The ProblemTheType2diabetesmellitus(T2DM)epidemicisgrowingrapidly,withanestimated285millionpeopleworldwidelivingwithT2DMin2010.Almosthalfofthoseaffectedareinthe20-60age-group.Ithasbeenestimatedthatamandiagnosedwithdiabetesattheageof40yearswillloseonaverage11.6life-yearsand18.6qualityadjustedlifeyears(QALY)andwomenwilllose14.3life-yearsand22.0QALYs(1).Thus,primarypreventionofT2DManditscomplicationsisamajorpublichealthissue.

The Opportunity

Impairedfastingglucose(IFG)andImpairedGlucoseTolerance(IGT)areoftenlabeledtogetheras

pre-diabetes(Table1).Thenaturalhistoryandpathophysiologyoftype2diabetesindicatethat

thereexistsaprolongedprediabeticphaseinmostpatients.Ithasbeenestimatedthatthemajority

ofindividuals(upto70%)withprediabeteswilleventuallydevelopT2DM(2).Particularlyhighcon-

versionrates(>10%peryear)havebeenobservedinsubjectswithacombinationof2or3predia-

beticconditions(IGT±IFG±MetabolicSyndrome)(2).Hence,familyphysiciansandspecialistshave

auniqueopportunitytoidentifythesepatientsathighriskfordevelopingdiabetesandintervene.

InadditiontoaveryhighrateofconversiontoT2DM,anincreasedriskofcardiovasculardiseaseis

alreadypresentinprediabeticstates.Consequently,early,preventativeinterventionwillyield

greatbenefit.

C L I N I C A L P R A C T I C E U P D A T E I N

0603

V OLUM E

I S S U E

From the Endocrinology & Diabetes Specialists of the LMC Endocrinolgy Centres. The opinions expressed in this paper are those of the authors and do not necessarily reflect

the opinions of LMC Endocrinology Centres or the editorial board of Clinical Practice Update.

EditorSamantha Sandler

MD, FRCPC

ONTARIOBARRIE

Suzan Abdel-Salam Diane Zatelny

BRAMPTONHarpreet Bajaj

ETOBICOKEHasnain Khandwala

Anila Seth-Sharma

MARKHAMSorin Beca

OAKVILLED. Y. Twum-Barima

THORNHILLJulie Daitchman

Meri GalterRonald Goldenberg

Gloria Rambaldini Robert Schlosser

Nina Wine

TORONTORonnie Aronson

Kimberly Mah-Poy Samantha Sandler

William Singer George Steiner

Adam Telner

QUEBECMONTRÉAL

Nouhad SalibaNahla Aris-Jilwan

MONTRÉALOUEST / WEST

Alex Skamene

ALBERTACALGARY

Munish KhoslaSue Pedersen

Stuart Ross

Dr. Harpreet BajajMD, MPH, ECNUNEPHROLOGIST, HRRHLECTURER, UNIVERSITY OF TORONTO

IMPAIRED FASTING

GLUCOSE (IFG)

IMPAIRED GLUCOSE

TOLERANCE (IGT)or

Shall We Treat?

• Reductionintotalintakeoffatandintake

ofsaturatedfat

• • Increasingintakeofdietaryfiber

• Increasingphysicalactivity

OtheriatrogeniccontributorstoIFG/IGTneed

tobeaddressedaswell.Drugsthatadversely

affectglucosetoleranceshouldbereplacedor

minimized,suchasthiazidediuretics,cortico-

steroidsandatypicalanti-psychotics.

The EvidenceDiabetesPreventionProgram(DPP)—inthis

landmarktrial,3234obesesubjects(average

age51years)athighriskfordiabetes(fasting

and2-hourglucoseconcentrationsbetween5.3

to6.9mmol/Land7.8to11.1mmol/L,respec-

tively)wererandomlyassignedtooneofthe

followinggroups:

• Intensivelifestylechangesthrougha

behavioralmodificationprogram

• TreatmentwithMetformin(850mg

twicedaily)

• Placebo

TheIntensivelifestylegrouplostanaverageof15

pounds(6.8kg;7percent)ofweightinthefirstyear,

mostofwhichwassustainedforthedurationofthe

study.TheintensivelifestyleandMetformininterven-

tionsreducedthecumulativeincidenceofdiabetes

by58and31percent,respectively,comparedwith

placebo(4).

