Algoritma Terapi DM

540 ENDOCRINE PRACTICE Vol 15 No. 6 September/October 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.

STATEmENT by ANAmERICAN ASSOCIATION Of ClINICAl ENDOCRINOlOgISTS/

AmERICAN COllEgE Of ENDOCRINOlOgyCONSENSuS 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

glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6) 541

AACE/ACE glyCEmIC CONTROl AlgORIThm CONSENSuS PANEl

CochairpersonsHelena W. Rodbard, MD, FACP, MACE

Paul S. Jellinger, MD, MACE

Panel MembersZachary T. Bloomgarden, MD, FACE

Jaime A. Davidson, MD, FACP, MACEDaniel Einhorn, MD, FACP, FACEAlan J. Garber, MD, PhD, FACE

James R. Gavin III, MD, PhDGeorge Grunberger, MD, FACP, FACEYehuda Handelsman, MD, FACP, FACE

Edward S. Horton, MD, FACEHarold Lebovitz, MD, FACE

Philip Levy, MD, MACEEtie S. Moghissi, MD, FACP, FACE

Stanley S. Schwartz, MD, FACE

542 glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6)

ABSTRACT

This report presents an algorithm to assist primarycarephysicians,endocrinologists,andothers in theman-agement of adult, nonpregnant patients with type 2 dia-betesmellitus. Inorder tominimize the riskofdiabetes-relatedcomplications, thegoalof therapyis toachieveahemoglobinA1c(A1C)of6.5%orless,withrecognitionoftheneedforindividualizationtominimizetherisksofhypoglycemia.WeprovidetherapeuticpathwaysstratifiedonthebasisofcurrentlevelsofA1C,whetherthepatientisreceivingtreatmentorisdrugnaïve.Weconsidermono-therapy,dualtherapy,andtripletherapy,including8majorclassesofmedications(biguanides,dipeptidyl-peptidase-4inhibitors,incretinmimetics,thiazolidinediones,a-gluco-sidaseinhibitors,sulfonylureas,meglitinides,andbileacidsequestrants) and insulin therapy (basal, premixed, andmultiple daily injections),with orwithout orally admin-isteredmedications.Weprioritizechoicesofmedicationsaccording to safety, risk of hypoglycemia, efficacy, sim-plicity,anticipateddegreeofpatientadherence,andcostofmedications.Werecommendonlycombinationsofmedi-cationsapprovedbytheUSFoodandDrugAdministrationthat provide complementary mechanisms of action. Itis essential tomonitor therapywithA1C and self-moni-toringofbloodglucoseand toadjustoradvance therapyfrequently (every 2 to 3months) if the appropriate goalforeachpatienthasnotbeenachieved.Weprovideaflow-chartandtablesummarizingthemajorconsiderations.Thisalgorithmrepresentsaconsensusof14highlyexperiencedclinicians,clinicalresearchers,practitioners,andacademi-ciansandisbasedontheAmericanAssociationofClinicalEndocrinologists/American College of EndocrinologyDiabetes Guidelines and the recent medical literature.(Endocr Pract. 2009;15:540-559)

Abbreviations:AACE = American Association of ClinicalEndocrinologists;A1C=hemoglobinA1c;ACCORD=ActiontoControlCardiovascularRiskinDiabetes;ACE =American College of Endocrinology;ADA= American Diabetes Association; ADVANCE =Action in Diabetes and Vascular Disease: Preteraxand Diamicron Modified Release ControlledEvaluation; AGIs = a-glucosidase inhibitors;DCCT/EDIC=DiabetesControlandComplicationsTrial/Epidemiology of Diabetes Interventions andComplications; DPP-4 = dipeptidyl-peptidase-4;EASD = European Association for the Study ofDiabetes;FDA=USFoodandDrugAdministration;GLP-1=glucagonlikepeptide-1;LDL=low-densitylipoprotein;PROACTIVE=ProspectivePioglitazoneClinicalTrialinMacrovascularEvents;RCTs=ran-domizedcontrolledtrials;RECORD=RosiglitazoneEvaluatedforCardiovascularOutcomesinOralAgent

CombinationTherapyforType2Diabetes;SMBG=self-monitoring of blood glucose;TZDs = thiazoli-dinediones;UKPDS =UnitedKingdomProspectiveDiabetes Study;VADT =VeteransAffairs DiabetesTrial

INTRODUCTION

Therearenearly24millionAmericanswithdiabetesintheUnitedStates.Everyyear,1.3millionpeoplearediag-nosedwithtype2diabetes.Therapidincreaseinnewcasesoftype2diabetesinpersons30to39yearsofageandinchildren and adolescents is of special concern.This epi-demicoftype2diabetesisglobalandcloselyreflectstheepidemicofoverweight,obesity,metabolicsyndrome,andsedentarylifestyle.Anurgentneedexistsforanauthorita-tive,practicalalgorithmformanagementofpatientswithtype2diabetesmellitusthatconsiderscurrentlyapprovedclasses of medications and emphasizes safety and effi-cacy, while also considering secondary factors such asthe cost ofmedications or the number of years of clini-cal experiencewith use of any specific drug.The intro-ductionof severalnewclassesofmedicationswithin thepast few years—especially incretin-based therapies suchas incretin mimetics and dipeptidyl-peptidase-4 (DPP-4) inhibitors—and the results from several recent large-scale clinical trials—Action to Control CardiovascularRisk in Diabetes (ACCORD), Action in Diabetes andVascular Disease: Preterax and Diamicron ModifiedRelease Controlled Evaluation (ADVANCE), VeteransAffairsDiabetesTrial (VADT), Prospective PioglitazoneClinical Trial in Macrovascular Events (PROACTIVE),andRosiglitazoneEvaluatedforCardiovascularOutcomesinOralAgentCombinationTherapyforType2Diabetes(RECORD)—combined with recently reported long-termfollow-upresultsinpatientsintheDiabetesControland Complications Trial/Epidemiology of DiabetesInterventionsandComplications(DCCT/EDIC),theUnitedKingdomProspectiveDiabetesStudy (UKPDS), and theSteno-2study,necessitatereevaluationofpreviouslypro-posed algorithms for selection of therapies. Numerousguidelines formanagement of patientswith diabetes areavailable—forexample,fromtheAmericanAssociationofClinicalEndocrinologists(AACE)(1),AmericanDiabetesAssociation(ADA)StandardsofMedicalCareinDiabetes(2), Veterans Health Administration/US Department ofDefense(VA/DOD)(3),InternationalDiabetesFederation(4),andmanyothers.Severaloftheseneedtobeupdatedtoreflecttherecentliteratureandclinicalexperience.Afewalgorithmsareavailableforthatpurpose:ADA/EuropeanAssociationfortheStudyofDiabetes(EASD)2006(5,6),ADA/EASD 2009 (7), Canadian Diabetes Association(8,9),andtheAmericanCollegeofEndocrinology(ACE)/AACERoadMapstoAchieveGlycemicControl(10).The


cost ofmedications represents only a very small portionofthetotalcostoftreatmentofpatientswithdiabetes.Themajorcostisrelatedtothetreatmentofthecomplicationsofdiabetes.Webelievethatidentificationofthesafestandmostefficaciousagentsisessential.

METHODS

AACE/ACE convened a panel of experts, includingclinicians and clinical investigators, both academiciansand practitioners. An algorithm was developed on thebasisof themedical literature,withcarefulconsiderationoflevelsofevidenceandevaluationfortheconsistencyofresultsfrommultiplestudiesandsources;greaterempha-siswasplacedonresultsfromrandomizedcontrolledtrials(RCTs)whenavailable.Wealsoconsideredmeta-analyses,USFood andDrugAdministration (FDA)-approvedpre-scribing information, and the extensive experience, col-lective knowledge, and judgment of the panelmembers.We envisioned the need for an algorithm that reflectedthe best practices for expert physicians, recognizing thatRCT data are not available to guide every clinical deci-sion. Considerations were based on theAACEMedicalGuidelines for Clinical Practice for the Management ofDiabetesMellitus (1), review of other guidelines (ADAStandards ofMedical Care inDiabetes—2009) (2), pre-vious algorithms—ACE/AACE Road Maps to AchieveGlycemic Control (10), ADA/EASD 2006 (5,6), ADA/EASD2009(7),CanadianDiabetesAssociation(8,9),andInzucchi(11)—theFDA-approvedprescribinginformationforindividualagents,pharmacoepidemiologicsurveillancestudies,andthecurrentliteraturedescribingrelevantclini-cal trials:DCCT/EDIC (12),UKPDS(13),Steno-2 (14),ACCORD(15),ADVANCE(16),VADT(17),RECORD(18),PROACTIVE(19),andothers.

