Are All GLP-1 Agonists Equal in the Treatment of Type 2 Diabetes?

Home , Agonist, Albiglutide, Dulaglutide, Exenatide, Insulin glargine, Liraglutide

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European Journal of Endocrinology -19-0566 heart failure). patients eitherpresentingwithorwithoutpre-existingcardiovasculardisease(atherosclerotic,ischemiccongestive cardiovascular riskfactors,andoftheinfluenceGLP-1receptoragonisttreatmentonoutcomesin pharmacokinetic behaviour,glucose-loweringpotency,effectivenessofreducingbodyweightandcontrollingother and all-causemortality.Itisthepurposeofpresentreviewtodescribeclinicallyimportantdifferences,regarding (non-fatal myocardialinfarctionandstroke,cardiovasculardeath).Liraglutide,inaddition,reduced liraglutide, semaglutide,albiglutide,anddulaglutidereducedthetimetofirstmajoradversecardiovascularevents outcomes studies.Beyondprovingtheirsafetyinvulnerablepatients,mostofwhomhadpre-existingheartdisease, q.w., allfors.c.injection,andthefirstoralpreparation,oralsemaglutide)havebeenexaminedincardiovascular GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide were recommendedasthefirstinjectablediabetestherapyafterfailureoforalglucose-loweringmedications.Most to glycaemiccontrolandbodyweightreductionhavebeendeveloped,inarecentADA/EASDconsensusstatement, Compounds withlongerdurationofaction(oncedaily,onceweekly)andincreasinglybetterefficacyrespect has beenusedtotreatpatientswithtype2diabetessince2007,whenexenatide(twicedaily)wasapprovedin2007. eliminated (mainlybykidneys)toofast(half-life1–2min)tobeusefulasatherapeuticagent.GLP-1receptoragonist identified asaparentcompoundfornoveltreatmentsofdiabetes,butwasdegraded(dipeptidylpeptidase-4)and GLP-1, apeptidehormonesecretedfromthegut,stimulatinginsulinandsuppressingglucagonsecretionwas Abstract Diabetes Division,St.Josef-Hospital,Ruhr-UniversityofBochum,Germany Michael A Nauck of type2diabetes? Are allGLP-1agonistsequalinthetreatment MANAGEMENT OFENDOCRINEDISEASE https://doi.org/ https://eje.bioscientifica.com Review Diabetes Association. Bertram Award (1993), theWerner-Creutzfeldt Award (2007)andthePaulLangerhansMedal(2012)of the German pharmacotherapy. His scientificcontributionshavebeenhonouredwithseveral awards,includingtheFerdinand- of type 2 diabetes, and the modification of cardiovascular risk in type 2-diabetic patients with glucose-lowering include spontaneous hypoglycaemia (insulinomas), pancreas transplantation, cardiovascular complications medications suchasGLP-1receptoragonistsandinhibitors ofdipeptidylpeptidase-4.Additionalareasinterest potential ofGLP-1intype2diabetes.Hehascontributed tothedevelopmentofincretin-basedglucose-lowering the pathophysiologyoftype2diabetes.Hehascontributed pivotalstudiesprovingatherapeutic GIP, andglucagon-likepeptide-1,GLP-1)inthephysiological regulationofmetabolismandin role ofgastrointestinalpeptidehormones(incretins:glucose-dependent insulinotropicpolypeptide, and Ruhr-University, Bochum,Germany. ProfessorNauckhasaparticularresearch interestinthe (Ruhr-University Bochum)inBochum,Germany. HeteachesatGeorg-AugustUniversity,Göttingen, Prof. Invited Authorprofile Michael 10.1530/EJE

Nauck and -19-0566 Juris J Meier MD 6 © isHeadofClinicalResearch attheDiabetesDivisionofSt.Josef-Hospital 2019EuropeanSociety ofEndocrinology M ANauckandJMeier Printed inGreatBritain comparison GLP-1 receptoragonist Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at09/27/202110:29:24PM (2019) Endocrinology European Journalof [email protected] Email Nauck A M to should be addressed Correspondence 181 181 :6 , R211–R234 ,