IncontrasttothefindingsintheentireDPPcohort

whichfavoredlifestyleintervention,Metforminand

lifestyleinterventionweresimilarlyeffectiveinreduc-

ingtheincidenceofdiabetesinwomenwithahistory

ofgestationaldiabetes(GDM)(5).Inapreplanned

subsetanalysisofwomenwithahistoryofGDMand

IGT,theincidenceofdiabeteswasreducedby50and

53percentinsubjectsassignedtoMetforminandlife-

styleintervention,respectively,comparedwithpla-

cebo.Thediscrepancyinthetwostudiesisthought

tobedue,inpart,tothehighercumulativeincidence

ofdiabetesinwomenassignedtoplacebowithGDM

versusnoGDM(38.4versus25.7percent)andinpart

duetotheinabilityofwomenwithahistoryofGDM

randomlyassignedtointensivelifestyleintervention

tosustainphysicalactivityandmaintainweightloss.

Inadditiontothishigh-riskGDMsubgroup,Met-

Case: Mrs. Angela AMrs.AngelaAisa42-year-oldadministrativeclerk.

ShehasahistoryofGestationaldiabetes(GDM).She

currentlytakesnomedications.Shehasbeenunable

toloseweightbecauseofherbusyschedule.On

physicalexam,herBMIis28.1andwaistcircumfer-

ence102cm.Bloodpressureis138/84.Hergeneral

physicaliswithinnormallimits,exceptforcentral

obesity.Herfastingglucoseiselevatedat6.4mmol/L.

2hourglucoseaftera75gmOGTTiselevatedto10.1

mmol/L.Twoyearsago,herFBGwas6.1mmol/Lwith

a2-hourvalueof9.2mmol/L.Herfastinglipidpanel

showstotalcholesterol7.03mmol/L,triglycerides4.37

mmol/L,HDL0.90mmol/LandacalculatedLDLof

4.14mmol/L.Basedontheaboveresults,youdiag-

noseMrs.AashavingIFG/IGTinadditiontofeatures

ofmetabolicsyndrome.

The ManagementThereisevidencethatlifestyleintervention(com-

bineddietandexerciseaimedatweightloss)can

improveglucosetoleranceandpreventprogression

fromIFG/IGTtotype2diabetes.Thiswasillustrated

byameta-analysisofeighttrialscomparingexercise

plusdietwithstandardtherapy(RRwithintervention

comparedtocontrol0.63,95%CI0.49-0.79)(3).The

lifestylemodificationadviceisessentiallythesameas

thatindiabetes:

• Weightreduction(5-10%),ifappropriate

(adaptedfromCDAguidelines2008)Note:CDAdoesnotrecommendspecificHbA1Ccriteriafordiagnosisofprediabetes.

Pre-Diabetes

Type 2 DM

ImpairedFastingGlucose

FPG(mmol/L)

2-HourGlucoseAfter75gmOGTT

(mmol/L)

NotAvailable

<7.8

7.8-11.0

7.8-11.0

6.1-6.9

6.1-6.9

6.1-6.9

<6.1

>7.0_ >11.1_

And

And

And

Or

IsolatedIFG

IsolatedImpairedGlucose

Tolerance

BothIFGandIGT

Type2DM

Table 1

Plasma Glucose (PG) levels for diagnosis of IFG, IGT and diabetes

Type 2 DM

forminwasalsofoundtobeparticularlyeffectivein

subjectswhowereyoungerandmoreobese(BMI>35

kg/m2).

The Metformin ArgumentInadditiontopreventionoftype2DMobservedin

DPPandotherpreventionstudies,Metforminhas

beenassociatedwithreductionsinmortality,car-

diovasculardiseaseandcancerincidenceinstudies

involvingtype2DMsubjects.Metforminisarela-

tivelyinexpensivemedicationandhasnoknown

long-termseriousadverseeffects.Gastrointestinal

intoleranceissueswiththisdrugareusuallytransient

andcangenerallybeovercomebyslowtitrationof

Metformindosageoruseofthelonger-actingGlu-

metzaformulation,whichisfrequentlybettertoler-

atedinsomepatients.Aswell,Glumetzamaybe

givenonce-dailyleadingtopotentialimprove-

mentinpatientadherencetothetreatment

regimen.Metforminandlifestyleinterventions

cangohandinhand,asthereisminimalriskof

hypoglycemiawiththecombination.Froman

economicsperspectivetoo,useofMetformin

maysavemoneyovertimewhenusedinprimary

preventionofT2DMby:

• delayorpreventionofT2DMbyreducing

progressionofbetacellfailure,

• betterachievementofglycemiagoals

leadingtolesscomplications,and

• delayorpreventionofMetformin

failureandneedforsecond-lineoral

hypoglycemicagentsinsubjectswhogo

ontodevelopT2DM(6).

Guidelinerecommendationsinmostcountries

(includingCanada)haveincorporatedMetfor-

minasapharmacotherapyoption;thoughmost

recommendlifestyleinterventions,overprescrip-

tionmedications,asthe“therapy”ofchoice

inpreventionoftype2DM.ADArecommends

considerationofMetforminfordiabetes

preventioninhigh-riskindividuals

(Table2).

