aace ace glycemic control algorithm

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540 ENDOCRINE PRACTICE Vo 15 No. 6 Septeer/Octoer 2009

AACE/ACE Consensus Statement

Address correspondence and reprint requests to Dr. Helena W. Rodbard, Suite 250, 3200 Tower Oaks Boulevard, Rockville,MD 20852. E-mail: [email protected].

2009 AACE. May not be reproduced in any form without express written permission from AACE

STATEmENT by ANAmERICAN ASSOCIATION Of ClINICAl ENDOCRINOlOgISTS/

AmERICAN COllEgE Of ENDOCRINOlOgy

CONSENSuS PANEl ON TyPE 2 DIAbETES mEllITuS:AN AlgORIThm fOR glyCEmIC CONTROl

Helena W. Rodbard, MD, FACP, MACE; Paul S. Jellinger, MD, MACE;

Jaime A. Davidson, MD, FACP, MACE; Daniel Einhorn, MD, FACP, FACE;

Alan J. Garber, MD, PhD, FACE; George Grunberger, MD, FACP, FACE;

Yehuda Handelsman, MD, FACP, FACE; Edward S. Horton, MD, FACE;

Harold Lebovitz, MD, FACE; Philip Levy, MD, MACE;

Etie S. Moghissi, MD, FACP, FACE; Stanley S. Schwartz, MD, FACE


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542 gceic Contro Aorit, Endocr Pract. 2009;15(No. 6)

ABSTRACT

This report presents an algorithm to assist primary

carephysicians,endocrinologists,andothersin theman-

agementofadult, nonpregnantpatients with type2 dia-

betesmellitus.Inordertominimizetheriskofdiabetes-

relatedcomplications,thegoaloftherapyistoachievea

hemoglobinA1c(A1C)of6.5%orless,withrecognition

oftheneedforindividualizationtominimizetherisksof

hypoglycemia.Weprovidetherapeuticpathwaysstratied

onthebasisofcurrentlevelsofA1C,whetherthepatient

isreceivingtreatmentorisdrugnave.Weconsidermono-

therapy,dualtherapy,andtripletherapy,including8major

classesofmedications(biguanides,dipeptidyl-peptidase-4

inhibitors,incretinmimetics,thiazolidinediones,a-gluco-

sidaseinhibitors,sulfonylureas,meglitinides,andbileacid

sequestrants) and insulin therapy (basal, premixed, and

multiple daily injections),with orwithoutorally admin-

isteredmedications.Weprioritizechoicesofmedications

accordingto safety, riskof hypoglycemia,efcacy, sim-plicity,anticipateddegreeofpatientadherence,andcostof

medications.Werecommendonlycombinationsofmedi-

cationsapprovedbytheUSFoodandDrugAdministration

that provide complementary mechanisms of action. It

isessential tomonitor therapywithA1Candself-moni-

toringofbloodglucoseandtoadjustoradvancetherapy

frequently (every 2 to3 months) iftheappropriategoal

foreachpatienthasnotbeenachieved.Weprovideaow-

chartandtablesummarizingthemajorconsiderations.This

algorithmrepresentsaconsensusof14highlyexperienced

clinicians,clinicalresearchers,practitioners,andacademi-

ciansandisbasedontheAmericanAssociationofClinical

Endocrinologists/American College of EndocrinologyDiabetes Guidelines and the recent medical literature.

(Endocr Pract. 2009;15:540-559)

Abbreviations:

AACE = American Association of Clinical

Endocrinologists;A1C=hemoglobinA1c;ACCORD

=ActiontoControlCardiovascularRiskinDiabetes;

ACE =AmericanCollege of Endocrinology;ADA

= American Diabetes Association; ADVANCE =

Action in Diabetes and Vascular Disease: Preterax

and Diamicron Modied Release Controlled

Evaluation; AGIs = a-glucosidase inhibitors;

DCCT/EDIC=DiabetesControlandComplicationsTrial/Epidemiology of Diabetes Interventions and

Complications; DPP-4 = dipeptidyl-peptidase-4;

EASD = European Association for the Study of

Diabetes;FDA=USFoodandDrugAdministration;

GLP-1=glucagonlikepeptide-1;LDL=low-density

lipoprotein;PROACTIVE=ProspectivePioglitazone

ClinicalTrialinMacrovascularEvents;RCTs=ran-

domizedcontrolledtrials;RECORD=Rosiglitazone

EvaluatedforCardiovascularOutcomesinOralAgent

CombinationTherapyforType2Diabetes;SMBG=

self-monitoring of blood glucose;TZDs = thiazoli-

dinediones;UKPDS=UnitedKingdomProspective

DiabetesStudy;VADT =VeteransAffairs Diabetes

Trial

INTRODUCTION

Therearenearly24millionAmericanswithdiabetesin

theUnitedStates.Everyyear,1.3millionpeoplearediag-

nosedwithtype2diabetes.Therapidincreaseinnewcases

oftype2diabetesinpersons30to39yearsofageandin

childrenandadolescentsisofspecialconcern.Thisepi-

demicoftype2diabetesisglobalandcloselyreectsthe

epidemicofoverweight,obesity,metabolicsyndrome,and

sedentarylifestyle.Anurgentneedexistsforanauthorita-

tive,practicalalgorithmformanagementofpatientswith

type2diabetesmellitusthatconsiderscurrentlyapproved

classes of medications and emphasizes safety and ef-cacy, while also considering secondary factors such as

the costofmedications orthenumber ofyears ofclini-

cal experiencewith use ofany specic drug.The intro-

ductionofseveralnewclassesofmedicationswithinthe

pastfewyearsespecially incretin-based therapies such

as incretin mimetics and dipeptidyl-peptidase-4 (DPP-

4) inhibitorsandthe results from several recent large-

scale clinical trialsAction to Control Cardiovascular

Risk in Diabetes (ACCORD), Action in Diabetes and

Vascular Disease: Preterax and Diamicron Modied

Release Controlled Evaluation (ADVANCE), Veterans

AffairsDiabetesTrial(VADT),ProspectivePioglitazone

Clinical Trial in Macrovascular Events (PROACTIVE),andRosiglitazoneEvaluatedforCardiovascularOutcomes

inOralAgentCombinationTherapyforType2Diabetes

(RECORD)combined with recently reported long-

termfollow-upresultsinpatientsintheDiabetesControl

and Complications Trial/Epidemiology of Diabetes

InterventionsandComplications(DCCT/EDIC),theUnited

KingdomProspectiveDiabetesStudy(UKPDS),andthe

Steno-2study,necessitatereevaluationofpreviouslypro-

posed algorithms for selection of therapies. Numerous

guidelines formanagement ofpatientswithdiabetesare

availableforexample,fromtheAmericanAssociationof

ClinicalEndocrinologists(AACE)(1),AmericanDiabetes

Association(ADA)StandardsofMedicalCareinDiabetes(2), Veterans Health Administration/US Department of

Defense(VA/DOD)(3),InternationalDiabetesFederation

(4),andmanyothers.Severaloftheseneedtobeupdatedto

reecttherecentliteratureandclinicalexperience.Afew

algorithmsareavailableforthatpurpose:ADA/European

AssociationfortheStudyofDiabetes(EASD)2006(5,6),

ADA/EASD 2009 (7), Canadian Diabetes Association

(8,9),andtheAmericanCollegeofEndocrinology(ACE)/

AACERoadMapstoAchieveGlycemicControl(10).The


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gceic Contro Aorit, Endocr Pract. 2009;15(No. 6) 543

cost ofmedications representsonlya verysmallportion

ofthetotalcostoftreatmentofpatientswithdiabetes.The

majorcostisrelatedtothetreatmentofthecomplications

ofdiabetes.Webelievethatidenticationofthesafestand

mostefcaciousagentsisessential.

METHODS

AACE/ACE convened apanel of experts, including

clinicians and clinical investigators, both academicians

and practitioners. An algorithm was developed on the

basisof themedicalliterature,withcarefulconsideration

oflevelsofevidenceandevaluationfortheconsistencyof

resultsfrommultiplestudiesandsources;greaterempha-

siswasplacedonresultsfromrandomizedcontrolledtrials

(RCTs)whenavailable.Wealsoconsideredmeta-analyses,

USFoodandDrugAdministration (FDA)-approvedpre-

scribing information, and the extensive experience, col-

lectiveknowledge, and judgmentof thepanelmembers.

We envisioned the need for an algorithm that reectedthebestpractices forexpertphysicians, recognizingthat

RCTdataare not available toguide everyclinical deci-

sion.Considerationswere based on theAACEMedical

Guidelines for ClinicalPractice for the Management of

DiabetesMellitus (1), review of other guidelines (ADA

StandardsofMedicalCareinDiabetes2009)(2),pre-

vious algorithmsACE/AACE Road Maps toAchieve

Glycemic Control (10),ADA/EASD 2006 (5,6), ADA/

EASD2009(7),CanadianDiabetesAssociation(8,9),and

Inzucchi(11)theFDA-approvedprescribinginformation

forindividualagents,pharmacoepidemiologicsurveillance

studies,andthecurrentliteraturedescribingrelevantclini-

caltrials:DCCT/EDIC(12),UKPDS(13),Steno-2(14),ACCORD(15),ADVANCE(16),VADT(17),RECORD

(18),PROACTIVE(19),andothers.