R211 –R234 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com hyperglycaemia infastingtype2-diabeticpatientsinto patients with type 2 diabetes ( polypeptide),GLP-1turnedouttobeactivein inhibitory insulinotropic polypeptide (GIP, formerly called gastric Unlike theotherincretinhormone,glucose-dependent On thesepremisesitqualifiedasanincretinhormone. activityinthecaseofhypoglycaemia( regulatory normo- andhyperglycaemia,butallowingitscounter- concentrations, andsuppressingglucagonsecretionat whenever plasmaglucosewashigherthanatfasting potent insulinotropicagent,stimulatinginsulinsecretion intestinal L-cellsin1987( GLP-1) - were identified as thepeptides produced in and -toalesserextent,GLP-1(7-37)(glycine-extended peptide structure.GLP-1(7-36amide)(amidatedGLP-1) details ofpost-translational processing andtheresulting (i.e., atthemRNAlevel)( two ‘glucagon-like’stretchesoftheproglucagonsequence GLP-1 in human subjects was detected in 1983 as one of type 2diabetes GLP-1 receptoragonistsinthetreatmentof (DPP-4). GLP-1 peptides.Thesemodifications concernaminoacidexchangesprohibitingproteolytic attackbydipeptidylpeptidase-4 compounds (righthandpanels) areshownschematicallyindicatingthelargeproteincomponent, spacerpeptides,andmodified shown inlightgreen,aminoacids differingfromtheparentcompoundareshownindark blue. Large-molecularweight compounds, theaminoacidsequence isshown(lefthandpanels).Aminoacidsidenticalwith mammalian(human)GLP-1are Molecular structuresofGLP-1receptoragonistsusedforthe treatmentoftype2diabetes.Forsmall-molecular-weight Figure 1 Review 1 2 ), whichleftuncertaintyabout , 3 ). GLP-1turnedouttobea 4 , M ANauckandJMeier 6 ). It was able to reduce 4 , 5 ). compound, GLP-1,areshownin structures ofGLP-1receptoragonistsandtheparent be clinicallyusefulglucose-loweringagents.Molecular DPP-4 andwithslowereliminationkinetics,inorderto needed tobemodifiedresultinpeptidesresistant Thus, itbecameevidentthattheoriginalGLP-1peptide when applyinglargedosesthatcausedsideeffects( short-lived peakslastingforamaximumof90min,even min only. Consequently, s.c.administrationgaveriseto from thecirculation quickly, resultinginahalf-lifeof1–2 protease, dipeptidylpeptiase-4(DPP-4)andalsoeliminated GLP-1 israpidlydegradedandinactivatedbyaubiquitous i.v. ors.c.administrationofGLP-1( food intake,andbodyweight( research alsoindicatedapotentialforreducingappetite, administered intravenously ( principle studiesemployingexogenoussyntheticGLP-1 post-meal glycaemicrisesaftermixedmealsinproof-of- the normalfastingplasmaglucoserange,andabolished was syntheticexendin-4,apeptidefromthesalivaof the treatmentoftype2diabeteswasexenatide,which comparison GLP-1 receptoragonist The firstGLP-1receptoragonisttobeapprovedfor Downloaded fromBioscientifica.com at09/27/202110:29:24PM 5 , 7 ). Pre-clinical and clinical 8 Fig. 1 , 9 10 ). Studiesemploying 181 ) alsoindicatedthat . :6 R212 5 , 7 via freeaccess ). European Journal of Endocrinology proteins are typically slowly degraded/eliminated from in thecaseofdulaglutide ( peripherally attached with the help of linker molecules the linearsequenceofalbumin inthecaseofalbiglutide, (DPP-4-resistant) GLP-1molecules, incorporatedinto case ofalbiglutide( fragment inthecaseofdulaglutide( and albiglutide:Biggerproteins(animmunoglobulin absorbed andeliminated. this treatment,itwilltakeweeksbeforeallexenatide is injections ( state within approximately 10 weeks with once weekly steady plasmaconcentrationsslowlyrisingtoa of theso-calledexenatidemircrospheres guarantees injected twicedaily);however, theslowabsorption is exenatide(identical to theun-retarded compound compound thatisthusslowlyreleasedintothecirculation injections intosubcutaneousadiposetissue( ‘encaged’ inapolymerwhichslowlydissolvesafter injections wasexentideonceweekly, whichisexenatide approved foroncedailys.c.injectionsin2009. approximate half-lifeis13h( to reach tissues and cells expressing GLP-1 receptors. The from which liraglutide can dissociate represents a reservoir in anon-albumin-boundstate,whilethemajority approximately 1–2%ofliraglutidearethoughttocirculate to albumin in extracellular fluid andplasma ( through alinkermolecule,whichpromotesbinding was achievedbyattachingafreefattyacidsidechain to theoriginalGLP-1peptide( 97%compared peptide backboneofwhichwaspreserved obvious consequencesforitstherapeuticefficacy( formation inthemajorityofpatients,however, without to provokesomeimmunogenicityleadingantibody to mammalianGLP-1and,thus,wasdissimilarenough Exenatide hada53%sequencehomologycompared breakfast andbeforedinner(twicedaily)wasapproved. a regimenforinjecting exenatide subcutaneously before two orthreetimesdailyadministrationsweretested,and half-life of approximately2–3 h ( be DPP-4-resistant and eliminated more slowly, with a slightly betterthan)GLP-1( to stimulateGLP-1receptorswithanaffinitylike(oreven structure toGLP-1wasnoticed( diabetes medication( purified withoutanyintentiontobeinsearch ofa lizard fromArizona, Review A novelapproachwastakeninthecaseofdulaglutide The firstcompounddesignedforonce-weekly The nextagenttobedevelopedwasliraglutide,the 14 , 18 ). Thismeansthatafterdiscontinuing 20 11 Heloderma )) werelinkedtotwomodified ). Thesimilarityofthepeptide 12 Fig. 1 ). Exenatidehappenedto Fig. 1 16 Fig. 1 M ANauckandJMeier

suspectum 7 ), andliraglutidewas , ). Thebig‘carrier’ 19 12 ). Prolongedaction ), anditwasfound ), albumininthe ). Regimens with , whichwas 17 15 , 18 13 ). Only ). The , 14 ). enhancer, SodiumN-(8-(2-hydroxybenzoyl)Amino) compound usedfors.c.injection)andanabsorption developed, which contains semaglutide (identical to the once-weekly dosing. such thateliminationisevenslower( binding ofthefattyacidsidechainseemstobetighter, make themoleculeentirelyDPP-4-resistant( DPP-4, has been exchanged for acid position2,whichisrecognizedand‘attacked’by like liraglutide( exenatide onceweekly( earlier onset of clinically noticeable action as compared to slow elimination,relativelyrapidabsorptionleadstoan dulaglutide andalbiglutideismainlysupportedbytheir be injectedonceweekly. Sincetheprotractedactionof the orderofmagnitude1week( the circulation. Thus,thesecompoundshavehalflivesin half-life, but was able to reduce glycated haemoglobin developed byrationaldrug design, hadarelativelyshort GLP-1 receptoragonistclass. and approvedforvariouscompounds belongingtothe betweensubsequentinjections suggested,tested intervals in individual GLP-1receptoragonistsaresummarized Important pharmacokineticcharacteristicsforthe receptor agonistcompounds Pharmacokinetic differencesbetweenGLP-1 and innovation. development ofanoraldrugisaremarkableachievement or othermedicationscanbetaken( the subsequentmealisrequired,beforemorefluid,food betweentheingestionofdrugand A 30-mininterval taken after an overnight fast with asmall volume of water. absorption andexposuretothedrugrequiresitbe is recommendedtobetakenoncedaily. Predictable variable absorption,thisoralpreparationofsemaglutide i.e. a98-folddifference).To compensateforlowand per weekinthecaseofsemaglutidefors.c.injection, and efficacy(upto14mgperdayascompared1 to beingestedachievesimilarplasmaconcentrations bioavailability is still low, and much more peptide needs most likelythroughgastricmucosa( degradation of semaglutide, and facilitates absorption, (SNAC), which locally raises pH, prevents Caprylat comparison GLP-1 receptoragonist Table 1 Recently, an oral preparation of semaglutide has been much Semaglutide has a molecular structure very Exenatide, asaproductof serendipityratherthan . Basically, thesedatasupportthedifferent Fig. 1 ). However, thealanineinamino 24 Downloaded fromBioscientifica.com at09/27/202110:29:24PM , 25 ). https://eje.bioscientifica.com α -amino butyric acid to 28 181 21 ). Nevertheless,the 28 27 , :6 ). Notethatthe 22 ), andsupports , 23 ) andcan 26 R213 ). The via freeaccess

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Table 1 Molecular details, pharmacokinetic features and dosing of various GLP-1 receptor agonists approved for the treatment of type 2 diabetes.