Inthedevelopmentofthisalgorithm,weattemptedtoaccomplishthefollowinggoalsasprioritiesintheselectionofmedications:

1. minimizingriskandseverityofhypoglycemia2. minimizingriskandmagnitudeofweightgain3. inclusionofmajorclassesofFDA-approvedglycemic

medication, including incretin-based therapies andthiazolidinediones(TZDs)

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

5. considerationofbothfastingandpostprandialglucoselevelsasendpoints

6. considerationoftotalcostoftherapytotheindividualandsocietyat large, includingcostsrelated tomedi-cations,glucosemonitoringrequirements,hypoglyce-micevents,drug-relatedadverseevents,andtreatmentofdiabetes-associatedcomplications

Webelievethatthisalgorithmrepresentsthetreatmentpreferences of most clinical endocrinologists, but in theabsenceofmeaningfulcomparativedata,itisnotnecessar-ilyanofficialAACEposition.BecauseoftheinsufficientnumberortotalabsenceofRCTsformanycombinationsoftherapies,theparticipatingclinicalexpertsusedtheirjudg-ment and experience. Every effort wasmade to achieveconsensus among the panelmembers.Many details thatcould not be included in the summarizing algorithm aredescribedinthefollowingtext.

RESULTS

Ourglycemiccontrolalgorithmwasdevelopedonthebasisoftheprinciplesoutlinedinthesubsequentsection.

Principles Underlying the AACE/ACE Algorithm• Lifestyle(dietaryandexercise)modificationsareessen-

tialforallpatientswithdiabetes.Reductionofobesityoroverweightandadjustmenttoanactivelifestylecanhavemajorbeneficialeffects.Inmanycases,delayingpharmacotherapytoallowforlifestylemodificationsisinappropriate because these interventions are usuallynotadequate.Lifestylemodificationtogetherwithspe-cific diabetes education, dietary consultation, and theintroductionofaprogramofself-monitoringofbloodglucose (SMBG) can be initiated concomitantly withmedicaltherapy.

• AchievinganA1Cof6.5%isrecommendedasthepri-mary goal, but this goal must be customized for theindividualpatient,withconsiderationofnumerousfac-torssuchascomorbidconditions,durationofdiabetes,history of hypoglycemia, hypoglycemia unawareness,patient education,motivation, adherence, age, limitedlifeexpectancy,anduseofothermedications.

• IfapatienthasfailedtoachievetheA1Cgoal,onecantitrate dosages of medications, change regimens (addor discontinue medications), or, under some circum-stances,reconsiderandrevisethegoal.

• Whencombinationtherapyisprescribed,itisimportanttouseclassesofmedicationsthathavecomplementarymechanismsofaction.

• Effectivenessoftherapymustbeevaluatedfrequently—forexample,every2to3months—withassessmentofA1C,logbookdataforSMBGrecords,documentedandsuspected hypoglycemia, and other potential adverseevents(weightgain,fluidretention,andhepatic,renal,orcardiacdisease)aswellasmonitoringofcomorbidi-ties,relevantlaboratorydata,concomitantdrugadmin-istration,diabetes-relatedcomplications,andpsychoso-cialfactorsaffectingpatientcare.

• Safety and efficacy should be given higher prioritiesthan cost of medications per se, inasmuch as cost ofmedicationsisonlyasmallpartof thecostofcareofdiabetes.


• Thealgorithmshouldbeassimpleaspossibletogainphysicianacceptanceandimproveitsutilityandusabil-ityinclinicalpractice.

• Thealgorithmshouldhelpeducatecliniciansandhelpguidetherapyatthepointofcare.

• The algorithm should conform, as nearly as possible,toaconsensusforcurrentstandardsofcarebyexpertendocrinologists who specialize in the managementofpatientswithtype2diabetesandhavethebroadestexperienceinoutpatientclinicalpractice.

• Thealgorithmshouldbeasspecificaspossibleandpro-vide guidance to physicians with prioritization and arationaleforselectionofanyparticularregimen.

• Rapid-actinginsulinanaloguesaresuperiorto“regularhumaninsulin”andprovideabetter,saferalternative.

• NPH insulin is not recommended. Use of NPH as abasalinsulinhasbeensupersededbythesyntheticana-loguesinsulinglargineandinsulindetemir,whichpro-videarelativelypeaklessprofileforapproximately24hoursandyieldbetterreproducibilityandconsistency,bothbetweenpatientsandwithinpatients,andacorre-spondingreductionintheriskofhypoglycemia.

The Glycemic Control Algorithm The AACE/ACE algorithm for glycemic control ispresentedinFigure1.

A1C Goal TherationaleforanA1Ctargetof6.5%ispresentedintheAACEDiabetesGuidelines(2007)(1).TheACCORDandVADT studies (15,17) have confirmed that progres-sively lowerA1Clevelsareassociatedwithreducedriskofbothmicrovascularandmacrovascularcomplications.Arecentmeta-analysisof5prospectiveRCTsdemonstratedasignificantreductionincoronaryeventsassociatedwithan overallA1C of 6.6% in comparisonwith 7.5% (20).Thesestudiesalsoindicatedthattheriskofcardiaceventsanddeathismorecommoninpatientswithhypoglycemicepisodes (and especially severe hypoglycemia) and thatthe benefit-to-risk ratio decreases progressively with thedurationofdiabetes,suchthattheuseofintensivetherapymaybeatleastrelativelycontraindicatedinpatientswithadurationofdiabeteslongerthan12years(VADT)(17).TheACCORDstudy(15)alsosuggestedthatexcessivelyrapidoraggressiveadjustmentoftherapymaybeassoci-atedwith increased risk.TheA1C levels showanexcel-lentcorrelationwiththemeanglucoselevel,butthisrela-tionship isalsoaffectedbyseveralother factors, suchashemoglobinopathies,hemolyticanemias,varyingratesofindividualglycation,genetics,andthevariabilitiesofdif-ferentlaboratorymethods.

Frequency of Monitoring of A1C Manyphysiciansfailtoimplementtheuniformlyrec-ommendedguidelinestomonitorA1Conaquarterlybasis.

Physicians are often slow in advancing therapy, relativeto either dosages ofmedications or switching to amoreefficacioustherapeuticregimeninatimelymanner.Oneofthemostimportantaspectsofthecurrentalgorithmisthestrongrecommendationtomonitortherapyclosely(every2to3months)andtointensifytherapyuntil thegoalforA1Chasbeenachieved.

Stratification by Current A1C level Animportantelementofthecurrentalgorithmistheneed for stratificationof the therapeutic approachon thebasisofthecurrentA1CLevel.

1. If thepatienthasanA1Cvalueof7.5%or lower, itmaybepossibletoachieveagoalA1Cof6.5%withuseofmonotherapy. Ifmonotherapyfails toachievethatgoal,oneusuallyprogresses todualand then totripletherapy;finally,insulintherapyshouldbeiniti-ated,withorwithoutadditionalagents.

2. If thepatienthasanA1Clevel in therangeof7.6%to 9.0%, then one should begin with dual therapybecausenosingleagentislikelytoachievethegoal.Ifdualtherapyfails,onecanprogresstotripletherapyandthentoinsulintherapy,withorwithoutadditionalorallyadministeredagents.

3. IfthepatienthasanA1Cvalueof>9.0%,thenthepos-sibilityofachievingagoalA1Cof6.5%issmall,evenifdualtherapyisused.Ifthepatientisasymptomatic,one might begin with triple therapy—for example,basedonacombinationofmetforminandanincretinmimetic or a DPP-4 inhibitor combined with eithera sulfonylurea or a TZD. If, however, the patient issymptomatic,ortherapywithsimilarmedicationshasfailed,itisappropriatetoinitiateinsulintherapy,eitherwithorwithoutadditionalorallyadministeredagents.

4. Whenthealgorithm(Fig.1)indicatesinsulintherapy,onemayuseanyofthefollowing4generalapproaches:

• basalinsulin,usingalong-actinginsulinanalogue(glargine,detemir),generallygivenoncedaily;

• premixed insulins, using a rapid-acting analogueandprotamine(NovoLogMix,HumalogMix),usu-allygiventwicedailywithbreakfastanddinnerbutoccasionallyusedonlywiththelargestmeal;

• basal-bolusinsulinormultipledailyinjections,usingrapid-actinginsulinanalogues—aspart(NovoLog),lispro (Humalog), or glulisine (Apidra)—togetherwith the long-acting insulin analogue glargine(Lantus)ordetemir(Levemir);

• a“prandial” insulinregimen, involvinguseof therapid-actinginsulinanalogues,butwithoutabasalorlong-actinginsulincomponent.Thismaybepos-sibleifthepatientisbeingtreatedwithaninsulinsensitizer(metformin)thatprovidesadequatecon-troloffastingplasmaglucose.


Wedonot recommenduseof regularhuman insulin(“R”),norofNPHinsulin(“N”)ifpossible,inviewofthefactthattheseinsulinpreparationsdonothaveasufficientlypredictabletimecoursethatadequatelymimicsthenormalphysiologicprofile.Asaresult,thedoserequiredtocontrolhyperglycemiaisoftenassociatedwithanincreasedriskofhypoglycemia. Wenowdescribethe3pathwayswithinthealgorithmcorrespondingtothe3broadrangesofA1C:6.5%to7.5%,7.6%to9.0%,and>9.0%.