Inthedevelopmentofthisalgorithm,weattemptedto

accomplishthefollowinggoalsasprioritiesintheselection

ofmedications:

1. minimizingriskandseverityofhypoglycemia

2. minimizingriskandmagnitudeofweightgain

3. inclusionofmajorclassesofFDA-approvedglycemic

medication, including incretin-based therapies and

thiazolidinediones(TZDs)

4. selection of therapy stratied by hemoglobin A1c(A1C) and based on documented A1C-lowering

potential

5. considerationofbothfastingandpostprandialglucose

levelsasendpoints

6. considerationoftotalcostoftherapytotheindividual

andsocietyatlarge,includingcostsrelatedtomedi-

cations,glucosemonitoringrequirements,hypoglyce-

micevents,drug-relatedadverseevents,andtreatment

ofdiabetes-associatedcomplications

Webelievethatthisalgorithmrepresentsthetreatment

preferences ofmost clinicalendocrinologists,but in the

absenceofmeaningfulcomparativedata,itisnotnecessar-

ilyanofcialAACEposition.Becauseoftheinsufcient

numberortotalabsenceofRCTsformanycombinationsof

therapies,theparticipatingclinicalexpertsusedtheirjudg-

ment andexperience.Every effortwasmade toachieve

consensusamong thepanelmembers.Manydetails that

could notbe included in thesummarizingalgorithm are

describedinthefollowingtext.

RESULTS

Ourglycemiccontrolalgorithmwasdevelopedonthe

basisoftheprinciplesoutlinedinthesubsequentsection.

Principles Underlying the AACE/ACE Algorithm

Lifestyle(dietaryandexercise)modicationsareessen-

tialforallpatientswithdiabetes.Reductionofobesity

oroverweightandadjustmenttoanactivelifestylecanhavemajorbenecialeffects.Inmanycases,delaying

pharmacotherapytoallowforlifestylemodicationsis

inappropriate because these interventions are usually

notadequate.Lifestylemodicationtogetherwithspe-

cicdiabetes education, dietary consultation,and the

introductionofaprogramofself-monitoringofblood

glucose (SMBG) canbe initiated concomitantly with

medicaltherapy.

AchievinganA1Cof6.5%isrecommendedasthepri-

mary goal,but this goalmust becustomized for the

individualpatient,withconsiderationofnumerousfac-

torssuchascomorbidconditions,durationofdiabetes,

historyof hypoglycemia,hypoglycemia unawareness,patienteducation,motivation,adherence, age,limited

lifeexpectancy,anduseofothermedications.

IfapatienthasfailedtoachievetheA1Cgoal,onecan

titratedosages ofmedications,change regimens(add

or discontinuemedications), or, under some circum-

stances,reconsiderandrevisethegoal.

Whencombinationtherapyisprescribed,itisimportant

touseclassesofmedicationsthathavecomplementary

mechanismsofaction.

Effectivenessoftherapymustbeevaluatedfrequently

forexample,every2to3monthswithassessmentof

A1C,logbookdataforSMBGrecords,documentedand

suspected hypoglycemia, and other potential adverseevents(weightgain,uidretention,andhepatic,renal,

orcardiacdisease)aswellasmonitoringofcomorbidi-

ties,relevantlaboratorydata,concomitantdrugadmin-

istration,diabetes-relatedcomplications,andpsychoso-

cialfactorsaffectingpatientcare.

Safety and efcacy should be givenhigher priorities

than cost ofmedicationsper se, inasmuchascost of

medicationsisonlyasmallpartofthecostofcareof

diabetes.


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Thealgorithmshouldbeassimpleaspossibletogain

physicianacceptanceandimproveitsutilityandusabil-

ityinclinicalpractice.

Thealgorithmshouldhelpeducatecliniciansandhelp

guidetherapyatthepointofcare.

Thealgorithm should conform,as nearly aspossible,

toaconsensusforcurrentstandardsofcarebyexpert

endocrinologists who specialize in the management

ofpatientswithtype2diabetesandhavethebroadest

experienceinoutpatientclinicalpractice.

Thealgorithmshouldbeasspecicaspossibleandpro-

vide guidance tophysicianswith prioritizationand a

rationaleforselectionofanyparticularregimen.

Rapid-actinginsulinanaloguesaresuperiortoregular

humaninsulinandprovideabetter,saferalternative.

NPH insulin is not recommended. Use of NPH as a

basalinsulinhasbeensupersededbythesyntheticana-

loguesinsulinglargineandinsulindetemir,whichpro-

videarelativelypeaklessproleforapproximately24

hoursandyieldbetterreproducibilityandconsistency,bothbetweenpatientsandwithinpatients,andacorre-

spondingreductionintheriskofhypoglycemia.

The Glycemic Control Algorithm

TheAACE/ACE algorithm for glycemic control is

presentedinFigure1.

A1C Goal

TherationaleforanA1Ctargetof6.5%ispresentedin

theAACEDiabetesGuidelines(2007)(1).TheACCORD

andVADTstudies (15,17)haveconrmed thatprogres-

sivelylowerA1Clevelsareassociatedwithreducedrisk

ofbothmicrovascularandmacrovascularcomplications.Arecentmeta-analysisof5prospectiveRCTsdemonstrated

asignicantreductionincoronaryeventsassociatedwith

anoverallA1C of6.6% incomparisonwith 7.5% (20).

Thesestudiesalsoindicatedthattheriskofcardiacevents

anddeathismorecommoninpatientswithhypoglycemic

episodes (and especially severe hypoglycemia) and that

thebenet-to-risk ratio decreases progressivelywiththe

durationofdiabetes,suchthattheuseofintensivetherapy

maybeatleastrelativelycontraindicatedinpatientswith

adurationofdiabeteslongerthan12years(VADT)(17).

TheACCORDstudy(15)alsosuggestedthatexcessively

rapidoraggressiveadjustmentoftherapymaybeassoci-

atedwithincreasedrisk.TheA1Clevelsshowanexcel-lentcorrelationwiththemeanglucoselevel,butthisrela-

tionshipisalsoaffectedbyseveralotherfactors,suchas

hemoglobinopathies,hemolyticanemias,varyingratesof

individualglycation,genetics,andthevariabilitiesofdif-

ferentlaboratorymethods.

Frequency of Monitoring of A1C

Manyphysiciansfailtoimplementtheuniformlyrec-

ommendedguidelinestomonitorA1Conaquarterlybasis.

Physicians areoften slowin advancingtherapy, relative

toeitherdosagesofmedicationsorswitching toa more

efcacioustherapeuticregimeninatimelymanner.Oneof

themostimportantaspectsofthecurrentalgorithmisthe

strongrecommendationtomonitortherapyclosely(every

2to3months)andtointensifytherapyuntilthegoalfor

A1Chasbeenachieved.

Stratication by Current A1C level

Animportantelementofthecurrentalgorithmisthe

needfor straticationof thetherapeuticapproachonthe

basisofthecurrentA1CLevel.

1. IfthepatienthasanA1Cvalueof7.5%orlower,it

maybepossibletoachieveagoalA1Cof6.5%with

useofmonotherapy.Ifmonotherapyfailstoachieve

thatgoal,oneusuallyprogressestodualandthento

tripletherapy;nally,insulintherapyshouldbeiniti-

ated,withorwithoutadditionalagents.

2. IfthepatienthasanA1Clevelintherangeof7.6%to 9.0%, then one should begin with dual therapy

becausenosingleagentislikelytoachievethegoal.

Ifdualtherapyfails,onecanprogresstotripletherapy

andthentoinsulintherapy,withorwithoutadditional

orallyadministeredagents.

3. IfthepatienthasanA1Cvalueof>9.0%,thenthepos-

sibilityofachievingagoalA1Cof6.5%issmall,even

ifdualtherapyisused.Ifthepatientisasymptomatic,

one might begin with triple therapyfor example,

basedonacombinationofmetforminandanincretin

mimetic or a DPP-4 inhibitor combined with either

a sulfonylurea or aTZD. If, however, the patientis

symptomatic,ortherapywithsimilarmedicationshasfailed,itisappropriatetoinitiateinsulintherapy,either

withorwithoutadditionalorallyadministeredagents.

4. Whenthealgorithm(Fig.1)indicatesinsulintherapy,

onemayuseanyofthefollowing4generalapproaches:

basalinsulin,usingalong-actinginsulinanalogue

(glargine,detemir),generallygivenoncedaily;

premixed insulins, using a rapid-acting analogue

andprotamine(NovoLogMix,HumalogMix),usu-

allygiventwicedailywithbreakfastanddinnerbut

occasionallyusedonlywiththelargestmeal;

basal-bolusinsulinormultipledailyinjections,using

rapid-actinginsulinanaloguesaspart(NovoLog),lispro (Humalog), orglulisine (Apidra)together

with the long-acting insulin analogue glargine

(Lantus)ordetemir(Levemir);

aprandialinsulinregimen,involvinguseofthe

rapid-actinginsulinanalogues,butwithoutabasal

orlong-actinginsulincomponent.Thismaybepos-

sibleifthepatientisbeingtreatedwithaninsulin

sensitizer(metformin)thatprovidesadequatecon-

troloffastingplasmaglucose.