Pharmacokinetics General features (single dose administration) Molecular Approved doses Interval between injections (h Initial up-titration Time to peak Elimination half-life Compound Structure (Fig. 1) weight (g/mol)* (µg or mg) or days) recommended? (h/days) (h/days) Exenatide b.i.d. Natural peptide 4186.6 • 5 µg Before breakfast and Yes 2.1–2.2 h (33) 3.3–4.0 h (33) (unretarded) (exendin-4) from the • 10 µg dinner (twice daily) (30) saliva of the lizard M ANauckandJMeier Heloderma suspectum (53% homology) Lixisenatide q.d. Exenatide plus poly-lysine 4858.6 • 10 µg Before breakfast or Yes ≈ 2 h (34) 2.6 h (34) tail • 20 µg before the most carbohydrate-rich meal (once daily) Liraglutide q.d. Slightly modified GLP-1 3751.3 • 0.6 mg Once daily (approximately Yes 11.0–13.8 h (35) 12.6–14.3 h (35) (97% homology) with • 1.2 mg the same time every free fatty acid side • 1.8 mg day) chain attached Exenatide once See exenatide 4186.6 • 2 mg Once weekly No† Slow‡ See exenatide weekly q.w. Dulaglutide q.w. Two modified GLP-1 59669.8 • 0.75 mg Once weekly No 48 h (23) 4.7-5.5 day (23) comparison GLP-1 receptoragonist molecules attached to • 1.50 mg an immunoglobulin (Fc) fragment Albiglutide q.w. Two modified GLP-1 72,970.4 • 30 mg Once weekly Yes 3–5 day (36) 5.7–6.8 day (36) molecules amino- • 50 mg terminally attached to the linear structure of albumin Semaglutide (for s.c. Slightly modified GLP-1 4113.6 • 0.5 mg Once weekly Yes 24 h (27) 7.6 day (27) Downloaded fromBioscientifica.com at09/27/202110:29:24PM injection) q.w. (94% homology) with • 1.0 mg Semaglutide (for oral free fatty acid side 4113.6 • 3 mg§ 30 min before breakfast║ Yes Early See semaglutide administration) chain attached • 7 mg§ (once daily) appearance for s.c. q.d. • 14 mg§ (within 1–4 h) injection (28) 181 *For comparison, the molecular weight of glucagon-like peptide-1is 3297.7 g/mol; ║total concentrations (including albumin-bound GLP-1 receptor agonist). Free (non-albumin-bound) concentrations :6 probably represent 1–2% of total concentrations; ***this was a study in healthy subjects; †due to slow absorption from s.c. depots, exenatide concentrations only rise to a steady-state within 8–10 weeks; ‡not formally assessed, since a single injection does not lead to measurable concentrations; the onset of glucose-lowering actions are seen after 4 weeks of treatment and onward; §all doses of oral semaglutide formulated with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). R214 via freeaccess European Journal of Endocrinology used inpatientswithadvanced stagesofrenalfunctional lixisenatide arerenallyeliminated andshouldnotbe hepatic functionalimpairment arealsoshown. Recommendations regarding theiruseinpatientswith receptor agonistsinsubjectswithimpairedrenalfunction. to pharmacokinetics,safetyandtolerabilityofGLP-1 elimination. and hepaticfunction,dependingontheroutes of Pharmacokinetic propertiesmaydependonrenal special populations Use ofGLP-1receptoragonistsin elimination kineticsofagivencompound( needstoreflectthe week, indicatingthattheinterval glucose reflectinglowerdrugexposureduringthesecond albiglutide to2weeksledfluctuationsinfastingplasma betweentwoinjectionsof Extending theinterval injections inthecaseofonce-weeklyinjectedcompounds. exposure duringa24-hperiodortheweekbetweentwo and exertbiologicaleffects( albumin-bound andisabletofreelydiffuseintotissues 37 fluctuations byapproximately30%duringeachday( small peak after each s.c. injection of liraglutide leads to 24-h period( steadily elevatedliraglutideconcentrationsoverafull agonist tobeinjectedoncedaily, butstillleadingto of thedaywithrelativelylowdrugexposure( reach aneffectiveexposureforestimated8h,leaving2/3 With theonce-dailyinjection,plasmaconcentrationswill before themealwithlargestcarbohydratecontent( meant tobeinjectedonceaday, eitherbeforebreakfastor C-terminus), it still has a rather short half-life ( of exenatide (with a poly-lysine tail added at the for loweringglucoseactions. to fullyexploitthepotentialofGLP-1receptoragonists period, exenatideplasmaconcentrationswillbetoolow that withexenatideinjectedtwiceaday, muchofa24-h not resultinconvincinglybetterefficacy( ( exposure aftereachinjection(forapproximately6–8h) only transientlyleadstopharmacologicallyactivedrug meaningful extent,butclearlyisashort-actingagentthat and bodyweightwithtwicedailyinjectionstoa 29 Review ). Approximately1–2%ofcirculating liraglutideisnot ). However, injectingexenatidethreetimesperdaydid Little isknownaboutpotentialfluctuationsindrug Liraglutide istheonlylong-actingGLP-1receptor While lixisenatideisasomewhatoptimizedderivative As arule,exenatideand related compoundslike Table 2 16 ). Theminordecayafterreachinga compilesdatageneratedwithrespect 38 ). M ANauckandJMeier 30 39 ). Thismeans 31 ). ). 31 ). It is 32 16 ). , on asmallstudytesting0.8 and2.0mgperweek,with further optimizedforphase 3 studies. The dosesidentifiedand up-titrationregimenswere substantially higher, butstilltolerable doserange( to preventexcessivesideeffects,thusarrivingat a A secondapproachwastaken,usinginitialup-titration performed witharelativelynarrowrangeofdoses( exenatide b.i.d.( receptor agonistswasfirstdescribedinthecase of receptor agonist. crucial for identifying optimum doses for any given GLP-1 regimen leadingtoslowlyrisingdruglevelsmaybe tolerable doses,andthechoiceofaninitialup-titration of a dose range, including ineffective and not-so-well interaction withthebrainstem)( effects, althoughtheyprobablyarecausedbyadirect or diarrhoea(commonlycalled‘gastrointestinal’side quickly andbymajorstepsmayprovokenausea,vomiting, Starting with too high a dose or increasing the dose too optimized effectsontargetparameters(e.g.HbA which aimatidentifyingdoseregimensthatleadto All newdrugsneedtobetestedinphase2clinicalstudies, receptor agonistsinphase2studies Finding theoptimumdoseforGLP-1 on thecompound. below eGFRsof15or30mL/min(1.73m chronic kidneydiseaseandloweGFRs,notatall all GLP-1receptoragonistswithcautioninpatients limited experience,ageneralrecommendationistouse with lowereGFRisrecommended.However, becauseof mild or moderate chronic renal disease, no dose reduction eliminated independentfromrenalfunction.Generally, in GLP-1 componentsattached(dulaglutide,albiglutide)are (liraglutide andsemaglutide)orlargeproteinswith impairment. Albumin-boundGLP-1receptoragonists the upperrangeofeffective,buttolerabledoses( first waveofphase2studiesdidnotsufficientlyidentify rise inexposuretothedrugwhenstartingtreatment( fact thattolerability, inpart,dependsonthevelocityofa receptor agonists,thisprocesscanbecomplicatedbythe phase 3trialsand,later, forapproval.InthecaseofGLP-1 side effectsisthemaincriterionforselectingdoses balance between(wanted)effectivenessand(unwanted) weight), whilebeingtolerableforpatients.Thus,the comparison GLP-1 receptoragonist Dose finding forexenatide onceweekly only relied The developmentofliraglutidewasdelayedbecausea The beneficialeffectofslowlyup-titratingGLP-1 55 ), but later the dose-finding studies were ), butlater the dose-findingstudies were Downloaded fromBioscientifica.com at09/27/202110:29:24PM https://eje.bioscientifica.com 56 181 ). Carefulselection :6 2 ) − 1 , depending 1c 59 57 R215 , body , , 58 61 60 55 via freeaccess ). ). ). ).