Management of Patients With A1C Levels of 6.5% to 7.5%

Monotherapy For the patient with anA1C level within the rangeof6.5% to7.5%, it ispossible that a single agentmightachievetheA1Cgoalof6.5%.Inthissetting,metformin,TZDs, DPP-4 inhibitors, and a-glucosidase inhibitors(AGIs)are recommended.Becauseof its safetyandeffi-cacy,metforministhecornerstoneofmonotherapyandisusuallythemostappropriateinitialchoiceformonotherapyunless there is a contraindication, such as renal disease,hepaticdisease,gastrointestinalintolerance,orriskoflac-ticacidosis. SomepatientswithdiabetesandA1Clevelsof<6.5%mayalsobeconsideredforpharmacotherapy.Useofaninsu-linsecretagogue(sulfonylureaormeglitinide/“glinide”)isnotrecommendedinthisA1Crange.Sulfonylureasmaybemorepotent thanmetformin,TZDs,DPP-4 inhibitors,orAGIs,althoughtheyhavearelativelyshort-livedeffective-nessandareassociatedwithasubstantialriskofhypogly-cemiaandweightgain,especiallyindrug-naïvepatients. The 4 agents recommended for the A1C range of6.5%to7.5%haveaveryminimalriskofhypoglycemia,especiallywhenusedasmonotherapy.TheTZDsrequireseveralweekstoachievemaximalbenefit;likewise,theireffectsdeclineslowlyafter theyhavebeendiscontinued.Inpatientswithclearevidenceofinsulinresistanceortheclinical “metabolic syndrome” and in patientswith non-alcoholic fatty liver disease, TZDsmay be preferred. Ifmonotherapy is unsuccessful in achieving theA1C goalevenafterthedosagehasbeentitratedappropriately,thenoneshouldadvancetodualtherapy.

Dual Therapy Asaresultofitssafetyandefficacy,metforminshouldbethecornerstoneofdualtherapyformostpatients.Whenmetformin iscontraindicated,aTZDmaybeusedas thefoundationforthisgroupofoptions.BecausemetforminoraTZDwillserveasaninsulinsensitizer,thesecondcom-ponentofthedualtherapyisusuallyanincretinmimetic,DPP-4inhibitor,glinide,orsulfonylurea.Theseagentsarerecommended in the following order: incretin mimetic,DPP-4inhibitor,oraninsulinsecretagoguesuchasaglinideand sulfonylurea. The glucagonlike peptide-1 (GLP-1)

agonistandDPP-4inhibitorsaresaferthantheglinideorsulfonylureaoptionswithregardtotheriskofhypoglyce-mia.Despiteitsriskofgastrointestinalsideeffects(whichareusuallytransitory)andtheneedfortwice-dailyinjec-tion,theGLP-1agonistispreferred,inviewofitssome-whatgreatereffectivenessinreducingpostprandialglucoseexcursionsrelativetotheDPP-4inhibitorandthefactthatapproximately 30%of patientswill experience consider-able weight loss. The DPP-4 inhibitors are used orallyoncedailywithexcellenttolerabilityandnomajoreffectsonweight.Glinidesarepreferredrelativetosulfonylureasbecause of the greater need for controlling postprandialglucoseexcursionsinpatientswithanA1Clevelalreadybelow7.5%andtheirrelativesafety.ThecombinationofTZDwithmetforminhasbeenusedextensivelyandiseffi-cacious,butitcarriestherisksoftheadverseeventsasso-ciatedwithbothagents.Werecommendthiscombinationwithahigherprioritythanaglinideorsulfonylureabecauseofalowerriskofhypoglycemiaandgreaterflexibilityintimingofadministration.Onemustconsiderthepotentialadverseeffectsofanyofthesemedicationsastheyapplytoanindividualpatient(seeTable1andAppendix1aswellasdefinitivesourcesofprescribinginformation). Twoadditionalregimensfordualtherapyareincludedin the algorithm: (1) metformin combined with cole-sevelamand(2)metformincombinedwithanAGI.Theseregimensareincludedbecauseoftheirsafety(minimalriskofhypoglycemia)andtheabilityofcolesevelamtolowerthe level of low-density lipoprotein (LDL) cholesterol,althoughthesecombinationsmayproducesomegastroin-testinalsideeffects. Ifdual therapy fails, evenafter eachcomponenthasbeen titrated to itsmaximallyeffectivedose (commonly,only50%to66%oftheFDAupperlimitforrecommendeddosage),onecanadvancetotripletherapyorinstituteinsu-lintherapy.

Triple Therapy Weconsiderthefollowing6optionsfortripletherapy,whicharepresentedinacondensedformatinFigure1:

1. Metformin+GLP-1agonist+TZD2. Metformin+GLP-1agonist+glinide3. Metformin+GLP-1agonist+sulfonylurea4. Metformin+DPP-4inhibitor+TZD5. Metformin+DPP-4inhibitor+glinide6. Metformin+DPP-4inhibitor+sulfonylurea

Becauseofitssafetyandeffectiveness,metforminisselectedas thecornerstone for triple therapy,unlessspe-cific contraindications are present. The GLP-1 agonist,exenatide, is the secondpreferredcomponentbecauseofits safety, with nearly complete absence of hypoglyce-mia attributable to the fact that its stimulationof insulinisdependentonglucose, andbecauseof itspotential for


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Fig. 1.SimplifiedflowchartforAmericanAssociationofClinicalEndocrinologists(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 Definition 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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inducingweightloss.Italsohastheabilitytoinhibitglu-cagonsecretioninaglucose-dependentmanneraftercon-sumptionofmeals, to increase satiety, and todelaygas-tricemptying.Physiciansshouldbeawareofthereportedpossible association of exenatide with pancreatitis andshouldavoiduseofthisdruginpatientswithahistoryofpancreatitis.A recent analysis of a very large database,however, revealednogreater incidenceofpancreatitis inpatientswithdiabetestakingexenatideincomparisonwiththealreadysubstantiallyincreasedincidenceofthisdisor-derinpatientswithdiabetes.Forthethirdmemberofthetriple-therapycombination,onemayselectaTZD,glinide,or sulfonylurea.These agents are recommended inordertominimize the risk of hypoglycemia. The combinationwithmetformin, especiallywhen coupledwith an incre-tinmimetic,may partially help to counteract theweightgain often associated with glinides, sulfonylureas, andTZDs.

Insulin Therapy Whentripletherapyfailstoachieveglycemiccontrol,it is likely that the insulin-secretorycapacityof thebetacellshasbeenexceeded; thus, insulintherapyisneeded.Onecan then institute therapyasbasal,premixed,pran-dial,orbasal-bolusinsulin.Atthispoint,thelistofavail-able agents touseas adjuvants to insulin isdiminished.ExenatideandDPP-4 inhibitorshavenotbeenapprovedbytheFDAforconcomitantusewithinsulin.AgentssuchascolesevelamandAGIsarenotlikelytocontributemate-riallytoeffectiveness.Sulfonylureasandglinidesshouldbediscontinuedwhenprandialinsulinisintroduced,inas-muchaspostprandialexcursionscanusuallybemanagedbetterwitharapid-actinginsulinanalogueorapremixedinsulinpreparation.UseofTZDsjointlywithinsulinhasbeen associatedwith a high probability of weight gain,fluid retention, increased risk of congestive heart fail-ure, and significantly increased risk of fractures both inmen and in women.Although some studies have beencontroversial, recent clinical trials—ADVANCE (16),VADT (17), andACCORD (15)—showed no increasedrisk of mortality associated with rosiglitazone, and thePROACTIVEtrial(19)showedasmallbeneficialeffectofpioglitazoneoncardiacevents.Overall,metforministhemost commonly used and safestmedication to combinewithinsulin.

Basal Insulin: Long-acting basal insulin is gener-ally the initial choice for initiation of insulin therapy intheUnitedStates.InsulinglargineandinsulindetemirarestronglypreferredoverhumanNPHinsulinbecausetheyhave relatively peakless time-action curves and a moreconsistenteffectfromdaytoday,resultinginalowerriskofhypoglycemia.Basal insulintherapyisgenerallyiniti-atedwithasmallarbitrarydose(usually10U)atbedtime.Thedosage is titratedslowly(forexample,an increment

of1 to3U)every2 to3days if thefastingplasmaglu-coselevelreachesthedesiredtarget.Incontrast,thedos-ageisreducedifthefastingplasmaglucosedeclinesbelowanotherspecifiedthreshold. Premixed Insulins:Analternativeapproachtostart-ing insulin therapy is to use premixed insulin analogues(lispro-protamine or aspart-protamine). Onemay initiatetherapy for themajormealof theday (typically, dinner)and subsequently add another injection at the next larg-estmeal.Theinsulindosebeforebreakfastisadjustedbymeasurementoftheglucoselevelbeforedinner;theinsulindosebeforedinner isadjustedprimarilybymeasurementofthefastingglucoseconcentrationonthefollowingday.Useofpremixedinsulingenerallyinvolves2injectionsperdayratherthanthe4injectionsperdayrequiredforbasal-bolus insulin. Ingeneral,however,withuseofpremixedinsulin,thepatientmusthaveafairlyconstantlifestyleandmayhaveahigherriskofhypoglycemia.Ifthepatienthasfailed to achieve goals for glycemiawith use of a basalinsulin regimen, one may institute the premixed insulinregimenwith2injectionsperday. Basal-Bolus Insulin Regimens: In comparisonwithpremixed insulins, a basal-bolus insulin regimen involv-ing 4 injections per day is usuallymore efficacious andprovidesgreaterflexibilityforthosepatientswithvariablemealtimesandcarbohydratecontentofmeals.Ingeneral,before-meal insulin doses for adults can initially be setat about 5Upermeal or about 7%of the daily dose ofbasalinsulin.Thebefore-mealinsulindosecanbetitratedupwardby2to3Uevery2to3daysonthebasisofmoni-toringofthe2-hourpostprandialglucoselevelandtakinginto account the before-meal bloodglucose level for thesubsequentmeal.The dose should be titrated to achievegoodcontrolintermsofboththeA1Clevelandthepre-prandialandpostprandialglycemia.