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Wedonotrecommenduseofregularhumaninsulin

(R),norofNPHinsulin(N)ifpossible,inviewofthe

factthattheseinsulinpreparationsdonothaveasufciently

predictabletimecoursethatadequatelymimicsthenormal

physiologicprole.Asaresult,thedoserequiredtocontrol

hyperglycemiaisoftenassociatedwithanincreasedriskof

hypoglycemia.

Wenowdescribethe3pathwayswithinthealgorithm

correspondingtothe3broadrangesofA1C:6.5%to7.5%,

7.6%to9.0%,and>9.0%.

Management of Patients With A1C

Levels of 6.5% to 7.5%

Monotherapy

Forthe patientwithanA1Clevel within therange

of6.5%to7.5%,itispossiblethatasingleagentmight

achievetheA1Cgoalof6.5%.Inthissetting,metformin,

TZDs, DPP-4 inhibitors, and a-glucosidase inhibitors

(AGIs)arerecommended.Becauseofitssafetyandef-

cacy,metforministhecornerstoneofmonotherapyandisusuallythemostappropriateinitialchoiceformonotherapy

unless there is a contraindication,suchas renal disease,

hepaticdisease,gastrointestinalintolerance,orriskoflac-

ticacidosis.

SomepatientswithdiabetesandA1Clevelsof


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Availableatwww.aac.cm/pub

AACEDecember2009Update.Maynotbereproducedinanyformwithoutexpresswritte

npermissionfromAACE

AACE/ACEDiab

etesAlgorithm

ForGlycemicControl

A1CGal

6.5%*

Li

festyLeModifiCAtion


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Fig. 1.SimpliedowchartforAmericanAssociationofClinicalEndocrinologists(AACE)/AmericanCollegeofEndocrinology(ACE)2009glycemiccontrolalgorithm.PathwaysareprovidedforpatientswithhemoglobinA1c(A1C)in3ranges:6.5%to7.5%,>7.6%to9.0%,and>9.0%.Thereisaprogressionfrommonotherapy,todualtherapy,totripletherapy,toinsulintherapywithorwithoutaddi-tionalagents.Theorderofpresentationofregimensindicatesgeneralprioritiesthatshouldbecustomizedtotheindividualpatient,withconsiderationofcontraindicationsandprecautions,allergies,comorbidconditions,drug-druginteractions,anddrug-laboratoryinterac-tions.Physiciansmustbethoroughlyfamiliarwithcompleteprescribinginformationbeforeselectionoftherapy.Ineachcase,responsetotherapyshouldbemonitoredclosely(determinationofA1Cevery2to3months),andtitrationofdosagesorchangesofregimenshouldbeimplementedinatimelymanner.Rx=treatment.NoteaccompanyingTableofAnnotatedAbbreviationsforFigure1.

Table of Annotated Abbreviations for Figure 1a

Abbreviation Class Generic name Trade name

AGI a-Glucosidaseinhibitor Acarbose Precose

Miglitol Glyset

DPP4 Dipeptidyl-peptidase-4 Sitagliptin Januvia

(DPP-4)inhibitor Saxagliptin Onglyza

GLP-1 Incretinmimetics Exenatide Byetta

(glucagonlikepeptide-1

agonist)

MET Biguanide Metformin Metformin(generic),

GlucophageXR,

Glumetza,Riomet,

Fortamet

SU Sulfonylurea Glyburide DiaBeta,Glynase,

Micronase

Glipizide Glipizide(generic),

Glucotrol,Glucotrol

XL

Glimepiride Amaryl

TZD Thiazolidinedione Rosiglitazone Avandia

Pioglitazone Actos

Abbreviation Denition Comment

FPG Fastingplasmaglucose Afterovernightfastofatleast8hours

PPG Postprandialglucose 2hoursafterameal

a Thefollowingsingle-tabletcombinationsofagentsareavailable: sitagliptin+metformin(Janumet),pioglitazone+metformin(ActoPlusMet), rosiglitazone+metformin(Avandamet),repaglinide+metformin(PrandiMet), glipizide+metformin(Metaglipandgeneric),andglyburide+metformin(Glucovanceandgeneric).


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October2009

Benetsareclassiedaccordingtomajoreffectsonfastingglucose,postprandialglucose,andnonalcoholicfattyliverdisease(NAFLD).Eightbroadcategoriesof

risksaresumma

rized.Theintensityofthebackgroundshadin

gofthecellsreectsrelativeimportanceofth

ebenetorrisk.*

Table1

Summar

yofKeyBenefitsandRisk

sofMedicat

ions

*

Theabbreviationsusedherecorrespondtothoseusedonthealgorithm(Fig.1).

**

Thetermglin

ideincludesbothrepaglinideandnateglinide.

Available

atwww.aace.com/pub

AACEDecember2009Update.Mayn

otbereproducedinanyformwithoutexpresswrittenpermissionfromAACE


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inducingweightloss.Italsohastheabilitytoinhibitglu-

cagonsecretioninaglucose-dependentmanneraftercon-

sumptionofmeals,toincreasesatiety,andtodelaygas-

tricemptying.Physiciansshouldbeawareofthereported

possible association of exenatide with pancreatitis and

shouldavoiduseofthisdruginpatientswithahistoryof

pancreatitis.A recent analysis of a very large database,

however,revealednogreaterincidenceofpancreatitisin

patientswithdiabetestakingexenatideincomparisonwith

thealreadysubstantiallyincreasedincidenceofthisdisor-

derinpatientswithdiabetes.Forthethirdmemberofthe

triple-therapycombination,onemayselectaTZD,glinide,

orsulfonylurea.Theseagentsarerecommendedin order

tominimize the risk ofhypoglycemia.Thecombination

withmetformin,especiallywhencoupledwithan incre-

tinmimetic,maypartiallyhelp tocounteract theweight

gain often associated with glinides, sulfonylureas, and

TZDs.

Insulin Therapy Whentripletherapyfailstoachieveglycemiccontrol,

itislikelythattheinsulin-secretorycapacityofthebeta

cellshasbeenexceeded;thus,insulintherapyisneeded.

Onecantheninstitutetherapyasbasal,premixed,pran-

dial,orbasal-bolusinsulin.Atthispoint,thelistofavail-

ableagentstouseasadjuvantstoinsulinisdiminished.

ExenatideandDPP-4inhibitorshavenotbeenapproved

bytheFDAforconcomitantusewithinsulin.Agentssuch

ascolesevelamandAGIsarenotlikelytocontributemate-

riallyto effectiveness.Sulfonylureasandglinidesshould

bediscontinuedwhenprandialinsulinisintroduced,inas-

muchaspostprandialexcursionscanusuallybemanaged

betterwitha rapid-actinginsulinanalogueorapremixedinsulinpreparation.UseofTZDsjointlywithinsulinhas

been associatedwith a high probability ofweightgain,

uid retention, increased risk of congestive heart fail-

ure,and signicantly increased riskoffractures both in

men and inwomen.Although some studies have been

controversial, recent clinical trialsADVANCE (16),

VADT(17), andACCORD (15)showedno increased

risk ofmortality associated with rosiglitazone, and the

PROACTIVEtrial(19)showedasmallbenecialeffectof

pioglitazoneoncardiacevents.Overall,metforministhe

most commonlyusedandsafestmedication tocombine

withinsulin.

Basal Insulin: Long-acting basal insulin is gener-

allythe initialchoice forinitiation of insulin therapy in

theUnitedStates.Insulinglargineandinsulindetemirare

stronglypreferredoverhumanNPHinsulinbecausethey

have relatively peakless time-action curves and a more

consistenteffectfromdaytoday,resultinginalowerrisk

ofhypoglycemia.Basalinsulintherapyisgenerallyiniti-

atedwithasmallarbitrarydose(usually10U)atbedtime.

Thedosageistitratedslowly(forexample,anincrement

of1to3U)every2to3daysifthefastingplasmaglu-

coselevelreachesthedesiredtarget.Incontrast,thedos-

ageisreducedifthefastingplasmaglucosedeclinesbelow

anotherspeciedthreshold.

Premixed Insulins:Analternativeapproachtostart-

inginsulin therapy is tousepremixedinsulinanalogues

(lispro-protamineor aspart-protamine). Onemay initiate

therapyforthemajormealof theday (typically,dinner)

and subsequently addanother injectionat thenext larg-

estmeal.Theinsulindosebeforebreakfastisadjustedby

measurementoftheglucoselevelbeforedinner;theinsulin

dosebeforedinneris adjustedprimarilybymeasurement

ofthefastingglucoseconcentrationonthefollowingday.

Useofpremixedinsulingenerallyinvolves2injectionsper

dayratherthanthe4injectionsperdayrequiredforbasal-

bolusinsulin.Ingeneral,however,withuseofpremixed

insulin,thepatientmusthaveafairlyconstantlifestyleand

mayhaveahigherriskofhypoglycemia.Ifthepatienthas

failed toachievegoals for glycemiawithuseofa basal

insulin regimen, onemay institute the premixed insulinregimenwith2injectionsperday.