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Table 2 Potential restrictions in the use of GLP-1 receptor agonists in patients with impaired renal and hepatic function and potential renal benefits demonstrated in clinical trials with various GLP-1 receptor agonists.

Exenatide Compound Exenatide (b.i.d.) Lixisenatide (q.d.) Liraglutide (q.d.) (q.w. = once weekly) Dulaglutide (q.w.) Albiglutide (q.d.) Semaglutide (q.w.) Route of administration s.c. s.c. s.c. s.c. s.c. s.c. s.c. Renal elimination and safety in patients with impaired renal function Evidence for elimination Yes (40) Yes (41) No (42) Yes (40) No Yes (minor) Yes (minor, in through the kidneys (43) patients with (yes/no, reference) end-stage renal M ANauckandJMeier failure) (27) Safety/tolerability issues Yes (40) Yes (41) Yes (44) Yes (40) Not reported Yes (45) No (27) in patients with severely impaired renal function? (yes/no, commentary) Dose reduction No (40) No (41) No (44) No (40) No No No recommended for mild/ moderate reductions in renal function? (yes/no) Approved lower limit of 30 30 Approved except for 30 ≥15 30 Approved except eGFR [ml/min 1.73 m2] terminal renal for terminal

failure renal failure comparison GLP-1 receptoragonist Potential renal benefits Evidence for reduction in No (46) Yes (in patients with Yes (48) No (49) Yes (50, 51) Not reported Yes (52) albuminuria? macro-albuminuria) (47) Slowed reduction in eGFR No (46) No (47) Yes (48) Not reported Yes (50, 53) Not clear (54) Not reported (52) over time [yes/no] Evidence for beneficial No No Yes (48) No (49) Yes (50) Not reported Yes (52) influence on clinical renal endpoints?

Downloaded fromBioscientifica.com at09/27/202110:29:24PM (yes/no, reference) Use in patients with impaired hepatic function Dose reduction No (limited No (limited experience) No (limited No No No (limited No (limited recommended in experience) experience); use experience) experience) patients with hepatic in patients with dysfunction? (yes/no) severe hepatic 181 dysfunction not