Pramlintide Pramlintide, an analogue of pancreatic amylin, hasbeen used as an adjunct to prandial insulin therapy inpatientswithtype1diabetesandcanbehelpfulinpatientswith type 2 diabetes for control of postprandial glucose.Thisinvolvesseveraladditionalcarefullytimedinjectionsimmediatelybeforemeals.

Insulin Pump Somepatientswithtype2diabetesusingbasal-bolusinsulintherapybenefitfromuseofaninsulinpump(con-tinuous subcutaneous insulin infusion).An insulin pumpcanprovidemaximalflexibilitywithregardtomealtimes,sizeofmeals,exercise,ortravel.

Continuous Glucose Monitoring Somepatientswithtype2diabetesclearlybenefitfromuseofcontinuousglucosemonitoring(21).Thiscanedu-catethepatientregardingtheglycemiceffectsofvarious


foods,helpthepatienttitrateinsulin,andprovidewarningswhenthepatient isexperiencinghyperglycemiaorhypo-glycemia.Continuousglucosemonitoringshouldbecon-sidered inpatientswith type2diabetes receiving insulintherapywhosediseaseisotherwisedifficulttocontrol.

Self-Monitoring of Blood Glucose Whenapatientbeginsinsulintherapy,SMBGshouldbeincreasedinfrequency.Forpatientsstartingbasalinsu-lintherapyatbedtime,themorningfastingbloodglucoselevels should be determined daily. This same approachappliesforthepatientinitiatingpremixedinsulintherapybefore dinner. For each additional injection of insulin,SMBGshouldbeincreasedinfrequencytoensuresuccess-fultitrationofeachdose.

Reinforcement of Patient Education Advancementtoinsulintherapyisanimportantoppor-tunitytoreinforcepatienteducationwithregardtolifestylemodification, diet, exercise, weight management (weightlossorweightmaintenance),andotheraspectsofdiabeteseducation, including prevention, identification, and treat-mentofhypoglycemia.Onemayalsoreevaluateandpossi-blymodifygoalsfortherapy,reviewtheneedsfortreatmentofothercommonlyassociatedriskfactors(suchashyperten-sion,dyslipidemia,smoking,andstress),andconsiderther-apywithlow-doseaspirin,angiotensin-convertingenzymeinhibitorsorangiotensinreceptorblockers,andstatins.

Management of Patients With A1C Levels of 7.6% to 9.0%

Management of patients with anA1C value in therange of 7.6% to 9.0% is similar to that just described,except that one can bypass the use ofmonotherapy andproceeddirectly todual therapybecausemonotherapy isunlikely to be successful in this group.We recommendsomechanges,however,intheuseofdualtherapyortripletherapy in thisgroupofpatients incomparisonwith thatforpatientswithA1C≤7.5%,inviewoftheneedformoreefficacioustherapy.

Dual Therapy Weconsiderthefollowing5optionsfordualtherapyinpatientswiththisA1Crange(Fig.1):

1. Metformin+GLP-1agonist2. Metformin+DPP-4inhibitor3. Metformin+TZD4. Metformin+sulfonylurea5. Metformin+glinide

Metforminisagainthefoundationoftherapybecauseof its safety,mechanismof action, and insulin sensitiza-tion.Usually,aGLP-1agonistoraDPP-4inhibitoristhepreferred second component, in view of the safety and

efficacy of these agents in combinationwithmetformin.AGLP-1agonist isgivenahigherprioritythanaDPP-4inhibitor,inviewofitssomewhatgreatereffectonreduc-ing postprandial glucose excursions and its potential forinducing substantial weight loss. The lower position ofTZDs is attributable to their associated risks of weightgain,fluidretention,congestiveheartfailure,andfractures.Sulfonylureasandglinidesarerelegatedtothelowestposi-tionbecauseof theirgreater riskof inducinghypoglyce-mia.Therelativepositionsforsulfonylureasandglinidesare reversed in comparison with their positions in dualtherapy for patientswithA1C values ≤7.5%.There is aneedforthegreaterglucose-loweringefficacyofsulfonyl-ureasintheA1Crange7.6%to9.0%.

Triple Therapy WhendualtherapydoesnotachievetheA1Cgoal,athirdagentshouldbeadded.TheoptionsfortripletherapyforpatientswithanA1CinthisrangearesimilartothoserecommendedforpatientswithlowerA1Cvalues.Wecon-siderthefollowing5options:

1. Metformin+GLP-1agonist+TZD2. Metformin+DPP-4inhibitor+TZD3. Metformin+GLP-1agonist+sulfonylurea4. Metformin+DPP-4inhibitor+sulfonylurea5. Metformin+TZD+sulfonylurea

Metformin is the foundation towhich either aTZDorsulfonylureaisadded,followedbyincretin-basedther-apy—either a GLP-1 agonist or a DPP-4 inhibitor. ThepreferenceformetforminandtheGLP-1agonistorDPP-4inhibitor is based on their safety, in view of theirmini-mal associated risks of hypoglycemia. Similarly, TZDsareassignedaprioritygreaterthanthatforasulfonylureabecauseoftheirlowriskofhypoglycemia.AGLP-1ago-nistisgivenahigherprioritythanaDPP-4inhibitorowingto its somewhat greater effect on reducing postprandialglucoseexcursionsandthepossibilitythatitmightinduceconsiderableweightloss.Thecombinationofmetformin,TZD,andsulfonylurea is relegated to the lowestprioritybecauseof its increasedriskofweightgainfor thecom-binationofTZDsandsulfonylureasandtheriskofhypo-glycemia,particularlyforpatientsatthelowerendofthisA1Crange(~7.5%).Glinides,AGIs,andcolesevelamarenotconsideredinthisA1Crange,inviewoftheirlimitedA1C-loweringpotential.

Insulin Therapy Theconsiderationsforinsulintherapyforpatientswitha currentA1Cof 7.6% to9.0%are similar to thosedis-cussedpreviouslyforpatientswithanA1Clevelof6.5%to 7.5%. When transitioning to insulin from a regimeninvolvingtripletherapy,itiscustomarytodiscontinueoneormoreoftheorallyadministeredagents.UseofTZDsor


ofsulfonylureasconjointlywithinsulinisassociatedwithariskofweightgainandfluidretention.Inpatientsatrisk,TZDsmaycauseoraggravatecongestiveheartfailure,andtheyincreasetheriskofbonefracturesinbothwomenandmen(22,23).NeitherGLP-1agonistsnorDPP-4inhibitorshavebeenapprovedbytheFDAforusewithinsulin.Thus,metformin is the onlymedicationwith a relatively clearindication for use in conjunctionwith insulin in patientswithtype2diabetes.Ifitbecomesclearthatapremixedorabasal-bolusinsulinregimenisrequiredtoachieveglyce-micgoals, insulin secretagogues shouldbediscontinued.Useofpramlintide should alsobe considered inpatientswithpersistentpostprandialhyperglycemia.

Management of Patients With A1C Levels of >9.0%

Combination Therapy Fordrug-naïvepatientswithA1Clevelsof>9%,itisunlikelythatuseof1,2,oreven3agents(otherthaninsu-lin)willachievetheA1Cgoalof≤6.5%.Ifthepatientisasymptomatic,particularlywitharelativelyrecentonsetofdiabetes,agoodprobabilityexistsforpreservationofsomeendogenousbeta-cellfunction,implyingthatdualtherapyortripletherapymaybesufficient.Weconsiderthefollow-ing8options:

1.Metformin+GLP-1agonist2.Metformin+GLP-1agonist+sulfonylurea3.Metformin+DPP-4inhibitor4.Metformin+DPP-4inhibitor+sulfonylurea5.Metformin+TZD6.Metformin+TZD+sulfonylurea7.Metformin+GLP-1+TZD8.Metformin+DPP-4inhibitor+TZD

Metforminprovides the foundation.Onecanaddanincretin-basedtherapy(GLP-1agonistorDPP-4inhibitor).Itmaybepreferable touse aGLP-1 agonist, in viewofitsgreatereffectivenessatcontrollingpostprandialglyce-miaanditspotentialforinducingweightloss.TheDPP-4plus metformin combinations have also demonstrated arobust benefit for drug-naïve patients in thisA1C range.Inturn,onecanaddeitherasulfonylureaoraTZD.Thesulfonylurea is preferred here because of its somewhatgreaterefficacyandmorerapidonsetofaction.Incontrast,ifthepatientissymptomaticwithpolydipsia,polyuria,andweight loss, or if the patient has already been receivingtreatmentandregimenssimilartotheaforementionedoneshavefailed,thenitisappropriatetoinitiateinsulintherapywithoutdelay.