Basal-Bolus Insulin Regimens:Incomparisonwith

premixed insulins,a basal-bolus insulinregimen involv-

ing 4 injectionsper day isusuallymoreefcacious and

providesgreaterexibilityforthosepatientswithvariable

mealtimesandcarbohydratecontentofmeals.Ingeneral,

before-meal insulin doses for adults can initially be set

atabout5Upermealorabout7%ofthedailydoseof

basalinsulin.Thebefore-mealinsulindosecanbetitrated

upwardby2to3Uevery2to3daysonthebasisofmoni-

toringofthe2-hourpostprandialglucoselevelandtaking

intoaccountthebefore-mealbloodglucoselevelforthe

subsequentmeal.Thedoseshouldbe titratedto achievegoodcontrolintermsofboththeA1Clevelandthepre-

prandialandpostprandialglycemia.

Pramlintide

Pramlintide, an analogue of pancreatic amylin, has

been used as an adjunct to prandial insulin therapy in

patientswithtype1diabetesandcanbehelpfulinpatients

withtype2diabetesforcontrolofpostprandialglucose.

Thisinvolvesseveraladditionalcarefullytimedinjections

immediatelybeforemeals.

Insulin Pump

Somepatientswithtype2diabetesusingbasal-bolusinsulintherapybenetfromuseofaninsulinpump(con-

tinuoussubcutaneous insulininfusion).An insulinpump

canprovidemaximalexibilitywithregardtomealtimes,

sizeofmeals,exercise,ortravel.

Continuous Glucose Monitoring

Somepatientswithtype2diabetesclearlybenetfrom

useofcontinuousglucosemonitoring(21).Thiscanedu-

catethepatientregardingtheglycemiceffectsofvarious


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foods,helpthepatienttitrateinsulin,andprovidewarnings

whenthepatient isexperiencinghyperglycemiaorhypo-

glycemia.Continuousglucosemonitoringshouldbecon-

sideredinpatientswithtype2diabetesreceivinginsulin

therapywhosediseaseisotherwisedifculttocontrol.

Self-Monitoring of Blood Glucose

Whenapatientbeginsinsulintherapy,SMBGshould

beincreasedinfrequency.Forpatientsstartingbasalinsu-

lintherapyatbedtime,themorningfastingbloodglucose

levels should be determined daily. This same approach

appliesforthepatientinitiatingpremixedinsulintherapy

before dinner. For each additional injection of insulin,

SMBGshouldbeincreasedinfrequencytoensuresuccess-

fultitrationofeachdose.

Reinforcement of Patient Education

Advancementtoinsulintherapyisanimportantoppor-

tunitytoreinforcepatienteducationwithregardtolifestyle

modication, diet, exercise, weight management (weightlossorweightmaintenance),andotheraspectsofdiabetes

education, including prevention, identication, and treat-

mentofhypoglycemia.Onemayalsoreevaluateandpossi-

blymodifygoalsfortherapy,reviewtheneedsfortreatment

ofothercommonlyassociatedriskfactors(suchashyperten-

sion,dyslipidemia,smoking,andstress),andconsiderther-

apywith low-doseaspirin,angiotensin-convertingenzyme

inhibitorsorangiotensinreceptorblockers,andstatins.

Management of Patients

With A1C Levels of 7.6% to 9.0%

Management of patients with anA1C value in the

rangeof7.6% to9.0% issimilar to that just described,except thatone can bypass the use ofmonotherapy and

proceeddirectlytodualtherapybecausemonotherapyis

unlikely to be successful in this group.We recommend

somechanges,however,intheuseofdualtherapyortriple

therapyinthisgroupofpatientsincomparisonwiththat

forpatientswithA1C7.5%,inviewoftheneedformore

efcacioustherapy.

Dual Therapy

Weconsiderthefollowing5optionsfordualtherapy

inpatientswiththisA1Crange(Fig.1):

1. Metformin+GLP-1agonist2. Metformin+DPP-4inhibitor

3. Metformin+TZD

4. Metformin+sulfonylurea

5. Metformin+glinide

Metforminisagainthefoundationoftherapybecause

ofitssafety,mechanismof action,and insulinsensitiza-

tion.Usually,aGLP-1agonistoraDPP-4inhibitoristhe

preferred second component, in view of the safety and

efcacyof these agents incombinationwithmetformin.

AGLP-1agonistisgivenahigherprioritythanaDPP-4

inhibitor,inviewofitssomewhatgreatereffectonreduc-

ingpostprandialglucoseexcursions and itspotential for

inducing substantialweight loss.The lower position of

TZDs is attributable to their associated risks of weight

gain,uidretention,congestiveheartfailure,andfractures.

Sulfonylureasandglinidesarerelegatedtothelowestposi-

tionbecauseoftheirgreaterriskofinducinghypoglyce-

mia.Therelativepositionsforsulfonylureasandglinides

are reversed in comparison with their positions in dual

therapy for patientswithA1Cvalues 7.5%.Thereis a

needforthegreaterglucose-loweringefcacyofsulfonyl-

ureasintheA1Crange7.6%to9.0%.

Triple Therapy

WhendualtherapydoesnotachievetheA1Cgoal,a

thirdagentshouldbeadded.Theoptionsfortripletherapy

forpatientswithanA1Cinthisrangearesimilartothose

recommendedforpatientswithlowerA1Cvalues.Wecon-siderthefollowing5options:

1. Metformin+GLP-1agonist+TZD

2. Metformin+DPP-4inhibitor+TZD

3. Metformin+GLP-1agonist+sulfonylurea

4. Metformin+DPP-4inhibitor+sulfonylurea

5. Metformin+TZD+sulfonylurea

Metforminis thefoundationtowhicheither aTZD

orsulfonylureaisadded,followedbyincretin-basedther-

apyeither a GLP-1 agonist or a DPP-4 inhibitor.The

preferenceformetforminandtheGLP-1agonistorDPP-4

inhibitor isbased ontheir safety, inviewoftheirmini-mal associated risks of hypoglycemia. Similarly, TZDs

areassignedaprioritygreaterthanthatforasulfonylurea

becauseoftheirlowriskofhypoglycemia.AGLP-1ago-

nistisgivenahigherprioritythanaDPP-4inhibitorowing

to its somewhat greater effect on reducing postprandial

glucoseexcursionsandthepossibilitythatitmightinduce

considerableweightloss.Thecombinationofmetformin,

TZD,andsulfonylureaisrelegatedtothelowestpriority

becauseofitsincreasedriskofweightgainforthecom-

binationofTZDsandsulfonylureasandtheriskofhypo-

glycemia,particularlyforpatientsatthelowerendofthis

A1Crange(~7.5%).Glinides,AGIs,andcolesevelamare

notconsideredinthisA1Crange,inviewoftheirlimitedA1C-loweringpotential.

Insulin Therapy

Theconsiderationsforinsulintherapyforpatientswith

acurrentA1Cof7.6% to9.0%are similarto thosedis-

cussedpreviouslyforpatientswithanA1Clevelof6.5%

to 7.5%. When transitioning to insulin from a regimen

involvingtripletherapy,itiscustomarytodiscontinueone

ormoreoftheorallyadministeredagents.UseofTZDsor


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ofsulfonylureasconjointlywithinsulinisassociatedwith

ariskofweightgainanduidretention.Inpatientsatrisk,

TZDsmaycauseoraggravatecongestiveheartfailure,and

theyincreasetheriskofbonefracturesinbothwomenand

men(22,23).NeitherGLP-1agonistsnorDPP-4inhibitors

havebeenapprovedbytheFDAforusewithinsulin.Thus,

metformin is theonlymedicationwitha relatively clear

indicationforuse inconjunctionwithinsulin inpatients

withtype2diabetes.Ifitbecomesclearthatapremixedor

abasal-bolusinsulinregimenisrequiredtoachieveglyce-

micgoals,insulinsecretagoguesshouldbediscontinued.

Useof pramlintideshouldalsobe considered inpatients

withpersistentpostprandialhyperglycemia.

Management of Patients With A1C Levels of >9.0%

Combination Therapy

Fordrug-navepatientswithA1Clevelsof>9%,itis

unlikelythatuseof1,2,oreven3agents(otherthaninsu-

lin)willachievetheA1Cgoalof6.5%.Ifthepatientisasymptomatic,particularlywitharelativelyrecentonsetof

diabetes,agoodprobabilityexistsforpreservationofsome

endogenousbeta-cellfunction,implyingthatdualtherapy

ortripletherapymaybesufcient.Weconsiderthefollow-

ing8options:

1.Metformin+GLP-1agonist

2.Metformin+GLP-1agonist+sulfonylurea

3.Metformin+DPP-4inhibitor

4.Metformin+DPP-4inhibitor+sulfonylurea

5.Metformin+TZD

6.Metformin+TZD+sulfonylurea

7.Metformin+GLP-1+TZD8.Metformin+DPP-4inhibitor+TZD

Metforminprovidesthe foundation.One canadd an

incretin-basedtherapy(GLP-1agonistorDPP-4inhibitor).