recommended :6

Information in the present table has mainly been compiled from official package inserts for the medications listed. Recommendations for oral semaglutide have not been issued, since approval is pending. They are likely to be similar to those regarding s.c. semaglutide, since the active ingredient is identical. R216 via freeaccess European Journal of Endocrinology technical details( their optical appearance and concerning essential considerably,GLP-1 receptoragonistsvary bothregarding Injection devicescomingwith aprescriptionofindividual agonist treatment and adherencetoGLP-1receptor Injection devices,easeofadministration of GIsideeffects. dose up-titrationstepsmayfurthermitigatetheoccurrence demonstrated that implementing even moreandsmaller ( combinations, suchasliraglutide/insulindegludec with anunequivocallypositivebenefit–riskrelationship. to non-tolerable doses, which allows the selection of doses carefully identifyingthefulldoserangefromnon-effective seems tobeaconsequence,amongotherdeterminants,of agonists. Generallyspeaking,greaterclinicaleffectiveness to-head comparisonsbetweendifferentGLP-1receptor compound willbecrucialfordeterminingresultsofhead- the optimumdose(s)havebeenidentifiedforagiven in definiteclinical trials( may be reflected inthe efficacy andtolerability observed was highlyvariablefromprogrammetoprogramme,and for phase3,tofurtherreducetheriskadverseevents. the oral( a widerangeofcandidatedoses,bothforthes.c.( into phase3. range ofdosesusedonce-weeklywastestedandcarried monthly injectionsofalbiglutide( not onlyincludeonce-weekly, butalsobi-weeklyand for lackofeffectivenessorintolerance. as theoptimizeddoserangeweretestedanddiscontinued Initially, bothdoseslowerandhigherthanthoseidentified adaptive, dose-finding,seamlessphase2/3study)( for adurationoftreatmenttypicalphase3trials(an tolerability relationship,andcontinuingthosedoses regimens, selecting doses withabeneficial effectivity– approach, startingwithmanydifferentdoses/up-titration clinical developmentandinalltrials. range, and2mgperweekhavebeenusedthroughoutthe further attemptsweremadetodefinetheoptimumdose the higher dose being significantly more effective ( 66 Review , The experiencemade with fixed-dose GLP-1/insulin Overall, thecareappliedinselectingoptimumdoses Semaglutide dosesforphase3wereselectedbasedon In thecaseofalbiglutide,phase2studydid Dulaglutide dosefindingwastheresultofanovel 67 ) orlixisenatide/insulinglargine( 28 , 65 ) preparations.Up-titrationwasoptimized Fig. 2 ). Exenatideonceweekly is a vide infra M ANauckandJMeier 39 ). Whether or not ). Thus,alimited 68 , 69 64 62 17 ) has ) and , ). No 63 ). semaglutide, the pen device has to be changed during the treatment becauseofsideevents. potentially reducingthenumberofpatientsstopping which may be viewed as a major benefit of thisdevice, which makeslow and individual up-titration possible, of 0.6,1.2and1.8mgperdose(andeveninbetween), determined dose, the liraglutide pen allows to dial step pre-filled pendevices.Somecanonlydeliveronepre- a clearsolution.Allothercompoundsareinjectedfrom This processrequiredapproximately15mintoguarantee to bedissolved,again using adual-chamber pen device. Albiglutide is solublein an aqueous solution, but needed requiring thoroughshakingtoreachanevensuspension. became available,containingbothconstituents,however, and aliquidsolvent.Later, asingle-chamberpendevice device containing the active ingredient as a powder needed toberesuspendedusingadual-chamberpen suspension ofpolymer-’encaged’exenatidethatoriginally troughs nearzeroconcentrations, thatis,intermittent thus,ischaracterizedbypeaksand concentration curve, lowlevels afterafewhours( very each injection,and,afterreaching apeak,decaytowards injection regimen,drugconcentrations risesharplyafter GLP-1 receptor agonists, becauseontherecommended Exenatide (b.i.d.)andlixisenatide(q.d.)areshort-acting and post-mealglycaemiccontrol fasting plasmaglucose,gastricemptying receptor agonistsandconsequencesfor Definition ofshort-vslong-actingGLP-1 address theproblemofnon-adherence. been approvedsofar, buthasbeendesignedtospecifically after implantation.ThisITCA650device( subcutaneous adiposetissueforaperiodof3or6months minipump continuouslydeliveringexenatide to adherence ( injection perweekpredictingthebestindicesfor two injectionsperdayresultingintheworst,andone betweentwoinjections, factor seemstobetheinterval discontinuing treatmentaltogether).Oneimportant the number of missed doses low) and to persistence (not and thatitcontributestoadherencetreatment(keeping determinate ofpreferringonecompoundoveranother, the easeofusepen-injectiondevicesisanimportant is tobeimplemented( initial up-titrationperiod,whenthenextdoseincrease comparison GLP-1 receptoragonist For exenatideb.i.d.,lixisenatide,albiglutide,and Clinical trialshavebeenperformedwithanosmotic 70 , 71 , 72 ). Fig. 2 Downloaded fromBioscientifica.com at09/27/202110:29:24PM ). Itisoftenassumedthat https://eje.bioscientifica.com 29 , 181 75 :6 ). Thetime–drug 73 , 74 ) hasnot R217 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com prominent tachyphylaxis has been observed ( prominent tachyphylaxishas beenobserved ( patients treatedwithshort-acting GLP-1receptoragonists post-meal risesinplasma glucose concentrationsthan acting GLP-1receptoragonistsdisplaymoreprominent when plasmaglucoseprofilesinpatientstreatedwithlong- within hoursordaysandiscompleteafterafewweeks, containing meal ( rise inglucoseconcentrations following acarbohydrate- and retardedgastricemptyingflattensreducesthe is amajordeterminantofpost-mealglycaemicrises( all GLP-1receptoragonists( emptying, whichinitiallyisdeceleratedwithGLP-1and are thattachyphylaxisdevelopsforeffectsongastric between injectionsis1dayorweek.Theconsequences 24-h period,and/oroveraweek’s period,eveniftheinterval receptor agonistconcentrationsmaintainedoverawhole to a more constant drug exposure, with effective GLP-1 once weekly, dulaglutide,albiglutide,semaglutide)lead Long-acting GLP-1receptoragonists(liraglutide,exenatide exposure is typical for short-acting GLP-1 receptor agonists. (e.g., exenatideonceweekly))). for re-suspension(mixingdrymaterialwithasolventreachingclearsolution(e.g.,albiglutide)orhomogeneoussuspension (single ormultipleuse,variablepre-determinedfixeddosing,availabilityofpensdeliveringdifferent(maximal)doses, necessity preparations. Theopticalappearanceofeachpeninjectiondeviceisshownaswellsomeessentialtechnicalcharacteristics Pen injectiondevicesforGLP-1receptoragonistsandfixed-dosecombinationsofwithbasalinsulin Figure 2 14 Review , 81 ). With short-acting GLP-1receptoragonists,no 78 , 80 ). Tachyphylaxis is observed 76 , 77 M ANauckandJMeier , 78 ). Gastricemptying 82 ). Onthe 79 ), agonists havethemore prominent effectlimiting However, quantitatively, short-acting GLP-1receptor of insulinandsuppression ofglucagonsecretion( effects on gastric emptying, but ratherto the stimulation rises inglycaemia,butthemechanismisnotrelated to agonists donothavetheabilitytocontrolpost-meal of glucoseabsorptionwithsuchtherapeuticagents( may contributetooveralleffectsonthetemporalpattern also leadstoeffectsonsmallintestinalmotility, which than scintigraphy were used.GLP-1 receptor stimulation acting GLP-1receptoragonists( regarding the velocity of gastric emptying with long- occurred ( GLP-1 receptor stimulation evenafter tachyphylaxis has are residualeffectsongastricemptyingaftersustained of exenatideb.i.d.). It shouldbenotedthatthereusually in thecaseoflixisenatide,twomealsperday receptor agonisthasbeenadministered(onemealperday occurs aftermealsbeforewhichtheshort-actingGLP-1 other hand,retardationofgastricemptyingalmostonly comparison GLP-1 receptoragonist This isnottosaythatlong-actingGLP-1receptor 76 , 77 ). Instudiesaddressingtachyphylaxis Downloaded fromBioscientifica.com at09/27/202110:29:24PM 81 ), lessreliablemethods 181 :6 R218 83 82 ). via freeaccess ).