Insulin Therapy InsulintherapyforpatientswithA1Clevelsexceeding9.0% follows the same principles as outlined previously

forpatientswithA1Cvaluesof≤9.0%.Onecanprescribebasalinsulin,premixedinsulins,orbasal-bolusinsulin.

Reversal of Glucotoxicity and Lipotoxicity Insulin therapy,properly instituted,should lower theA1Cleveltoclosetothegoalof6.5%.Intheprocess,itis likely that the effects of glucotoxicity and lipotoxic-ityon thesecretorycapacityof thebetacellwouldhavebeen reduced or nearly eliminated.Hence, after one hasachievedameaningfulreductioninA1Ctoalevelbelow7.5%withuseofinsulintherapy,onemaythenattemptuseofdualtherapy(asdescribedintheforegoingmaterial)asanadjuvanttoinsulintherapy,withconcomitantreductionofinsulintominimizetherisksofhypoglycemicevents.Iftheseeffortsaresuccessful,onecanthenattempttodiscon-tinuetheuseofinsulintherapyandconsiderdualtherapyortripletherapy. The AACE/ACE Glycemic Control AlgorithmConsensus Panel has constructed a carefully consideredrationaleforthechoiceofeachoftheregimensinFigure1andfortheirorderofpresentation.Thesechoices,however,arebasedongeneralprinciplesandstatisticalaveragesforlargegroupsofpatientsorbasedonmeta-analysesoflarge-scale studies.Whenmanaging the individualpatient, thephysician must exercise judgment to weigh the benefitsandrisks,or theprosandcons,ofeachof theseoptions.Abriefusefuloverviewofsomeofthecoreconsiderationsfor selectionof agentsor combinationsof agents is pro-vided inTable1.This table is not intended tobe a sub-stituteforacomprehensivereviewofFDA-approvedpre-scribinginformation.

Hypoglycemia Perhaps themost important guidingprincipleof ourcurrentalgorithm is the recognitionof the importanceofavoiding hypoglycemia (24-28). Severe hypoglycemiastimulates sympathetic adrenergic discharge, causingarrhythmiasorautonomicdysfunction (orboth), andhaslongbeenrecognizedtohavepotentialforcausingmortal-ity.Hypoglycemiamayhaveasubstantialnegativeclinicaleffect,intermsofmortality,morbidity,adherencetother-apy,andqualityoflife(24).Therecentlyreportedclinicaltrials of intensive therapy—ACCORD,ADVANCE, andVADT(15-17,20,29)—haveshownthatintensiveglycemiccontrolwasassociatedwitha3-to4-foldincreaseintheincidenceofhypoglycemia.IntheACCORDstudy,iatro-genichypoglycemiawasassociatedwithexcessmortalityinboththeintensivelytreatedgroupandtheconventionallytreatedgroup(20,29).Theriskofhypoglycemiaincreaseswithadvancingageanddurationofdiabetes,thedurationofinsulintherapy(24,28),coexistingseverecomorbidities,andthepresenceofhypoglycemiaunawareness. Insulin and sulfonylurea are the agents that mostcommonly cause hypoglycemia. The incidence of


hypoglycemia in insulin-treatedpatientswith type2dia-betesisonlyone-thirdthatinpatientswithtype1diabetes(27).The incidenceofhypoglycemianecessitatingemer-gency medical treatment in insulin-treated patients withtype2diabetesapproachesthatobservedforpatientswithtype1diabetes.Theglinides,repaglinideandnateglinide,areassociatedwithalowerriskofhypoglycemia,presum-ablybecauseofamorephysiologictimecourseofactioncombined with somewhat lower efficacy in comparisonwithsulfonylureas. For some patients, the risk of hypoglycemia maywarrant specific choices of therapy and reevaluation oftherapeuticgoals.Thesepatients include thosewhohaveadurationofdiabetesgreaterthan15yearsandadvancedmacrovascular disease, hypoglycemia unawareness, lim-itedlifeexpectancy,orotherseriouscomorbidities.

DISCUSSION

Thecurrentalgorithm(Fig.1)wasdevelopedtoassistprimary care physicians, endocrinologists, and others inthemanagementofpatientswith type2diabetes. In thisalgorithm,weconsiderallclassesofeffectivedrugs.Weemphasizesafetyandthequalityofglycemiccontrolasourfirstpriorities.Accordingly,wehavegiven sulfonylureasmuch lessprioritybecauseuseof theseagents is associ-atedwithhypoglycemia,weightgain,andlimiteddurationofeffectivenessafterinitiationoftherapy.PlacinggreateremphasisonsafetyandabilitytoachieveanA1Cgoalof6.5%will result in earlier andmore frequent use of theincretin-based therapies—the GLP-1 agonists (incretinmimetics)andtheDPP-4inhibitors.Atpresent,onlyoneGLP-1agonist(exenatide)isavailable.TwoDPP-4inhibi-tors(sitagliptinandsaxagliptin)arenowavailable.Onthebasisofthelevelofongoingresearchwiththese2classesofagents,itislikelythatseveralnewagentswillbecomeavailable during the next few years. Our algorithm uti-lizes4typesofmonotherapy,9typesofdualtherapy,and6 types of triple therapy.We consider 5 types of insulintherapy (basal,premixed,prandial,basal-bolus, andcon-tinuoussubcutaneousinsulininfusion),eachofwhichcanbecombinedwithavarietyoforallyadministeredagentsorwithpramlintide. Thisalgorithmforglycemiccontrolhasthefollowingfeatures:

1. ItfavorstheuseofGLP-1agonistsandDPP-4inhibi-torswithhigherprioritybecauseoftheireffectivenessand overall safety profiles. In view of the millionsofpatientswhohavebenefitedfromtheuseoftheseagentsandtheirexcellentperformanceinawiderangeof clinical studies, in combinationwith the growing

literature indicating the serious risks of hypoglyce-mia,theseagentsareincreasinglypreferredformostpatientsinplaceofsulfonylureasandglinides.

2. Itmovessulfonylureastoalowerprioritybecauseoftheassociatedrisksofhypoglycemia,weightgain,andthefailureoftheseagentstoprovideimprovedglyce-miccontrolafteruseforarelativelyshortperiod(1to2yearsintypicalpatients).

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

4. ItincludesTZDsas“well-validated”effectiveagentswithdemonstratedextendeddurabilityofaction,butwithalowerpriorityformanypatientsinlightoftheirpotential adverse effects, especiallywhenTZDs areusedincombinationwithsulfonylureasorinsulin,andtherecentconfirmationofpreviousreportsofasignifi-cant increase in bone fractures associatedwith theiruseinbothmenandwomen(22,23).

5. It considers 3 other classes of agents (AGIs, cole-sevelam, and glinides) only for relatively narrow,well-definedclinical situations, inviewof their lim-itedefficacy.TheLDLcholesterol-loweringpropertyofcolesevelamisabeneficialfactor.

This algorithm is intended to provide guidance.Individual institutions, clinics, and physiciansmaywanttomodifyittoincorporatetheirownexperienceandpref-erences, the nature of their patient populations, second-aryconsiderationssuchastheavailabilityofmedicationsin their local formulary, and costs. Theymay also wishto reconsider the choice of agents for inclusion in theirformulary.

CONCLUSION AND RECOMMENDATIONS

Thecurrentalgorithmisintendedforuseinconjunc-tionwithamoredetailedandcomprehensiveguideline—for example, theAACEDiabetesGuidelines (1) and theACE/AACE Road Maps to Achieve Glycemic Control(10)—andwith comprehensive sets of prescribing infor-mationandacompendiumofdrug-druginteractions.Thisalgorithmrepresentsasignificantadvancerelativetomostoftheotheravailable“treatmentpathways”(3-9)byvirtueof its inclusiveness, rationale and justification, emphasisonsafety,documentationofsupportingevidence,simplic-ity,andanticipatedeaseofimplementation.Thisalgorithmprovidesafoundationthatcanbemodifiedinthefutureasnewmedicationsandclassesofmedicationsbecomeavail-ableorasnewdatabecomeavailableregardingthesafety,adverseevents, efficacy, and long-termoutcomesassoci-atedwiththemedications.


APPENDIX 1

OVERVIEW OF THERAPEUTIC AGENTS

Physicians should consult the complete prescribinginformation and the general literature (for example, 30).Thefollowingmaterialisofferedasabriefreview,apré-cis.Asummaryoverviewoftheprincipalbenefitsandrisksof the therapeuticagentsused formanagementof type2diabetesispresentedinTable1(maintext).Furtherdetailsareprovidedinthefollowingtext.