Itmaybepreferable touseaGLP-1agonist, inviewof

itsgreatereffectivenessatcontrollingpostprandialglyce-

miaanditspotentialforinducingweightloss.TheDPP-4

plus metformin combinations have also demonstrated a

robustbenetfordrug-navepatientsinthisA1Crange.

Inturn,onecanaddeitherasulfonylureaoraTZD.The

sulfonylurea is preferred here because of its somewhat

greaterefcacyandmorerapidonsetofaction.Incontrast,

ifthepatientissymptomaticwithpolydipsia,polyuria,andweight loss,or ifthepatienthas alreadybeen receiving

treatmentandregimenssimilartotheaforementionedones

havefailed,thenitisappropriatetoinitiateinsulintherapy

withoutdelay.

Insulin Therapy

InsulintherapyforpatientswithA1Clevelsexceeding

9.0% follows thesame principles asoutlinedpreviously

forpatientswithA1Cvaluesof9.0%.Onecanprescribe

basalinsulin,premixedinsulins,orbasal-bolusinsulin.

Reversal of Glucotoxicity and Lipotoxicity

Insulintherapy,properlyinstituted,shouldlowerthe

A1Cleveltoclosetothegoalof6.5%.Intheprocess,it

is likely that the effects of glucotoxicity and lipotoxic-

ityonthesecretorycapacityofthebetacellwouldhave

beenreducedornearlyeliminated.Hence, after onehas

achievedameaningfulreductioninA1Ctoalevelbelow

7.5%withuseofinsulintherapy,onemaythenattemptuse

ofdualtherapy(asdescribedintheforegoingmaterial)as

anadjuvanttoinsulintherapy,withconcomitantreduction

ofinsulintominimizetherisksofhypoglycemicevents.If

theseeffortsaresuccessful,onecanthenattempttodiscon-

tinuetheuseofinsulintherapyandconsiderdualtherapy

ortripletherapy.

The AACE/ACE Glycemic Control Algorithm

ConsensusPanel has constructed a carefully considered

rationaleforthechoiceofeachoftheregimensinFigure1andfortheirorderofpresentation.Thesechoices,however,

arebasedongeneralprinciplesandstatisticalaveragesfor

largegroupsofpatientsorbasedonmeta-analysesoflarge-

scalestudies.Whenmanagingthe individualpatient,the

physician must exercise judgment toweigh the benets

andrisks,ortheprosandcons,ofeachoftheseoptions.

Abriefusefuloverviewofsomeofthecoreconsiderations

forselectionofagentsorcombinationsofagentsispro-

videdinTable1.Thistableis not intendedtobea sub-

stituteforacomprehensivereviewofFDA-approvedpre-

scribinginformation.

Hypoglycemia Perhapsthemost importantguidingprincipleofour

currentalgorithmistherecognitionoftheimportanceof

avoiding hypoglycemia (24-28). Severe hypoglycemia

stimulates sympathetic adrenergic discharge, causing

arrhythmiasorautonomicdysfunction(orboth),andhas

longbeenrecognizedtohavepotentialforcausingmortal-

ity.Hypoglycemiamayhaveasubstantialnegativeclinical

effect,intermsofmortality,morbidity,adherencetother-

apy,andqualityoflife(24).Therecentlyreportedclinical

trials of intensive therapyACCORD,ADVANCE,and

VADT(15-17,20,29)haveshownthatintensiveglycemic

controlwasassociatedwitha3-to4-foldincreaseinthe

incidenceofhypoglycemia.IntheACCORDstudy,iatro-genichypoglycemiawasassociatedwithexcessmortality

inboththeintensivelytreatedgroupandtheconventionally

treatedgroup(20,29).Theriskofhypoglycemiaincreases

withadvancingageanddurationofdiabetes,theduration

ofinsulintherapy(24,28),coexistingseverecomorbidities,

andthepresenceofhypoglycemiaunawareness.

Insulin and sulfonylurea are the agents that most

commonly cause hypoglycemia. The incidence of


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hypoglycemiaininsulin-treatedpatientswithtype2dia-

betesisonlyone-thirdthatinpatientswithtype1diabetes

(27).Theincidenceofhypoglycemianecessitatingemer-

gency medical treatment in insulin-treated patientswith

type2diabetesapproachesthatobservedforpatientswith

type1diabetes.Theglinides,repaglinideandnateglinide,

areassociatedwithalowerriskofhypoglycemia,presum-

ablybecauseofamorephysiologictimecourseofaction

combinedwith somewhat lower efcacy in comparison

withsulfonylureas.

For some patients, the risk of hypoglycemia may

warrant specic choices of therapy and reevaluation of

therapeuticgoals.Thesepatientsincludethosewhohave

adurationofdiabetesgreaterthan15yearsandadvanced

macrovasculardisease, hypoglycemia unawareness, lim-

itedlifeexpectancy,orotherseriouscomorbidities.

DISCUSSION

Thecurrentalgorithm(Fig.1)wasdevelopedtoassistprimary carephysicians, endocrinologists, and others in

themanagementofpatientswithtype2diabetes.Inthis

algorithm,weconsiderallclassesof effectivedrugs.We

emphasizesafetyandthequalityofglycemiccontrolasour

rstpriorities.Accordingly,wehavegivensulfonylureas

muchlessprioritybecauseuseoftheseagentsisassoci-

atedwithhypoglycemia,weightgain,andlimitedduration

ofeffectivenessafterinitiationoftherapy.Placinggreater

emphasisonsafetyandabilitytoachieveanA1Cgoalof

6.5%will result inearlierandmore frequentuse ofthe

incretin-based therapiesthe GLP-1 agonists (incretin

mimetics)andtheDPP-4inhibitors.Atpresent,onlyone

GLP-1agonist(exenatide)isavailable.TwoDPP-4inhibi-tors(sitagliptinandsaxagliptin)arenowavailable.Onthe

basisofthelevelofongoingresearchwiththese2classes

ofagents,itislikelythatseveralnewagentswillbecome

available during the next few years. Our algorithm uti-

lizes4typesofmonotherapy,9typesofdualtherapy,and

6typesoftripletherapy.Weconsider5typesofinsulin

therapy(basal,premixed,prandial,basal-bolus,and con-

tinuoussubcutaneousinsulininfusion),eachofwhichcan

becombinedwithavarietyoforallyadministeredagents

orwithpramlintide.

Thisalgorithmforglycemiccontrolhasthefollowing

features:

1. ItfavorstheuseofGLP-1agonistsandDPP-4inhibi-

torswithhigherprioritybecauseoftheireffectiveness

and overall safety proles. In view of the millions

ofpatientswhohavebenetedfromtheuseofthese

agentsandtheirexcellentperformanceinawiderange

ofclinicalstudies, incombinationwiththe growing

literature indicating the serious risks of hypoglyce-

mia,theseagentsareincreasinglypreferredformost

patientsinplaceofsulfonylureasandglinides.

2. Itmovessulfonylureastoalowerprioritybecauseof

theassociatedrisksofhypoglycemia,weightgain,and

thefailureoftheseagentstoprovideimprovedglyce-

miccontrolafteruseforarelativelyshortperiod(1to

2yearsintypicalpatients).

3. ItusesGLP-1agonists(incretinmimetics)andDPP-4

inhibitorsasimportantcomponentsofthetherapeutic

armamentarium.

4. ItincludesTZDsaswell-validatedeffectiveagents

withdemonstratedextendeddurabilityofaction,but

withalowerpriorityformanypatientsinlightoftheir

potential adverseeffects, especiallywhenTZDs are

usedincombinationwithsulfonylureasorinsulin,and

therecentconrmationofpreviousreportsofasigni-

cantincrease inbonefractures associatedwiththeir

useinbothmenandwomen(22,23).

5. It considers 3 other classes of agents (AGIs, cole-sevelam, and glinides) only for relatively narrow,

well-denedclinicalsituations,inviewoftheirlim-

itedefcacy.TheLDLcholesterol-loweringproperty

ofcolesevelamisabenecialfactor.

This algorithm is intended to provide guidance.

Individual institutions,clinics, andphysiciansmaywant

tomodifyittoincorporatetheirownexperienceandpref-

erences, thenature of their patient populations, second-

aryconsiderationssuchastheavailabilityofmedications

intheir localformulary, and costs. Theymay alsowish

to reconsider the choice ofagents for inclusion in their

formulary.

CONCLUSION AND RECOMMENDATIONS

Thecurrentalgorithmisintendedforuseinconjunc-

tionwithamoredetailedandcomprehensiveguideline

forexample,theAACEDiabetesGuidelines(1)andthe

ACE/AACE Road Maps toAchieve Glycemic Control

(10)andwithcomprehensivesets ofprescribing infor-

mationandacompendiumofdrug-druginteractions.This

algorithmrepresentsasignicantadvancerelativetomost

oftheotheravailabletreatmentpathways(3-9)byvirtue

of its inclusiveness, rationale and justication,emphasis

onsafety,documentationofsupportingevidence,simplic-ity,andanticipatedeaseofimplementation.Thisalgorithm

providesafoundationthatcanbemodiedinthefutureas

newmedicationsandclassesofmedicationsbecomeavail-

ableorasnewdatabecomeavailableregardingthesafety,

adverseevents,efcacy,andlong-termoutcomesassoci-

atedwiththemedications.