European Journal of Endocrinology (nausea representing‘gastrointestinal’ adverseevents are summarizedin regarding glycaemiccontrol andbodyweightreduction treated withoralglucose-lowering medications.Results receptor agonistshavebeenperformedinpatients Numerous head-to-headcomparisonsamongGLP-1 lowering medications) (on abackgroundoforalglucose- receptor agonistsonglycaemiccontrol Comparative effectivenessofvariousGLP-1 less comparable( questionnaire, whichmakesresultsfromdifferentstudies is byself-reportingratherthanastructured,validated the captureofthesesideeffectsinclinicaltrialsusually these differencesarenotknown.Oneshouldbeawarethat associated with more diarrhoea ( events), whilelong-actingGLP-1receptoragonistsare (and drugdiscontinuationsassociatedwithsuchadverse agonists areassociatedwithmorenauseaandvomiting ( (perhaps indicating more advanced stages of diabetes) itself can elicit such side effects) or insulin treatment on a background of metformin treatment (metformin more thanoneapproveddose)andareprominent such adverse events are dosedependent (for agents with with long-actingGLP-1receptoragonists( in mostpatients.Perhaps,thisdecayismoreprominent an up-titration regimen, and symptoms decay thereafter receptor agonist,orwhenthedoseisincreasedaspartof Usually, thisoccursuponinitialexposuretoaGLP-1 and mayleadtodiscontinuationofdrugtreatment( occur in up to 30, 15 and 15% of patients, respectively, agonists arenausea,vomitinganddiarrhoea,whichmay The mostcommonadverseeventswithGLP-1receptor different GLP-1receptoragonists Differences inadverseeffectselicitedby during theovernightfastingperiod. is theresultofhigherdrugconcentrations maintained and fasting plasma glucose concentrations ( agonists havemoreprofoundeffectsloweringovernight injection oftheagent( post-meal glycaemic rises after meals covered by an 56 Review ). Generallyspeaking,short-actingGLP-1receptor On theotherhand,long-actingGLP-1receptor 86 ). Fig. 3 78 , 81 . Importantadverseevents , 84 56 M ANauckandJMeier ). ). The exact reasons for 85 Fig. 2 ). Asarule, ). This

56 ). related tothegreatertemporalexposurewithtworather body weightisreducedmorebyexenatide,perhaps differences in glycaemic efficacy ( b.i.d. vslixisenatideq.d.)theredonotappeartobemajor within theshort-actingGLP-1receptoragonists(exenatide drawn fromsuchhead-to-headcomparisons: inmind,severalgeneralconclusionscanbe reservations inform, butnotdefine,clinicalpractice. With such interests. Therefore, results fromsuch studies should and drug doses often have been guided by commercial background glucose-lowering medication, ofcomparators possibility ofbias.Thechoicepatientsexamined,their majority ofthesehavebeen‘open-label’,withtheinherent gastrointestinal adverseeffects,orbodyweight:The of comparativetrialsaddressingglycaemiccontrol, in and hypoglycaemia)areshownfromthesamestudies a 7-dayperiod).However, dulaglutide q.w. turnedout (e.g., duetopotentialfluctuations indrugexposureover injections implied someweakeningof the effectiveness have thoughtthatgoingfrom once-dailytoonce-weekly these resultswere the only ones available, one could exenatide q.w. ( agonists, liraglutideq.d.comparedfavourably to readily availablepatientfactors. but couldofferawaytooptimizedrugchoicesbasedon has notbeenspecificallyaddressedinclinicalstudies, greater atlowerfastingglucoseconcentrations( impact ofpostprandialglucoseincrementsonHbA on baselinefastingplasmaglucose,sincetherelative ( tachyphylaxis regardingaretardationofgastricemptying acting GLP-1 receptor agoniststriggered by differential vs postprandialplasmaglucosebetweenshort-andlong- reductions. to beaprerequisiteforclinicallymeaningfulbodyweight ( clinically significantdifferencesinbodyweightreduction in fasting glucose ( 3B on glycatedhaemoglobinwiththelong-actingagent( receptor agonistwerecompared,theregreatereffects agents, anyshort-actingwithlong-actingGLP-1 than 1injectionperday. comparison GLP-1 receptoragonist 82 14 and Fig. 4 ), theireffectivenessonreducingHbA , On abackgroundoforalglucose-loweringmedications, There aresomeobviousmethodologicallimitations Within thesub-classoflong-actingGLP-1receptor Given thedifferencesinaddressingfasting/preprandial When, againonabackgroundoforalglucose-lowering 85 , E 87 . ), mainlydrivenbyamoresubstantiallowering , 88 ). Thus,continuousexposuredoesnotseem 90 14 ) andalbiglutideq.w. ( , 85 Downloaded fromBioscientifica.com at09/27/202110:29:24PM , 87 , 88 https://eje.bioscientifica.com ). However, there were no Fig. 3A 181 :6 and 1c maydepend 91 D ). When 89 ), while R219 ). This 1c Fig. is via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com and approvalhavebeenused. not identicaltothoseselected for phase3trialsandapproval.Inthesecases,dosescoming closetothoseselectedforphase3 comparing subcutaneoussemaglutide withliraglutideandDavies for anyagent,onlyresultswith thehighestdosearedepicted.GLP-1receptoragonistdoses fromphase2trials(Nauck reported, this is indicated as n.s.c.(forno statistical comparison).If an original publication has reportedresultsfromseveraldoses Other conclusions(non-inferiority,non-inferioritynotmet)are indicatedastext.Ifnoformalstatisticalcomparisonhasbeen head-to-head comparisonasreportedintheoriginalpublication. Non-significantdifferencesaremarkedn.s.(fornotsignificant). homogenously filledbars,butwithastripedpattern.Asterisks indicateasignificantdifference( semaglutide) isshowninthesamecolour(orange)as compoundinjectedsubcutaneously,however,notas specific GLP-1receptoragonistcompound(seelegend).The only oralGLP-1receptoragonistpreparationstudied(oral receptor agonist(middlepanels)anddifferentlong-actingGLP-1 receptoragonists(righthandpanels).Eachcolourrepresentsa comparing differentshort-actingGLP-1receptoragonists(left handpanels),fortrialscomparingashort-tolong-actingGLP-1 row ofpanels),fastingplasmaglucose(middlepanels) andbodyweight(lowerrowofpanels)areshownfortrials Clinical efficacyresultsfromclinicaltrialscomparingdifferent GLP-1receptoragonistshead-to-head.ReductionsinHbA Figure 3 Review GH D A Ro