Metformin Metformin is a biguanide that improves the effec-tivenessof insulin in suppressingexcesshepaticglucoseproduction,inboththefastingandthepostprandialstate.Metformindecreasesexcessivehepaticglucoseproductionin thefastingstateprimarilybydecreasinggluconeogen-esis and, to a lesser extent, by decreasing glycogenoly-sis. Insulin suppression of hepatic glucose production isenhanced in the postprandial state. Thus, metformin iseffectiveindecreasingbothfastingandpostprandialglu-cose concentrations. Decreased gastrointestinal glucoseabsorption, increased insulin sensitivity inperipheral tis-sues, and enhanced synthesis ofGLP-1mayhaveminorroles.Metformin often has beneficial effects on compo-nentsofthemetabolicsyndrome,includingmildtomod-erate weight loss, improvement of the lipid profile, andimprovedfibrinolysis. Metformin is effective asmonotherapy and in com-bination with other antidiabetic agents, including sulfo-nylureas,TZDs,AGIs,DPP-4inhibitors,GLP-1agonists,andpramlintide. Itcanalsobeused incombinationwithinsulin.Becauseofitrelativelyshortdurationofaction,itisusuallyadministered2to3timesdailyandisbesttoler-atediftakenwithmeals.Along-acting,once-dailyformu-lationisalsoavailable.Themaximalrecommendeddosageis2,500mgdaily,althoughlittleadditionalbenefitisseenwithdosagesexceeding2,000mgdaily. Sideeffectsincludeametallictaste,anorexia,nausea,abdominalpain,anddiarrhea.Thesesymptomsaremini-mizedbyinitiatingtherapyatalowdosageof500mgdailyand gradually increasing to the maximal effective dose.Gastrointestinalsideeffectsusuallydiminishwithcontin-ueduse,althoughsomepatientsdonottoleratemetforminwellanddiscontinuethemedicationorfailtoachievefullyeffectivedoses. Lacticacidosisisanextremelyrarebutseriouscom-plicationofmetforminuse.Becausemetforminisprimar-ilyexcretedby thekidneys, impairedrenal functionmayresult in excessive plasma concentrations of metforminandpredisposetolacticacidosis.Therefore,impairedrenalfunctionisacontraindicationforuseofmetformin.Inclin-icalpractice,thisisdefinedasaplasmacreatinineconcen-trationof≥1.5mg/dLformenand≥1.4mg/dLforwomen

oracreatinineclearanceof<60mL/min.Metforminisalsocontraindicated in patientswho are at increased risk forlacticacidosisbecauseofotherconditions—forexample,patientswithcongestiveheartfailurerequiringpharmaco-logicmanagement,elderlypatientswithdecreasedcreati-nineclearance,activeliverdisease,chronicalcoholabuse,orsepsis,orpatientswhohaveotheracuteillnesseswithanassociatedriskofdecreasedtissueperfusionorhypoxemia.Metformin is also contraindicated during intravenousadministration of radiographic contrast material, whichmayimpairrenalfunction. Whenusedasmonotherapy,metforminhasaverylowriskofhypoglycemia.Whenmetforminisusedincombi-nationwith an insulin secretagogue or insulin, however,hypoglycemiamay occur.Another rare adverse effect ofmetforminismegaloblasticanemiaduetoimpairedabsorp-tionofvitaminB12.Thiscanbepreventedbyadministra-tionofvitaminB12.

Insulin Secretagogues Insulin secretagogues include the sulfonylureas,repaglinide, and nateglinide. Sulfonylureas stimulate thedelayed,secondphaseofinsulinsecretionaftermealinges-tionandhavelittleeffectonfirst-phaseinsulinsecretion.Thesecharacteristicsmayresultinfastingorlatepostpran-dialhypoglycemia,whichisthemostsevereadversesideeffectofthesulfonylureas. Repaglinide has a more rapid onset of action and ashorterdurationofactionincomparisonwiththesulfonyl-ureas.Thesefeaturesresultinearlierinsulinsecretionandasomewhatdecreasedriskoflatepostprandialhypoglycemia.Forachievementofmaximalbenefits,however,administra-tionbeforeeachmeal isnecessary.Nateglinidealsohasarapidonsetofactionandashortduration,increasesboththefirstandsecondphasesofinsulinsecretion,andisprimarilyglucosedependentinitsaction.Likerepaglinide,itsmajoreffectistoreducepostprandialhyperglycemia,anditshouldbe administered before eachmeal.Most of the beneficialeffects of insulin secretagogues are achieved at submaxi-maldoses,andifadequateglucosecontrolisnotachieved,addingasecondagentofadifferentclassisgenerallymoreeffective than increasing the insulinsecretagogues to theirmaximaldosagelevel.Thedurabilityofeffectivenessofsul-fonylureasislessthanwithTZDsorAGIs. The major side effect of sulfonylureas is hypogly-cemia.Thisoccursmorecommonlywith the long-actingsulfonylureas, chlorpropamide and glyburide, than withshorter-actingcompounds.Mildtomoderateweightgainisfrequentlyobserved.Whensulfonylureasareusedincom-binationwithinsulinorTZDs,risksofweightgain,fluidretention,andcongestiveheartfailureareincreased.

Thiazolidinediones The TZDs first became available for treatment ofpatientswith type2 diabetes in themid-1990s.Thefirst


approved TZD, troglitazone, was associated with rarecasesof liverdamage, leading to liver failureanddeath;therefore,itsusewasdiscontinuedapproximately10yearsago.ThecurrentlyavailableTZDs,pioglitazoneandrosi-glitazone, are effective insulin-sensitizing agents. Theseagents increase the insulin sensitivityof skeletalmuscle,adiposetissue,and,toalesserextent,theliver,resultinginincreased insulin-stimulated glucose uptake andmetabo-lismandimprovedinsulin-mediatedsuppressionofhepaticglucoseproduction.Theyalsostimulate theformationofpre-adipocytes inperipheral adipose tissue, accompaniedby decreases in ectopic fat deposition, plasma free fattyacidconcentration,andinsulinresistance. When used asmonotherapy or in combinationwithother antidiabetic agents (including insulin), TZDs areeffectiveindecreasingbothfastingandpostprandialglu-coseconcentrations.Whenusedasmonotherapy,theydonotcausehypoglycemia.WhenTZDsareusedwithinsu-lin secretagoguesor insulin, however, hypoglycemia canoccur.Themajorsideeffectof theTZDs isweightgain,duetobothincreasedadiposetissuemassandfluidreten-tion.Peripheral edemaoccurs in somepatients and typi-cally responds poorly to loop diuretics and angiotensin-convertingenzymeinhibitors.Mildanemiamayoccur. TheTZDsnotonlyareeffectiveinthemanagementofhyperglycemiabutalsohavebeneficialeffectsonthelipidprofile, with lowering of plasma triglycerides, increas-ing the level of high-density lipoprotein cholesterol, anddecreasing small, denseLDLcholesterol.The associatedweight gain and fluid retention, however, may precipi-tate congestive heart failure. In patients with NewYorkHeartAssociation class III or class IV congestive heartfailure, TZDs are contraindicated.Weight gain can be amajorproblemforpatientswhoareoverweightorobese.An extensive but highly controversialmeta-analysis andoneprematurelyabortedstudy(ACCORD)suggestedthepossibility of increasedmortality associated with use ofrosiglitazone.Subsequentmoredefinitive analyses, how-ever,haveindicatedthatrosiglitazonehasnoeffect,posi-tiveornegative,oncardiovascularortotalmortality.ThePROACTIVEprospectivestudyshowedamodestreduc-tion of cardiovascular end points associatedwith use ofpioglitazone(19).A1.5-to2.5-foldincreasedriskofbonefractures has been documented in bothmen andwomenusingTZDs(22,23).

a-Glucosidase Inhibitors TheAGIs,acarboseandmiglitol, inhibit theconver-sionofoligosaccharidesintomonosaccharidesattheintes-tinalbrushborderandtherebydecreasetheriseinplasmaglucoseconcentrationsafter ingestionof complexcarbo-hydrates.AlthoughthemaineffectofAGIsistodecreasepostprandialhyperglycemiainpatientswithtype2diabe-tes, their use is also associatedwith a slight decrease infasting glucose concentrations. This change is probably

attributable to an overall improvement in glycemic con-trol and reductionofglucose toxicity.Theyareeffectiveas monotherapy or in combination with other antidia-beticagents,particularlyifthedietcontainsatleast50%carbohydrate. The major side effects ofAGIs are gastrointestinaland include abdominal discomfort, increased formationofintestinalgas,anddiarrhea.Theseadversegastrointes-tinaleffectsareduetoexcessiveamountsofcarbohydratereaching the large intestineandundergoingbacterial fer-mentation.Acarboseisnotsubstantiallyabsorbedfromthegastrointestinaltract,whereasmiglitolisabsorbedrapidlyandexcretedbythekidneys.Acarbose,however,ismetab-olizedbybacterialactioninthecolon,anditsmetabolitesareabsorbed,conjugated,andexcretedinbile.Rarecasesofcholestatic jaundicehavebeen reported.Effectivenessismoderate in people consuming a typicalWestern diet,andAGIsaremosteffectivewhenthedietcontainslargeamountsofcomplexcarbohydrates,asistypicalofmanyAsian diets. The risk of hypoglycemia isminimalwhenAGIsareusedasmonotherapy.HypoglycemiamayoccurwhenAGIsareusedincombinationwithinsulinsecreta-goguesorinsulintherapy.Whenhypoglycemiadoesoccur,it must be treated with glucose, inasmuch as digestionandabsorptionofsucroseandcomplexcarbohydratesareinhibitedbythesedrugs.