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APPENDIX 1

OVERVIEW OF THERAPEUTIC AGENTS

Physicians should consult the complete prescribing

informationand thegeneral literature (forexample, 30).

Thefollowingmaterialisofferedasabriefreview,apr-

cis.Asummaryoverviewoftheprincipalbenetsandrisks

ofthetherapeuticagentsusedformanagementoftype2

diabetesispresentedinTable1(maintext).Furtherdetails

areprovidedinthefollowingtext.

Metformin

Metformin is a biguanide that improves the effec-

tivenessofinsulininsuppressingexcesshepaticglucose

production,inboththefastingandthepostprandialstate.

Metformindecreasesexcessivehepaticglucoseproduction

inthefastingstateprimarilybydecreasinggluconeogen-

esis and, to a lesser extent, bydecreasing glycogenoly-

sis. Insulin suppression ofhepaticglucoseproduction isenhanced in the postprandial state. Thus, metformin is

effectiveindecreasingbothfastingandpostprandialglu-

cose concentrations. Decreased gastrointestinal glucose

absorption, increasedinsulin sensitivityinperipheral tis-

sues,andenhancedsynthesisofGLP-1mayhaveminor

roles.Metformin often hasbenecialeffectson compo-

nentsof themetabolicsyndrome,includingmildtomod-

erateweight loss, improvementof the lipidprole, and

improvedbrinolysis.

Metforminis effectiveasmonotherapyandin com-

binationwith other antidiabetic agents, including sulfo-

nylureas,TZDs,AGIs,DPP-4inhibitors,GLP-1agonists,

andpramlintide.Itcanalsobeusedincombinationwithinsulin.Becauseofitrelativelyshortdurationofaction,it

isusuallyadministered2to3timesdailyandisbesttoler-

atediftakenwithmeals.Along-acting,once-dailyformu-

lationisalsoavailable.Themaximalrecommendeddosage

is2,500mgdaily,althoughlittleadditionalbenetisseen

withdosagesexceeding2,000mgdaily.

Sideeffectsincludeametallictaste,anorexia,nausea,

abdominalpain,anddiarrhea.Thesesymptomsaremini-

mizedbyinitiatingtherapyatalowdosageof500mgdaily

and gradually increasing to themaximal effective dose.

Gastrointestinalsideeffectsusuallydiminishwithcontin-

ueduse,althoughsomepatientsdonottoleratemetformin

wellanddiscontinuethemedicationorfailtoachievefullyeffectivedoses.

Lacticacidosisisanextremelyrarebutseriouscom-

plicationofmetforminuse.Becausemetforminisprimar-

ilyexcretedbythekidneys,impairedrenalfunctionmay

result in excessive plasma concentrations ofmetformin

andpredisposetolacticacidosis.Therefore,impairedrenal

functionisacontraindicationforuseofmetformin.Inclin-

icalpractice,thisisdenedasaplasmacreatinineconcen-

trationof1.5mg/dLformenand1.4mg/dLforwomen

oracreatinineclearanceof


15/20


approved TZD, troglitazone, was associated with rare

casesofliverdamage,leadingtoliverfailureanddeath;

therefore,itsusewasdiscontinuedapproximately10years

ago.ThecurrentlyavailableTZDs,pioglitazoneandrosi-

glitazone, are effective insulin-sensitizing agents. These

agents increasethe insulinsensitivityof skeletalmuscle,

adiposetissue,and,toalesserextent,theliver,resultingin

increasedinsulin-stimulatedglucoseuptake andmetabo-

lismandimprovedinsulin-mediatedsuppressionofhepatic

glucoseproduction.Theyalsostimulatetheformationof

pre-adipocytes inperipheraladiposetissue,accompanied

bydecreases in ectopic fatdeposition,plasma freefatty

acidconcentration,andinsulinresistance.

When used asmonotherapyorincombinationwith

other antidiabetic agents (including insulin), TZDs are

effectiveindecreasingbothfastingandpostprandialglu-

coseconcentrations.Whenusedasmonotherapy,theydo

notcausehypoglycemia.WhenTZDsareusedwithinsu-

linsecretagogues orinsulin, however,hypoglycemiacan

occur.ThemajorsideeffectoftheTZDsisweightgain,duetobothincreasedadiposetissuemassanduidreten-

tion.Peripheraledemaoccursinsomepatientsandtypi-

cally respondspoorly to loopdiureticsandangiotensin-

convertingenzymeinhibitors.Mildanemiamayoccur.

TheTZDsnotonlyareeffectiveinthemanagementof

hyperglycemiabutalsohavebenecialeffectsonthelipid

prole, with lowering of plasma triglycerides, increas-

ingthe level ofhigh-densitylipoproteincholesterol,and

decreasing small,denseLDLcholesterol.The associated

weightgainanduidretention,however,mayprecipitate

congestive heart failure(19). InpatientswithNewYork

HeartAssociationclassIIIorclassIVcongestiveheartfail-

ure,TZDsarecontraindicated.Weightgaincanbeamajorproblem for patients who are overweight or obese. An

extensivebuthighlycontroversialmeta-analysissuggested

thepossibilityofincreasedischemicheartdiseaseassoci-

atedwithuseofrosiglitazone.Subsequent,moredenitive

analyses,however,haveindicatedthatrosiglitazonehasno

effect,positiveornegative, ontheoccurrenceofcardio-

vasculardisease.A1.5-to2.5-foldincreasedriskofbone

fractureshas beendocumented inbothmen andwomen

usingTZDs(22,23).

a-Glucosidase Inhibitors

TheAGIs,acarboseandmiglitol,inhibit theconver-

sionofoligosaccharidesintomonosaccharidesattheintes-tinalbrushborderandtherebydecreasetheriseinplasma

glucoseconcentrationsafter ingestionofcomplexcarbo-

hydrates.AlthoughthemaineffectofAGIsistodecrease

postprandialhyperglycemiainpatientswithtype2diabetes,

theiruseisalsoassociatedwithaslightdecreaseinfast-

ingglucoseconcentrations.Thischangeisprobablyattrib-

utabletoanoverallimprovementinglycemiccontroland

reductionofglucosetoxicity.Theyareeffectiveasmono-

therapyor incombinationwithother antidiabetic agents,

particularlyifthedietcontainsatleast50%carbohydrate.

Themajor side effects of AGIs are gastrointestinal

and include abdominal discomfort, increased formation

ofintestinalgas,anddiarrhea.Theseadversegastrointes-

tinaleffectsareduetoexcessiveamountsofcarbohydrate

reachingthe largeintestineandundergoingbacterialfer-

mentation.Acarboseisnotsubstantiallyabsorbedfromthe

gastrointestinaltract,whereasmiglitolisabsorbedrapidly

andexcretedbythekidneys.Acarbose,however,ismetab-

olizedbybacterialactioninthecolon,anditsmetabolites

areabsorbed,conjugated,andexcretedinbile.Rarecases

ofcholestaticjaundicehavebeen reported.Effectiveness

ismoderatein peopleconsuminga typicalWesterndiet,

andAGIsaremosteffectivewhenthedietcontainslarge

amountsofcomplexcarbohydrates,as istypicalofmany

Asian diets.Theriskofhypoglycemia isminimalwhen

AGIsareusedasmonotherapy.Hypoglycemiamayoccur

whenAGIsareusedincombinationwithinsulinsecreta-goguesorinsulintherapy.Whenhypoglycemiadoesoccur,

itmust be treated with glucose, inasmuch as digestion

andabsorptionofsucroseandcomplexcarbohydratesare

inhibitedbythesedrugs.

Dipeptidyl-Peptidase-4 Inhibitors

TheDPP-4inhibitorsdecreasethemetabolismofthe

incretinhormones,GLP-1andgastricinhibitorypolypep-

tide,byinhibitionoftheDPP-4enzyme,whichremoves

the2end-terminalaminoacidsandcausesrapidinactiva-

tionofthesegastrointestinalhormones.ActiveGLP-1and

gastricinhibitorypolypeptideplasmalevelsareincreased

approximately2-foldaftermealingestion.Thisresultsinincreasedrst-phaseinsulinsecretion,suppressionofglu-

cagon secretion in the postprandial state, and improved

suppressionofhepaticglucoseproductionandperipheral

glucoseuptakeandmetabolism.Hepaticglucoseproduc-

tionisalsodecreasedinthefastingstate;theresultislower

fasting plasma glucose concentrations.Thus, theDPP-4

inhibitorsdecreasebothfastingandpostprandialglucose

levels.Inclinicaltrials,theyhaveeffectivenesssimilarto

thatofmetforminandsulfonylureas.Becausetheeffects

ofGLP-1on insulinandglucagonsecretion areglucose

dependent, there is insignicant risk of hypoglycemia

when itis used asmonotherapyorin combinationwith

metforminoraTZD.ThecurrentlyavailableDPP-4inhibi-tors,sitagliptinandsaxagliptin,areconvenientlyadminis-

teredoncedaily.Sitagliptin iseliminatedalmostentirely

by the kidneys; its dosage must be reduced for patients

withmoderate or severe renal insufciency. Saxagliptin

islikewiseprimarilyexcretedbythekidneysbutisalso

subjecttohepaticmetabolism;itsdosagemustbereduced

onlyinsubjectswithsevererenalinsufciency.Nomajor


16/20


long-termtoxicitieshavebeenreported.Rareallergicreac-

tionshavebeendescribed.