However,somewouldarguethatpreferenceof

lifestyleoverMetformin(ratherthaninitiationof

bothtogetherfromthebeginning)mayengender

the“denial”phaseinpatientswithpre-diabetes

andearlyT2DM.Practicallyspeaking,therationale

forMetformininpreventionisstrengthenedbytwo

facts:1)onceapatienthasdevelopedIFG/IGT,they

areataveryhighriskforT2DM,2)mostpatientsfind

itdifficulttoinitiateandmaintainweightlosseven

afterrepeatcounseling.Ifintensivelifestyleinterven-

tionischosensolely,overpharmacotherapy,patients

shouldbefollowedannuallywitharepeatOGTT.In

theabsenceofweightlossorwithanyworseningof

IFG/IGT(evenwithinthenon-diabeticrange),addi-

tionofMetforminmaybeindicated.

Back to the case: Mrs. Angela AReviewing,Mrs.AngelaAisayoungwomanwith

ahistoryofGDMandmetabolicsyndrome.Shehas

hadaworseningofherIFG+IGTover2yearsandhas

beenunsuccessfulatweightloss.Hence,basedon

theaboveargumentsandresultsofDPP,Metformin

initiation(eitherastwice-dailyMetforminHydrochlo-

rideorasonce-dailyGlumetza)shouldbestrongly

consideredtoprevent/delayherdevelopmentoftype

2DMandassociatedcomplications.

References:1. Narayan K M, Boyle J P, et al. Lifetime risk for diabetes mellitus in the United States. JAMA 2003; 290: 1884-18902. de Vegt F, Dekker J M, et al. Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population: The Hoorn Study. JAMA 2001; 285: 2109-21133. Orozco LJ, Buchleitner AM, et al. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev 20084. Knowler WC, Barrett-Connor E, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393.5. Ratner RE, Christophi CA, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008; 93:4774.

(adaptedfromAmericanDiabetesAssociationGuidelines2011)

Population Treatment

Table 2

Treatment Recommendation for Individuals with IFG, IGT or both

Lifestylemodification(ie.5to10%weightloss,moderateintensityphysicalactivity–30min/day

Lifestylemodification(asabove)and/orMetforim850mgtwiceperday

IFGorIGT

IFG + IGT + any of the following

<60yearsofage

BMI>35kg/m2

Familyhistoryofdiabetesinfirstdegreerelative

Elevatedtriglycerides

ReducedHDLcholesterol

Hypertension

HbA1c>6.0%

•½cupsteelcutoatmeal•1cupmixedberries•¾cuplowfatyogurt

•¼cupalmonds

•1cupMixedbeansaladwithtomatoes,lemonjuiceandbalsamicvinaigrettedressing•1cupbroccolisalad•1cuplowfatmilk

•1mediumapple

DAY 1 DAY 2

•2piecesofsourdough/stonegroundwholegrainbread•1-2Tbsppeanutbutter•1cuplowfatmilk

•3/4cuplowfatyogurt

•Tunapastasalad•1cuppasta,cookedeldente•2cupsmixedvegetables•1/2cuptuna•Lightmayonnaise•Lemonjuice•1cuplowfatmilk

•3/4cuplowfatyogurt

breakfast

snack

lunch

snack

dinner•2/3cupbasmatiorDoongararice•4-5ounceporkchop•Mushroomsaladwithbalsamicvinaigrette•Mixedgreensaladwithlowfatdressing•1cupfruitsalad

•4-5ouncechickenbreast•3/4cupQuinoasalad•Largespinachsaladwithraspberryvinaigrettedressing•1cuplowfatmilk

Supported by educational grants from members of the pharmaceutical industry.

TORONTO• OAKVILLE • ETOBICOKE • THORNHILL • BARRIE • MARKHAM• BRAMPTON• MONTREAL • CALGARY

Bothreally.Theglycemicindex(GI)wasactuallydevelopedwithsignificantCanadianscientificcontributionthroughtheteamofDavidJenkinsetalatourownSt.Michael’sHospitalinToronto.Itwasdevelopedinrecog-nitionofobservationsthatsomehighly-favoureddiets,suchastheMediterraneandiet,doincorporatecarbo-hydrate(CHO),butthattheirCHOwerelesslikelytocausepost-prandialhyperglycemia,eveninpatientswithdiabetes.Onotherwords,somecarb’sare‘better’thanothers.

Theglycemicindexwasdevelopedtoquantify‘betterorworse’.ItisbasedonthepremisethatonesliceofwhitebreadhasaGIof1.Overthepastdecade,manycarb’shavebeenscoredrelativetoonesliceofwhitebread,producingaGIforeachone.Lowglycemicindexcarbohydratestendtoincludehighfibrecontent,suchaswholegrains.Theirslowerrateofdigestionresultsinmorelimitedanddelayedincreasesinbloodglucoselevels.