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al. 2019 R221 No 93 via freeaccess ) European Journal of Endocrinology https://eje.bioscientifica.com lowering agents( GLP-1 receptoragonistson a backgroundoforalglucose- the differencesin glycaemic efficacy displayedby thetwo HbA only, IdegLiraseems toproducegreaterdifferencesin fixed-dose combinationswiththeinsulincomponent prevent suchsideeffects.Instudiescomparingthese underscoring theconceptofaslowriseinexposure to nausea, vomitinganddiarrhoea( considerably lowerproportionsofpatientsreporting same agentswith insulin, thisslowtitration results in for basal insulin. Compared to free combinations of the other. Theyhavetobetitratedslowly, likeitiscustomary components being proportional (’fixed ratio’)toeach are injectedfromthesamedevice,withdosesofboth (abbreviated IdegLira)( as afixed-dosecombinationwithinsulindegludec the long-acting compound liraglutide, which isavailable (called iGlarLixi or, formerly, LixiLan) ( available as a fixed-dose combination with insulin glargine for bothcomponents. insulin asafreecombination,allowingindividualdosing 100 ( mechanisms of action ( complementary to basalinsulin.Additiveeffectsareexpecteddue GLP-1 receptoragonistshavebeenusedinaddition (on abackgroundofbasalinsulintherapy) receptor agonistsonglycaemiccontrol Comparative effectivenessofvariousGLP-1 the samepeptideagent,semaglutide. effective comparedtothesubcutaneouspreparationof of semaglutide,whichturnedouttobealmostequally compounds, even including a novel oral preparation greater effectiveness with the most recently introduced period between2007andtodayhaveevolvedtogain than short-actingGLP-1receptoragonists,butoverthe agonists havenotonlyproventobemoreeffective was superiorfororalsemaglutide. endpoint).After52weeks,theeffectonHbA (primary but moreprofoundlyloweredbodyweightafter26weeks had similar effects on HbA ( weight (noformalstatisticalcomparisonwasperformed) reductions inHbA 65 96 Review ). Oral semaglutide compared to liraglutide (s.c., q.d.) , , The short-actingcompoundlixisenatideisalso Thus, the sub-class of long-acting GLP-1 receptor 1c 97 101 ( , 66 98 , 102 , ) andlong-actingGLP-1receptoragonists( 67 ) havebeenusedinconjunctionwithbasal ) than IglarLixi ( 1c 87 , fastingplasmaglucose,andbody ). Accordingtoameta-analysis, 66 1c , and fasting plasma glucose, 67 68 M ANauckandJMeier ). Thesecombinations , 66 69 , ), compatible with 67 68 95 , , ). Both short- 68 69 , , 103 69 ,

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gastric emptying (which remains an effect of short-acting This canbetakenasindirect evidencethatdecelerationof long-acting agentswithrespect toweightloss( receptor agonistsdonotsystematically showsuperiorityof head comparisonsbetween short- andlong-actingGLP-1 amount ofweightlostwithtreatmentwillbere-gained. weight. IfGLP-1receptortreatmentisdiscontinued, the mechanism howGLP-1receptoragonistslowerbody (like withanenergy-restricteddiet),apparentlythemain is theexpectedconsequenceofloweringcaloricintake be maintained as long as the treatment is adhered to. This months oftreatment.Mostthisinitialweightlosswill steady-state plateau of body weight is reached after 3–6 a periodofhalfyear( even gaining weight), while others lose up to 25kg over with GLP-1receptoragonistsnotlosinganyweight(or is forglycaemiccontrol,withsomesubjectstreated individual variabilityregardingweightlossthanthere and observations). glucose (HuthmacherJ,MeierJNauckMA,unpublished driven bytheirmorepronouncedeffectonfastingplasma and bodyweightcomparedtoshort-actingones,mainly a greaterreductioninHbA1c,fastingplasmaglucose, suggests thatlong-actingGLP-1receptoragonistsprovide recent indirectcomparisonperformedbyameta-analysis to long-actingGLP-1receptoragonistsarelacking.A have beeninjectedbefore.Head-to-headcomparisons mainly afterthosemeals,whenexenatideorlixisenatide the post-prandialloweringofglycaemicexcursionsoccurs acting insulinpreparations( plasma glucosebeingcontrolledbyintermediate-orlong- superior additional post-prandial effects on top of fasting acting GLP-1receptoragonistshavebeenshowntoprovide weight thaniGlarLixi IdegLira ismorepotentincontrollingglycaemiaandbody different for various GLP-1 receptor agonists ( balance ( energy (food)intake,expenditure,and receptors in brain areas involved in the homeostasis of satiety, thatis,mainlythroughaninteractionwithGLP-1 induce weightlossbydecreasingappetiteandincreasing All approvedGLP-1receptoragonistshavethepotentialto receptor agonistsonbodyweightreduction Comparative effectivenessofvariousGLP-1 comparison GLP-1 receptoragonist When used in conjunction with (basal) insulin, short- In contrasttotheglucose-loweringeffect,head-to- F ). Furthermore,thereissubstantiallymoreinter- 7 ). However, thequantitativeimpactismarkedly

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European Journal of Endocrinology with thevariousagents(i.e. continuouswithlong-acting the exposure to effective GLP-1 receptorstimulation the duration of which within a 24-h period matching in patientstreatedwithGLP-1 receptoragonists( increase inpulserateof2–5 beats perminhasbeennoted blood pressure( by 2–5 mmHg, with less consistent effects on diastolic All GLP-1receptoragonistslowersystolicbloodpressure heart rate) risk factors(bloodpressure,lipoproteins, receptor agonistsonothercardiovascular Comparative effectivenessofvariousGLP-1 antibody formationisonlyrarelyobserved. dulaglutide ( a reducedeffectiveness( since evenhightitreswerenotobviouslyassociatedwith However, thiswasofuncertainfunctionalconsequences, low sequencehomologytomammalianGLP-1( the majorityofpatients( preparation) has promptedantibodyformation, even in Exenatide (boththeb.i.d.andonce-weekly Comparative effectsonantibodyformation weights aredepictedin is lacking. Effects of GLP-1 receptor agonists on body as anexplanation.However, convincingdirectevidence access throughsubfornicalorgans)havebeenpostulated in uptakeacrosstheblood–brainbarrier(orbrain absorption enhancer)( the once-daily oral preparation (co-formulated with an once weeklysubcutaneouspreparation( well), andmorewithsemaglutide,bothconcerningthe with whichisassociatedlessnausea/vomitingas appears tobelesswithalbiglutide( with considerableinter-individualvariation,whileit q.d., liraglutide q.d., and dulaglutide q.w. is 2–4 kg, such ‘gastro-intestinal’adverseevent( almost thesamedegreeinpatientsnevercomplainingof provide themainreasonforweightloss,sinceitoccursto nausea andvomitinginducedinsomepatientsdoesnot in appetiteduetoincompletegastricemptying.Likewise, GLP-1 receptoragonists) ( while itislostduetotachyphylaxiswithlong-acting GLP-1 receptoragonistsevenduringlong-termtreatment, Review Average weightlosswithexenatideb.i.d.,lixisenatide 115 ), albiglutide ( 117 ). Atthesametime,anaverage Fig. 3 109 14 82 14 , , ) doesnottriggeramajorloss 113 ,