Long-Acting GLP-1 Analogues

Currently, one long-termGLP-1 analogue is avail-

ableforclinicaluse,althoughseveralothersareinvarious

stagesofdevelopmentandmaybecomeavailableinthe

nearfuture.Thecurrentlyavailablecompound,exenatide,

isabiosyntheticversionofasalivarypeptidefromaliz-

ard,theGilamonster.Exenatidehasapproximately50%

homologytohumanGLP-1butishighlyresistanttoinac-

tivationbytheDPP-4enzyme.Thebindingofexenatide

tothehumanGLP-1receptorresultsinglucose-dependent

stimulation of insulin secretion and glucose-dependent

suppressionofglucagonsecretion.Exenatideisadminis-

teredbyinjectiontwicedailyandiseffectiveindecreas-

ingbothfastingandpostprandialplasmaglucoseconcen-

trations.Exenatidehascentralnervoussystemeffectsto

reduceappetiteandincreasethesenseofsatiety;theout-

comeisdecreasedfoodintakeandweightloss.Themajorsideeffectsaregastrointestinal,withnauseaandvomiting

insomepatients.Theseeffectsaredoserelatedandusu-

allywaneovertime.Exenatideisadministeredatalow

dosage(5gtwicedaily)fortherst4weeksoftreat-

mentandthenincreasedtoahigherdosage(10gtwice

daily)afterthegastrointestinalsideeffectshaveabated.

Overalleffectivenessisgenerallyverygoodwhenexena-

tideisaddedtosingle-ordual-agentregimensinvolving

metformin,sulfonylureas,orTZDs.Currently,exenatide

isnotapprovedforuseasmonotherapyorincombination

withinsulin.

Additionaleffectsthathavebeenobservedwithlong-

actingGLP-1agonistsaresubstantialreductionsinplasmatriglyceride levels, diminished liver fat content, and

decreasedsystolicanddiastolicbloodpressures.Towhat

extentthesearedirecteffectsof thedrugsorareattribut-

abletoweightlossisnotyetclear.

Bile Acid Sequestrants

Colesevelamisabileacidsequestrantusedprimarily

to treat hypercholesterolemia, either as monotherapy or

in combinationwith hydroxymethylglutaryl-coenzymeA

reductaseinhibitors.Colesevelamalso reducesthe blood

glucoselevelinpatientswithtype2diabetesmellitus,par-

ticularly inpersons inadequatelycontrolledwithmetfor-

min, a sulfonylurea,or insulin.Themajor sideeffectofcolesevelamisconstipation;thus,itshouldnotbeusedin

patientswithgastroparesisorothergastrointestinalmotil-

itydisorders,inpatientsaftermajorgastrointestinalsurgi-

calprocedures,andinothersatriskforbowelobstruction.

Othersideeffectsincludeanincreaseinthelevelofserum

triglycerides and possible malabsorption of fat-soluble

vitamins.

Pramlintide

Pramlintideisasyntheticanaloguethatexhibitsmany

ofthepropertiesofthenaturalbeta-cellhormone,amylin.

When injected preprandially, pramlintide lowers plasma

glucagon,delaysgastricemptying,andpromotessatiety.

Themajoreffectsare todecreasepostprandialhypergly-

cemiaandfacilitateweightloss.Pramlintidecanbeused

effectivelyinthetreatmentofobesepatientswithtype2

diabeteswhousebefore-meal insulin injections,withor

withoutorallyadministeredantidiabetic agents.The rec-

ommendedstartingdoseis60g(10U)injectedimme-

diatelybefore themainmeal; somepatients toleratethe

medicationbetterwithaninitialstartingdoseof30 g(5

U)beforemeals.Thedoseshouldthenbetitratedgradually

to120g(20U),astolerated.Themajorsideeffectisnau-

sea,whichgenerallywaneswithcontinuedadministration.

Pramlintide decreases postprandial glycemic excursions

andincreasessatiety.Thedosageofthepreprandialrapid-

actinginsulinmayneedtobereducedandthetimeofits

administrationmayneedtobedelayedtocompensatefortheexpectedreducedfoodintakeanddelayedgastricemp-

tyingassociatedwithpramlintidetherapy.Hypoglycemia

may also occur if pramlintide is used in combination

withasulfonylurea,anddosagesmayneedtobeadjusted

appropriately.

Insulin

Weconsiderninetypesofinsulin (TableA1).These

canbeadministeredinanyofseveralregimens(TableA2).

Exogenousinsulinprovidesreplacementforthedeciency

ofthenaturalhormone.

Physiology Normally,insulin isdeliveredtotheportalvein and

thus reaches the liver within seconds.When insulin is

administeredsubcutaneously,averylengthydelayensues

beforeitdissociatesfromhexamertomonomerandisthen

absorbedintothecirculation.Accordingly,regularhuman

insulinadministered subcutaneously doesnotmimic the

normalkineticsanddynamicsofendogenousinsulin.As

aresult,regularhumaninsulindoesnotprovideadequate

effectforcontrolofpostprandialglycemicexcursionsand

hasapropensitytocausedelayedhypoglycemia.

Rapid-Acting Insulin Analogues

Therapidlyactinginsulinanalogueslispro,aspart,andglulisinehaveatimecourseofactionthatcloselymimics

thenormalphysiologicfeatures.

Premixed Insulins

Bothinsulinlisproandinsulinaspartareavailablein

mixtureswithprotamine.Thesepremixedinsulinsprovide

a timecourse that issuitable for coveragefor breakfast


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andlunchor fordinner andtheovernight period.These

mixturesorbiphasicinsulinsdonotresultin2discrete

peaks.Instead,thereisasinglemaximumatapproximately

1.5hours,followedby aslowdecline.Accordingly,they

donotmimicthenormalphysiologicprocessesandarenot

aseffectiveasafullyoptimizedbasal-bolusregimenwith

useofrapidlyactinginsulinanaloguesandalong-actinginsulinanalogue.Useofmixturesofregularhumaninsulin

andNPHinsulinisnotrecommendedbecausethemaximal

activitydoesnotoccuruntilapproximately2to2.5hours

afterinjection.

Basal Insulin

NPHinsulinshowswidevariabilityinitsabsorption

rate fromday today,evenwithin individuals, anddoes

nothaveasufcientlylongtimecoursetoprovideabasal

insulinizationfora24-hourperiod.Ithasapronounced

peak at approximately 9 hours.Accordingly, the long-

actinginsulinanaloguesglargineanddetemirarestrongly

preferred.

The various types of insulin regimens as shown in

TableA2arediscussedinthemainbodyofthetext.

Drug-Drug Interactions Thiazide diuretics, niacin, and b-adrenergic block-

ing agents arewell known to impair glucose homeosta-

sis (31). Systemic administration of glucocorticoids can

severely impair glucose tolerance. One should be cau-

tiouswheninitiatingtherapywiththeseagentsinpatients

with diabetesand should anticipate an increased risk of

hypoglycemiawhenone ofthese agents isdiscontinued.

Angiotensin-convertingenzymeinhibitorsandangiotensin

receptorblockershavedemonstratedbenecialmetabolic

effects.

Table A1

Outline of Various Types of Insulin

Type of insulin Trade name Comment

Rapid-acting insulin analogues

Aspart NovoLog Superiortoregularhumaninsulinintermsofmore

Lispro Humalog rapidactionprolewithreducedriskofhypoglycemia

Glulisine Apidra 2-5hoursafteramealorovernight

Premixed insulin/protamine

Aspart+aspart-protamine NovoLogMix Usuallyusedtwiceadaybeforebreakfastanddinner;

Lispro+lispro-protamine HumalogMix providespostprandialcoveragewith2injectionsper

day;lessexiblethanuseofbasal-bolustherapywith

acombinationofrapid-actingandlong-acting

analogues

Long-acting insulin analogues

Glargine Lantus Canbeusedwith1injectionperdayinpatientswith

type2diabetes

Detemir Levemir Canbeusedwith1injectionperdayinpatientswith

type2diabetes;excellentreproducibilityofabsorption

prolewithinindividuals;possiblylessweightgain

thanwithotherinsulins

Not recommended

Regularhumaninsulin HumulinR Onsetofactionistooslowandpersistenceofeffectis

NovolinR toolongtomimicanormalprandialphysiologic

prole;theresultisimpairedefcacyandincreased

riskofdelayedhypoglycemia

NPHinsulin HumulinN Doesnotprovideasufcientlyatpeaklessbasal

NovolinN insulin;highlyvariableabsorptionevenwithin

individuals;increasedriskofhypoglycemiacompared withthelong-actinginsulinanaloguesglargineor

detemir


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Combineduseofany2agentsthatareindependentlycapableofproducinghypoglycemiais likely to increase

theriskofhypoglycemia.Accordingly,itiscustomaryto

reduce the dosage ofoneorbothagentswhenasecond

agentisaddedandtoproceedcautiously.Themostimpor-

tantinteractionsofantidiabeticagentsarethoseamongsul-

fonylureas,TZDs,andinsulin;combineduseofany2or

all3oftheseagentsmayresultinincreasedriskofweight

gain,retentionofuid,andhypoglycemia.