Dipeptidyl-Peptidase-4 Inhibitors TheDPP-4inhibitorsdecreasethemetabolismoftheincretinhormones,GLP-1andgastricinhibitorypolypep-tide,by inhibitionof theDPP-4enzyme,which removesthe2end-terminalaminoacidsandcausesrapidinactiva-tionofthesegastrointestinalhormones.ActiveGLP-1andgastricinhibitorypolypeptideplasmalevelsareincreasedapproximately2-foldaftermealingestion.Thisresultsinincreasedfirst-phaseinsulinsecretion,suppressionofglu-cagon secretion in the postprandial state, and improvedsuppressionofhepaticglucoseproductionandperipheralglucoseuptakeandmetabolism.Hepaticglucoseproduc-tionisalsodecreasedinthefastingstate;theresultislowerfasting plasma glucose concentrations. Thus, the DPP-4inhibitorsdecreaseboth fastingandpostprandialglucoselevels.Inclinicaltrials,theyhaveeffectivenesssimilartothatofmetforminand sulfonylureas.Because theeffectsofGLP-1 on insulin and glucagon secretion are glucosedependent, there is insignificant risk of hypoglycemiawhen it is used asmonotherapy or in combinationwithmetforminoraTZD.ThecurrentlyavailableDPP-4inhibi-tors,sitagliptinandsaxagliptin,areconvenientlyadminis-teredoncedaily.Sitagliptin is eliminatedalmost entirelyby the kidneys; its dosagemust be reduced for patientswith moderate or severe renal insufficiency. Saxagliptinis likewise primarily excreted by the kidneys but is alsosubjecttohepaticmetabolism;itsdosagemustbereducedonlyinsubjectswithsevererenalinsufficiency.Nomajor


long-termtoxicitieshavebeenreported.Rareallergicreac-tionshavebeendescribed.

Long-Acting GLP-1 Analogues Currently, one long-term GLP-1 analogue is avail-ableforclinicaluse,althoughseveralothersareinvariousstagesofdevelopmentandmaybecomeavailable in thenearfuture.Thecurrentlyavailablecompound,exenatide,isabiosyntheticversionofasalivarypeptidefromaliz-ard,theGilamonster.Exenatidehasapproximately50%homologytohumanGLP-1butishighlyresistanttoinac-tivationbytheDPP-4enzyme.ThebindingofexenatidetothehumanGLP-1receptorresultsinglucose-dependentstimulation of insulin secretion and glucose-dependentsuppressionofglucagonsecretion.Exenatideisadminis-teredbyinjectiontwicedailyandiseffectiveindecreas-ingbothfastingandpostprandialplasmaglucoseconcen-trations.Exenatidehascentralnervoussystemeffects toreduceappetiteandincreasethesenseofsatiety;theout-comeisdecreasedfoodintakeandweightloss.Themajorsideeffectsaregastrointestinal,withnauseaandvomitinginsomepatients.Theseeffectsaredoserelatedandusu-allywaneover time.Exenatide is administeredat a lowdosage (5µg twicedaily) for thefirst 4weeksof treat-mentandthenincreasedtoahigherdosage(10µgtwicedaily) after the gastrointestinal side effects have abated.Overalleffectivenessisgenerallyverygoodwhenexena-tideisaddedtosingle-ordual-agentregimensinvolvingmetformin, sulfonylureas,orTZDs.Currently,exenatideisnotapprovedforuseasmonotherapyorincombinationwithinsulin. Additionaleffectsthathavebeenobservedwithlong-actingGLP-1agonistsaresubstantialreductionsinplasmatriglyceride levels, diminished liver fat content, anddecreasedsystolicanddiastolicbloodpressures.Towhatextentthesearedirecteffectsofthedrugsorareattribut-abletoweightlossisnotyetclear.

Bile Acid Sequestrants Colesevelamisabileacidsequestrantusedprimarilyto treat hypercholesterolemia, either as monotherapy orin combinationwith hydroxymethylglutaryl-coenzymeAreductase inhibitors.Colesevelamalso reduces thebloodglucoselevelinpatientswithtype2diabetesmellitus,par-ticularly in persons inadequately controlledwithmetfor-min, a sulfonylurea, or insulin.Themajor side effect ofcolesevelamisconstipation;thus,itshouldnotbeusedinpatientswithgastroparesisorothergastrointestinalmotil-itydisorders,inpatientsaftermajorgastrointestinalsurgi-calprocedures,andinothersatriskforbowelobstruction.Othersideeffectsincludeanincreaseinthelevelofserumtriglycerides and possible malabsorption of fat-solublevitamins.

Pramlintide Pramlintideisasyntheticanaloguethatexhibitsmanyofthepropertiesofthenaturalbeta-cellhormone,amylin.When injected preprandially, pramlintide lowers plasmaglucagon, delays gastric emptying, and promotes satiety.Themajor effects are todecreasepostprandial hypergly-cemiaandfacilitateweight loss.Pramlintidecanbeusedeffectively in the treatmentofobesepatientswith type2diabeteswho use before-meal insulin injections,with orwithout orally administered antidiabetic agents.The rec-ommendedstartingdose is60µg (10U) injected imme-diately before themainmeal; some patients tolerate themedicationbetterwithaninitialstartingdoseof30µg(5U)beforemeals.Thedoseshouldthenbetitratedgraduallyto120µg(20U),astolerated.Themajorsideeffectisnau-sea,whichgenerallywaneswithcontinuedadministration.Pramlintide decreases postprandial glycemic excursionsandincreasessatiety.Thedosageofthepreprandialrapid-actinginsulinmayneedtobereducedandthetimeofitsadministrationmayneedtobedelayedtocompensatefortheexpectedreducedfoodintakeanddelayedgastricemp-tyingassociatedwithpramlintide therapy.Hypoglycemiamay also occur if pramlintide is used in combinationwithasulfonylurea,anddosagesmayneedtobeadjustedappropriately.

Insulin Weconsidernine typesof insulin (TableA1).Thesecanbeadministeredinanyofseveralregimens(TableA2).Exogenousinsulinprovidesreplacementforthedeficiencyofthenaturalhormone.

Physiology Normally, insulin is delivered to theportal vein andthus reaches the liver within seconds. When insulin isadministeredsubcutaneously,averylengthydelayensuesbeforeitdissociatesfromhexamertomonomerandisthenabsorbedintothecirculation.Accordingly,regularhumaninsulin administered subcutaneously does notmimic thenormalkineticsanddynamicsofendogenous insulin.Asaresult,regularhumaninsulindoesnotprovideadequateeffectforcontrolofpostprandialglycemicexcursionsandhasapropensitytocausedelayedhypoglycemia.

Rapid-Acting Insulin Analogues Therapidlyactinginsulinanalogueslispro,aspart,andglulisinehaveatimecourseofactionthatcloselymimicsthenormalphysiologicfeatures.

Premixed Insulins Bothinsulinlisproandinsulinaspartareavailableinmixtureswithprotamine.Thesepremixedinsulinsprovidea time course that is suitable for coverage for breakfast


and lunch or for dinner and the overnight period.Thesemixturesor“biphasicinsulins”donotresultin2discretepeaks.Instead,thereisasinglemaximumatapproximately1.5hours, followedbyaslowdecline.Accordingly, theydonotmimicthenormalphysiologicprocessesandarenotaseffectiveasafullyoptimizedbasal-bolusregimenwithuseof rapidlyacting insulinanaloguesanda long-actinginsulinanalogue.UseofmixturesofregularhumaninsulinandNPHinsulinisnotrecommendedbecausethemaximalactivitydoesnotoccuruntilapproximately2to2.5hoursafterinjection.

Basal Insulin NPHinsulinshowswidevariabilityinitsabsorptionrate fromday to day, evenwithin individuals, and doesnothaveasufficientlylongtimecoursetoprovideabasalinsulinization for a 24-hour period. It has a pronounced

peak at approximately 9 hours. Accordingly, the long-actinginsulinanaloguesglargineanddetemirarestronglypreferred. The various types of insulin regimens as shown inTableA2arediscussedinthemainbodyofthetext.

Drug-Drug Interactions Thiazide diuretics, niacin, and b-adrenergic block-ing agents are well known to impair glucose homeosta-sis (31). Systemic administration of glucocorticoids canseverely impair glucose tolerance. One should be cau-tiouswheninitiatingtherapywiththeseagentsinpatientswith diabetes and should anticipate an increased risk ofhypoglycemiawhenone of these agents is discontinued.Angiotensin-convertingenzymeinhibitorsandangiotensinreceptorblockershavedemonstratedbeneficialmetaboliceffects.

