 7.7±0.5 7.7±0.01 0.931

Day 90 4.7±0.3 8±0.6 6.3±2 < 0.0012

Change from Baseline to Day 90 -3±0.5 0.3±0.4 -1.4±2 < 0.0012

Serum Glucose (mg/dL) Minute 30 110.1±24.1 205.1±18.5 157.6±52 < 0.0011

Minute 120 110±23 221.9±14.6 165.9±59 < 0.0012

Minute 180 109.5±23.3 225.8±12.6 167.6±61 < 0.0012

Triglycerides (mg/dL) Baseline 255.2±48.1 254.5±46.5 254.9±47 0.951

Day 30 234.6±50.2 259.3±45.4 247±49 0.012

Day 60 213.9±44.4 269.6±48.1 241.7±54 < 0.0012

Day 90 203.2±42.4 271.3±48.3 237.2±57 < 0.0012

Change from Baseline to Day 90 -52±23.7 16.8±28.6 -17.6±43 < 0.0012

Cholesterol (?g/?L) Baseline 338.5±96.9 301.3±89.4 319.9±95 0.011

Day 90 240±32.8 261.2±29.2 250.6±33 0.132

Change from Baseline to Day 90 -98.5±110 -40.1±99.6 -69.3±108 0.0042

Ratio of Cholesterols to High Density Lipoproteins

Baseline 8.5±5.9 7.2±5.1 7.8±6 0.101

Day 90 5.3±1.5 5.1±1.1 5.2±1 0.882

1F Test for treatment 2F Test for treatment based on a repeated measures ANOVA in terms of treatment, time and treatment by time and an AR(1) correlation structure (treatment by time interaction: p-value < 0.001).

DiaMetrix Human Study (14 October 2010)

(N=50) DiaMetrix

Figure 1 Mean triglycerides (mM) by treatment group (Blue: DiaMetrix- , Black: Placebo); whiskers extend

to the mean ±1 standard deviation. The treatment by time interaction was significant (p< 0.001);

treatment group contrasts on the mean were significant at 30 (p=0.01), 60 (p<0.001) and 90 days

(p<0.001) based on a repeated measures linear model with an autoregressive order 1 covariance

assumption.

Figure 2 Mean fasting serum glucose (ng/dl) by treatment group (Blue: DiaMetrix, Black: Placebo);

whiskers extend to the mean±1 standard deviation. The treatment by time interaction was significant

(p<0.001); treatment group contrasts on the mean were significant at 14 (p<0.001), 30 (p<0.001), 60

(p<0.001) and 90 days (p<0.001) based on a repeated measures linear model with an autoregressive

order 1 covariance assumption.

Figure 3 Mean diastolic blood pressure (mm Hg) by treatment group (Blue: DiaMetrix- , Black: Placebo);

whiskers extend to the mean±1 standard deviation. The treatment by time interaction was significant

(p<0.001); treatment group contrasts on the mean were significant at 6 (p<0.001) and 90 days

(p<0.001) based on a repeated measures linear model with an autoregressive order 1 covariance

assumption.

0