The combination drug trimethoprim-sulfamethoxa-

zolehasbeenassociatedwitha6.6-foldincreasedriskof

hypoglycemia(32),andcasereportsofextremehypogly-

cemiahavebeenreported.Theoxacinantibioticshave

beenassociatedwithasmallriskofhyperglycemiaandanevensmallerriskofhypoglycemia(33).

Thereisastronginteractionofgembrozilwithrepag-

linide and TZDs, resulting in considerable elevation of

plasma levels of repaglinide (34)orTZDs.Fortunately,

gembrozil isnowlesscommonlyused than inthepast

formanagementofdyslipidemia.Sulfonylureasaremetab-

olized byCYP2C9. Thus, agents that induce or inhibit

CYP2C9canpotentiallyaffectthemetabolismofsulfonyl-

ureas.Majordrug-druginteractionshavenotbeenreported

fornateglinide.

Metforminiseliminatedbytubularsecretionandglo-

merular ltration. Metformin may potentially compete

with other cationic drugs, such as cimetidine, for renalsecretion(35).Inprinciple,rosiglitazoneandpioglitazone

metabolismcouldbeaffectedbyinhibitorsorinducersof

CYP2C8,butsubstantialdrug-druginteractionshavenot

beenreported(36,37).

Acarbose andmiglitol do notappear to have appre-

ciablemetabolic interactions.Thesedrugsareassociated

withasmalldecreaseintheabsorptionofdigoxinandan

increaseinabsorptionofwarfarin(38,39).Exenatidemay

slowabsorptionofsomemedications,suchasacetamino-phenanddigoxin.Theredonotappeartobeanyimportant

metabolicinteractionsforsitagliptin.

ACKNOWLEDGMENT

JeffreyHollowayprovided excellentassistancewith

thedevelopmentof thegraphicdisplayof thealgorithm

(Fig.1).Dr.DavidRodbardprovidedvaluableassistance

with the preparation of the manuscript. Dr. Zachary T.

Bloomgardenmade important contributions to Table 1.

Lori Clawges provided excellent administrative support

fortheAlgorithmConsensusPanel.

DISCLOSURE

Dr. Helena W. Rodbard reports that she has

received consultant honoraria fromAbbott Laboratories,

AstraZeneca Pharmaceuticals LP, Biodel Inc.,

GlaxoSmithKline, MannKind Corporation, Merck &

Co., Inc., Novo Nordisk Inc., sano-aventis U.S., and

Takeda Pharmaceuticals America, Inc, speaker hono-

raria from Amylin Pharmaceuticals, Inc., AstraZeneca

Pharmaceuticals LP, Bristol-Myers Squibb Company,

GlaxoSmithKline, Eli Lilly and Company, Merck

& Co., Inc., Novo Nordisk Inc., and sano-aventis

U.S., and research grant support from Biodel Inc.,MacroGenics,Inc.,NovoNordiskInc.,andsano-aventis

U.S.

Dr. Paul S. Jellinger reports that he has received

speakerhonorariafromAmylinPharmaceuticals,Inc.,Eli

Lilly and Company,Merck&Co.,NovoNordisk, Inc.,

sano-aventisU.S.andTakedaPharmaceuticals,Inc.,and

consultanthonorariafromDaiichiSankyo,Inc.,MannKind

Corporation,andTethysBioscience.

Table A2

Summary of Insulin Regimens

Components and Injections

Insulin regimen frequency of administration per day

Basal Glargineordetemir(dailyortwiceaday) 1or2

Premixed NovoLogMixorHumalogMix(usuallytwiceaday; 2

occasionallyuseddailyor3timesaday)

Prandial NovoLog,Humalog,orApidra(usually3timesaday) 3

Basal-bolus(multipledaily NovoLog,Humalog,orApidra(usually3timesaday) 4

injections) incombinationwithglargineordetemir(daily)

Continuoussubcutaneous NovoLog,Humalog,orApidra Continuous

insulininfusion


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Dr. Jaime A. Davidson reports thathehasreceived

consultant honoraria from Bristol-Meyers Squibb

Company, Calisto Medical, Inc., CureDM, Inc.,

Daiichi Sankyo, Inc., Eli Lilly and Company, Generex

Biotechnology Corp., GlaxoSmithKline, MannKind

Corporation,Merck&Co.,Novartis,NovoNordiskInc.,

Pzer Inc., Roche Pharmaceuticals, sano-aventis U.S.,

andTakedaPharmaceuticals, speakerhonorariafromEliLilly and Company, GlaxoSmithKline, Merck & Co.,

Novo Nordisk, Inc., sano-aventis U.S., and Takeda

Pharmaceuticals,andresearchgrantsupportfromEliLilly

& Company, GlaxoSmithKline,MannKind Corporation,

Novartis,andNovoNordiskInc.

Dr. Daniel Einhorn reports that he has received

consultanthonorariafromAmylinPharmaceuticals,Inc.,

Eli Lilly and Company, MannKind Corporation, Novo

Nordisk Inc., andTakeda PharmaceuticalsAmerica, Inc

andresearchgrantsupportfromAmylinPharmaceuticals,

Inc., Eli Lilly and Company, Novo Nordisk Inc., and

sano-aventis U.S. and is a stockholderwithHalozyme

Therapeutics,Inc.andMannKindCorporation. Dr. Alan J. Garberreportsthathehasreceivedcon-

sultant honoraria from GlaxoSmithKline,Merck & Co.,

Inc., Novo Nordisk Inc., and Roche Pharmaceuticals,

speaker honoraria from GlaxoSmithKline, Merck &

Co., Inc., Novo Nordisk Inc., and Sankyo Pharma,

Inc., and research grant support from Bristol-Myers

SquibbCompany,GlaxoSmithKline,Merck&Co., Inc.,

MetabasisTherapeutics,Inc.,NovoNordisk Inc.,Roche

Pharmaceuticals,SankyoPharma,Inc.,andsano-aventis

U.S.

Dr. George Grunberger reports that hehas received

speaker honoraria and research grant support from

GlaxoSmithKline, Eli Lilly and Company, and sano-aventis, U.S. and speaker honoraria from Amylin

Pharmaceuticals, Inc., Daiichi Sankyo, Inc., Merck &

Co.,Inc.,NovoNordiskInc.,andTakedaPharmaceuticals

America,Inc.

Dr. Yehuda Handelsman reports that he has re-

ceived consultant honoraria from Bristol-Myers Squibb

Company, Daiichi Sankyo, Inc., GlaxoSmithKline,

Medtronic, Inc.,Merck & Co., Inc., Tethys Bioscience,

and Xoma LLC, speaker honoraria from AstraZeneca

Pharmaceuticals LP, Bristol-Myers Squibb Company,

Daiichi Sankyo, Inc., GlaxoSmithKline, and Merck &

Co.,Inc.,andresearchgrantsupportfromDaiichiSankyo,

Inc.,GlaxoSmithKline, Novo Nordisk Inc., and TakedaPharmaceuticalsAmerica,Inc.

Dr. Edward S. Horton reports that hehas received

advisory board honoraria from Abbott Laboratories,

AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb

Company,Daiichi Sankyo, Inc., Medtronic, Inc., Merck

& Co., Inc., Metabasis Therapeutics, Inc., Novartis

Pharmaceuticals Corporation, Novo Nordisk Inc.,

Roche Pharmaceuticals, sano-aventis U.S., Takeda

PharmaceuticalsAmerica,Inc,andTethysBioscienceand

researchgrantsupportfromAmylinPharmaceuticals,Inc.

andEliLillyandCompany.

Dr. Harold Lebovitz reports that he has received

consultant honorariafromAmylinPharmaceuticals,Inc.,

AstraZenecaPharmaceuticalsLP,GlaxoSmithKline,Novo

Nordisk Inc., and sano-aventisU.S., speaker honoraria

fromEliLillyandCompany,andadvisoryboardhonoraria

fromAmylin Pharmaceuticals, Inc. and is a stockholderwithAmylinPharmaceuticals,Inc.,andMerck&Co.,Inc.

Dr. Philip Levyreportsthathedoesnothaveanyrele-

vantnancialrelationshipswithanycommercialinterests.

Dr. Etie S. Moghissi reports that she has received

speaker honoraria from Bristol-Myers Squibb, Eli Lilly

andCompany,andNovoNordiskInc.andadvisoryboard

honoraria fromAmylin Pharmaceuticals, Inc.,Merck &

Co.,Inc.,andNovoNordiskInc.

Dr. Stanley S. Schwartzreportsthathehasreceived

speaker honoraria from Amylin Pharmaceuticals, Inc.,

EliLillyandCompany,Merck&Co.,Inc.,sano-aven-

tis U.S., and Takeda Pharmaceuticals America, Inc and

advisoryboard honoraria fromAmylinPharmaceuticals,Inc.,GileadSciences,Inc.,EliLillyandCompany,Novo

NordiskInc.,andTakedaPharmaceuticalsAmerica,Inc.

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