Table A1Outline of Various Types of Insulin

Type of insulin Trade name Comment

Rapid-acting insulin analogues Aspart NovoLog Superiortoregularhumaninsulinintermsofmore Lispro Humalog rapidactionprofilewithreducedriskofhypoglycemia Glulisine Apidra 2-5hoursafteramealorovernight

Premixed insulin/protamine Aspart+aspart-protamine NovoLogMix Usuallyusedtwiceadaybeforebreakfastanddinner; Lispro+lispro-protamine HumalogMix providespostprandialcoveragewith2injectionsper day;lessflexiblethanuseofbasal-bolustherapywith acombinationofrapid-actingandlong-acting analogues

Long-acting insulin analogues Glargine Lantus Canbeusedwith1injectionperdayinpatientswith type2diabetes Detemir Levemir Canbeusedwith1injectionperdayinpatientswith type2diabetes;excellentreproducibilityofabsorption profilewithinindividuals;possiblylessweightgain thanwithotherinsulins

Not recommended Regularhumaninsulin HumulinR Onsetofactionistooslowandpersistenceofeffectis NovolinR toolongtomimicanormalprandialphysiologic profile;theresultisimpairedefficacyandincreased riskofdelayedhypoglycemia NPHinsulin HumulinN Doesnotprovideasufficientlyflat“peakless”basal NovolinN insulin;highlyvariableabsorptionevenwithin individuals;increasedriskofhypoglycemiacompared withthelong-actinginsulinanaloguesglargineor detemir


Combineduseofany2agentsthatareindependentlycapable of producing hypoglycemia is likely to increasetheriskofhypoglycemia.Accordingly,itiscustomarytoreduce the dosage of one or both agentswhen a secondagentisaddedandtoproceedcautiously.Themostimpor-tantinteractionsofantidiabeticagentsarethoseamongsul-fonylureas,TZDs,andinsulin;combineduseofany2orall3oftheseagentsmayresultinincreasedriskofweightgain,retentionoffluid,andhypoglycemia. The combination drug trimethoprim-sulfamethoxa-zolehasbeenassociatedwitha6.6-foldincreasedriskofhypoglycemia(32),andcasereportsofextremehypogly-cemiahavebeenreported.The“floxacin”antibioticshavebeenassociatedwithasmallriskofhyperglycemiaandanevensmallerriskofhypoglycemia(33). Thereisastronginteractionofgemfibrozilwithrepag-linide and TZDs, resulting in considerable elevation ofplasma levels of repaglinide (34) or TZDs. Fortunately,gemfibrozil is now less commonly used than in the pastformanagementofdyslipidemia.Sulfonylureasaremetab-olized by CYP2C9. Thus, agents that induce or inhibitCYP2C9canpotentiallyaffectthemetabolismofsulfonyl-ureas.Majordrug-druginteractionshavenotbeenreportedfornateglinide. Metforminiseliminatedbytubularsecretionandglo-merular filtration. Metformin may potentially competewith other cationic drugs, such as cimetidine, for renalsecretion(35).Inprinciple,rosiglitazoneandpioglitazonemetabolismcouldbeaffectedbyinhibitorsorinducersofCYP2C8,but substantialdrug-drug interactionshavenotbeenreported(36,37). Acarbose andmiglitol do not appear to have appre-ciablemetabolic interactions.Thesedrugs are associatedwithasmalldecreaseintheabsorptionofdigoxinandanincreaseinabsorptionofwarfarin(38,39).Exenatidemay

slowabsorptionofsomemedications,suchasacetamino-phenanddigoxin.Theredonotappeartobeanyimportantmetabolicinteractionsforsitagliptin.

ACKNOWLEDGMENT

JeffreyHolloway provided excellent assistancewiththe development of the graphic display of the algorithm(Fig.1).Dr.DavidRodbardprovidedvaluableassistancewith the preparation of the manuscript. Dr. Zachary T.Bloomgarden made important contributions to Table 1.Lori Clawges provided excellent administrative supportfortheAlgorithmConsensusPanel.

DISCLOSURE

Dr. Helena W. Rodbard reports that she hasreceived consultant honoraria fromAbbott Laboratories,AstraZeneca Pharmaceuticals LP, Biodel Inc.,GlaxoSmithKline, MannKind Corporation, Merck &Co., Inc., Novo Nordisk Inc., sanofi-aventis U.S., andTakeda Pharmaceuticals America, Inc, speaker hono-raria from Amylin Pharmaceuticals, Inc., AstraZenecaPharmaceuticals LP, Bristol-Myers Squibb Company,GlaxoSmithKline, Eli Lilly and Company, Merck& Co., Inc., Novo Nordisk Inc., and sanofi-aventisU.S., and research grant support from Biodel Inc.,MacroGenics,Inc.,NovoNordiskInc.,andsanofi-aventisU.S. Dr. Paul S. Jellinger reports that he has receivedspeakerhonorariafromAmylinPharmaceuticals,Inc.,EliLilly and Company,Merck & Co., Novo Nordisk, Inc.,sanofi-aventisU.S.andTakedaPharmaceuticals,Inc.,andconsultanthonorariafromDaiichiSankyo,Inc.,MannKindCorporation,andTethysBioscience.

Table A2Summary 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


Dr. Jaime A. Davidson reports that he has receivedconsultant honoraria from Bristol-Meyers SquibbCompany, Calisto Medical, Inc., CureDM, Inc.,Daiichi Sankyo, Inc., Eli Lilly and Company, GenerexBiotechnology Corp., GlaxoSmithKline, MannKindCorporation,Merck&Co.,Novartis,NovoNordiskInc.,Pfizer Inc., Roche Pharmaceuticals, sanofi-aventis U.S.,andTakedaPharmaceuticals, speaker honoraria fromEliLilly and Company, GlaxoSmithKline, Merck & Co.,Novo Nordisk, Inc., sanofi-aventis U.S., and TakedaPharmaceuticals,andresearchgrantsupportfromEliLilly& Company, GlaxoSmithKline, MannKind Corporation,Novartis,andNovoNordiskInc. Dr. Daniel Einhorn reports that he has receivedconsultant honoraria fromAmylin Pharmaceuticals, Inc.,Eli Lilly and Company, MannKind Corporation, NovoNordisk Inc., and Takeda PharmaceuticalsAmerica, IncandresearchgrantsupportfromAmylinPharmaceuticals,Inc., Eli Lilly and Company, Novo Nordisk Inc., andsanofi-aventis U.S. and is a stockholder with HalozymeTherapeutics,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-MyersSquibbCompany,GlaxoSmithKline,Merck&Co., Inc.,MetabasisTherapeutics, Inc.,NovoNordisk Inc., RochePharmaceuticals,SankyoPharma,Inc.,andsanofi-aventisU.S. Dr. George Grunberger reports that he has receivedspeaker honoraria and research grant support fromGlaxoSmithKline, Eli Lilly and Company, and sanofi-aventis, U.S. and speaker honoraria from AmylinPharmaceuticals, Inc., Daiichi Sankyo, Inc., Merck &Co.,Inc.,NovoNordiskInc.,andTakedaPharmaceuticalsAmerica,Inc. Dr. Yehuda Handelsman reports that he has re-ceived consultant honoraria from Bristol-Myers SquibbCompany, Daiichi Sankyo, Inc., GlaxoSmithKline,Medtronic, Inc., Merck & Co., Inc., Tethys Bioscience,and Xoma LLC, speaker honoraria from AstraZenecaPharmaceuticals 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 he has receivedadvisory board honoraria from Abbott Laboratories,AstraZeneca Pharmaceuticals LP, Bristol-Myers SquibbCompany, Daiichi Sankyo, Inc., Medtronic, Inc., Merck& Co., Inc., Metabasis Therapeutics, Inc., NovartisPharmaceuticals Corporation, Novo Nordisk Inc.,Roche Pharmaceuticals, sanofi-aventis U.S., TakedaPharmaceuticalsAmerica,Inc,andTethysBioscienceand

researchgrantsupportfromAmylinPharmaceuticals,Inc.andEliLillyandCompany. Dr. Harold Lebovitz reports that he has receivedconsultant honoraria fromAmylin Pharmaceuticals, Inc.,AstraZenecaPharmaceuticalsLP,GlaxoSmithKline,NovoNordisk Inc., and sanofi-aventis U.S., speaker honorariafromEliLillyandCompany,andadvisoryboardhonorariafromAmylin Pharmaceuticals, Inc. and is a stockholderwithAmylinPharmaceuticals,Inc.,andMerck&Co.,Inc. Dr. Philip Levyreportsthathedoesnothaveanyrele-vantfinancialrelationshipswithanycommercialinterests. Dr. Etie S. Moghissi reports that she has receivedspeaker honoraria from Bristol-Myers Squibb, Eli LillyandCompany,andNovoNordiskInc.andadvisoryboardhonoraria fromAmylin Pharmaceuticals, Inc., Merck &Co.,Inc.,andNovoNordiskInc. Dr. Stanley S. Schwartz reports thathehasreceivedspeaker honoraria from Amylin Pharmaceuticals, Inc.,EliLilly andCompany,Merck&Co., Inc., sanofi-aven-tis U.S., and Takeda Pharmaceuticals America, Inc andadvisory board honoraria fromAmylin Pharmaceuticals,Inc.,GileadSciences,Inc.,EliLillyandCompany,NovoNordiskInc.,andTakedaPharmaceuticalsAmerica,Inc.

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