Themoreprocessedandrefinedacarbohydrate,generallythehighertheGI.Forexample,weconsideroatmealtobeahealthy,lowGIcarbanditis–aslongasit’spreparedinitstraditionalform:steelcutwholegrainsthatrequire45minutestocook.Popularprocessedoatmealpreparationsthatcanbecookedin5minutesormicro-wavedin1minute–haveaveryhighGIbecausethepre-cookingintheprocessingmethodhasdenaturedthecomplexCHO’s,leavingaproductnobetterthanwhitebread.

CookingmethodcanalsochangetheGIofafood.Forexample,slightlyundercookedpasta(aldente)hasalowerGIthanwell-cookedpasta.BakedpotatoesactuallyhavealowerGIthanmashed.RawvegetableshavealowerGIthancooked.

Finally,macronutrientcombinationscanalterafood’sGI.AddingfattendstodelayCHOdigestion,effectivelyraisingitsGI.Addingal-mondbuttertotoastisaneffectivewayofraisingitsGIandnutritivevalue.Inthepotatoeexampleabove,frenchfriesactuallyhavealowerGIthanmashedpotatoes.

Hereisasampleofatwodaylowglycemicindexdiet.

IthappenstobethatlowerGIdietfoods,orfoodcombinations,tendtoalsobemorefilling,makingthemappealingtopeoplewhoareactivelytryingtoreducetheirfoodportionsizeswhileavoidingexcessivehunger.RecentpopulardietbooksandTVshowshavereferencedtheGIconcept,andonedietisnamedafterit.Thisisonepopulardietphenomenonthatwecanactuallyendorse.

LowG.I.

HighG.I.

HighFibercerealsWholegrains

Lentils/Legumes

Mostfruit&vegetables,espwithskins,exceptmelons

MilkandyogurtPasta-cookedaldente

RefinedcerealsWhitebread

ShortgrainriceBakingpotatoes

SimpleSugars

The Glycemic Index – scientific tool or fad diet?

HIGH GI

1

LOW GI

TIME/HOURS

BLO

OD

GLU

COSE

LEV

ELS

The amount of carbohydrate in the reference and test food must be the same.

2

www.glycemicindex.com

s

August10,2011

DearColleagues

Type2Diabetesisarapidlygrowingepidemicinbothdevelopedanddevelopingnations.Itwillbeanin-creasingchallengetohealthcareprovidersastheCanadianpopulationages.InourAugustissueofClinicalPracticeUpdateDr.HarpreetBajajdiscussestheentityknownas“Pre-Diabetes”,exploringtheadditionofmetforminwhenlifestylemeasuresfailtoachievethedesiredgoalsofweightreductionandeuglycemia.MetforminiswellsupportedbycurrentevidencetodelayorpreventType2Diabetes.Glumetza,alongeractingformulationofmetformin,maybemoretoleratedbypatients,andasaonceadaydoseclaimbetteradherence.FromourownLMCpatientdatabase,aretrospectiveanalysisshowedatrendtowardlowerHbA1clevelsinpatientstakingGlumetzavsmeformin.

Alsointhisedition,TanyaLevin,aregistereddieticianatLMCBayview,givessomehelpfulinsightsontheLowGlycemicIndexDiet,whichwerecommendforourpre-diabeticanddiabeticpatients.

Sincerely,

Samantha SandlerMD,FRCPC

Editor,

ClinicalPracticeUpdate

C L I N I C A L P R A C T I C E U P D A T E I N

From the Endocrinology & Diabetes Specialists of the LMC Endocrinolgy Centres. The opinions expressed in this paper are those of the authors and do not necessarily reflect the opinions of LMC Endocrinology Centres or the editorial board of Clinical Practice Update.

EditorSamantha Sandler

MD, FRCPC

ONTARIOBARRIE

Suzan Abdel-Salam Diane Zatelny

BRAMPTONHarpreet Bajaj

ETOBICOKEHasnain Khandwala

Anila Seth-Sharma

MARKHAMSorin Beca

OAKVILLED. Y. Twum-Barima

THORNHILLJulie Daitchman

Meri GalterRonald Goldenberg

Gloria Rambaldini Robert Schlosser

Nina Wine

TORONTORonnie Aronson

Kimberly Mah-Poy Samantha Sandler

William Singer George Steiner

Adam Telner

QUEBECMONTRÉAL

Nouhad SalibaNahla Aris-Jilwan

MONTRÉALOUEST / WEST

Alex Skamene

ALBERTACALGARY

Munish KhoslaSue Pedersen

Stuart Ross