110 D 116 113 , ). With liraglutide( E M ANauckandJMeier , and ) and semaglutide ( ), probablyduetothe 111 14 54 , F . 112 , , 65 107 91 ). Differences , ) (treatment 93 ). , 94 Fig. 1 ) and 117 114 94 ), ), ), ). (lowering ofLDLcholesterolandtriglycerides)( slightly, butfavourablymodifylipoproteinconcentrations in systolicbloodpressure,allGLP-1receptoragonists ( of heartratethanoccasionalpulsemeasurements electrocardiographic monitoringdetectsmoreacceleration agents, intermittentwithshort-actingagents)( (or discontinuationofthe studydrug,respectively). duration, andvariablesindicating adherencetotreatment glomerular filtrationrate), patientandeventnumbers, kidney disease(significant albuminuriaand/orreduced on outcomesaretheproportion ofpatientswithchronic between studies.Otherparameterswithpotentialimpact vascular ischemia is a major important variable differing either previouscardio-vasculareventsordefinitecardio- vascular damage.Thus,theproportionofpatientswith lower-risk patientswithoutdefinitepre-existingcardio- arose, whethersimilarbenefitscouldbedemonstrated in vascular eventswithGLP-1receptoragonists,thequestion prevention ofcardio- supporting theideaofsecondary with pre-existingatheroscleroticcardio-vasculardisease, studies hadshownpositiveeffectsinsuchpopulations power to achieve the study objectives. After several still achievingnumbersofeventsprovidingthenecessary smaller samplesizesandshorterstudydurationswhile cardio-vascular event rates could be expected, leading to highly mostvulnerablepopulation,and(b)becausehigh studied, (a)becausesuchpatientswereconsideredtobea damage (e.g.,previouscardio-vascularevents)were populations withpre-existingdefinitecardio-vascular with theactivedrugascomparedtoplacebo.Typically, to showthatoutcomeswerenotworse(‘non-inferior’) their cardiovascularsafety. Thus,theoriginalaimwas forallnewdiabetesdrugsafter2008toprove mandatory 52 vascular benefitselicitedbyGLP-1receptoragonists( evidence hasaccumulatedonthepotentialcardio- examining liraglutideeffectsoncardiovascularoutcomes Since thefirstpositivereportonLEADERtrial technical aspects different GLP-1receptoragonists: Cardiovascular outcomesstudieswith observed. in patientswhomaprominentheartrateresponsewas cardio-vascular benefits of GLP-1 receptor agonists, even The accelerationinpulseratedoesnotseemtoprevent in high-risktype2-diabeticpatients( comparison GLP-1 receptoragonist 81 , ). Inadditiontobodyweightreduction,andlowering 54 , 109 , 119 , 120 ). Originally, suchtrialshadbecome Downloaded fromBioscientifica.com at09/27/202110:29:24PM https://eje.bioscientifica.com 181 :6 118 ), abodyof 81 ). 24-h R223 117 49 via freeaccess ). ,

European Journal of Endocrinology https://eje.bioscientifica.com n.r., notreported. § *Median; reported inthistable. If theoriginalpublicationdidnotreportdetailsforallpatients(treatedwithactivedrugorplacebo),dataontreatedstudy are number ofmajoradversecardiovascular (MACE)events hospitalization forcongestive heartfailureareshown. or cardiovasculardeath), all-and causemortality, or non-fatal acutemyocardial infarction, non-fatalstroke, to majoradversecardiovascularevents(’MACE’:first ( (dipeptidyl peptidase-4)inhibitors(greensymbols) inhibitors (bluesymbols)( employing SGLT-2 (sodium-glucosetransporter-2) (red symbols).Forcomparison,resultsofsimilarstudies a backgroundofstandardcareareshownin treatment withaGLP-1receptoragonisttoplaceboon Key findingsofcardiovascularoutcomestrialscomparing cardiovascular outcomes different GLP-1receptoragonists: Cardiovascular outcomesstudieswith vascular outcomestrialswithGLP-1receptoragonists. Table 3 eGFR Pre-existing heart Pre-existing BMI (kg/m HbA Diabetes duration(years) Sex: %female Age (years) Baseline patientcharacteristics Vital stateknown(%) Exposition todrug(%) Premature discontinuation(%) MACE Study duration Patient number Study characteristics Study acronym,reference Dose/interval Interval between Route ofadministration Details oftreatment Compound Table 3 75% ofthepatientstookstudydrugfor 44 Review failure (%) cardio-vascular disease(%) administrations , None oftheDPP-4inhibitors significantlychangedthe 124 1c (%) < † displays patient and study characteristics in cardio- endpoints 60 mL/min(%) † Mean bodyweight92.3kg; , Cardio-vascular outcomestrialswithGLP-1receptoragonists:studyandpatientcharacteristics. 125 2 )

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n.r. (mean:77 22.5 100 30.1 7.7 9 30 60 98.8 90.5 27.5 805 2.1 6068 ELIXA ( 20 µg/day Once daily s.c. Lixisenatide 121 ‡ mL/min) Expressed asindividualpercentageofthedurationobservationwithfulladherencetorandomizeddrug; > 1 year. , M ANauckandJMeier 120 122 ) , 123 ± 17.9 98.2 32.5 8.7 13 36 64 99.7 84.0 n.r. 1302 3.8 9340 LEADER ( 1.8 mg/day Once daily s.c. Liraglutide 23.9 ) andDPP-4 118 ) Fig. 5 72.2 n.r. 8.7 14 39 65 99.6 86.5 19.9/22.6 254 2.1 3297 SUSTAIN-6 ( 0.5/1.0 mg/week Once weekly s.c. Semaglutide 30.2/26.7 23.1 * : receptors forawhole24-h period( not leadtodruglevelssufficient tostimulateGLP-1 recommended useisoncedaily ( is arathershort-actingGLP-1 receptoragonists and its heart failure( on MACE,all-causemortality, orhospitalization for (ELIXA trial),didnotdescribeanynoticeableeffect results withaGLP-1receptoragonist,lixisenatide and dapagliflozin)( trends withoutsignificance inthecaseofcanagliflozin (substantial and highly significant for empagliflozin, and differedwidelywithrespecttoall-causemortality 123 in hospitalizationforcongestiveheartfailure( trend withlinagliptin( alogliptin, nochangewithsitagliptin,andabeneficial risk wasreportedforsaxagliptin,asimilartrendwith hospitalization for heart failure: As significantly increased results werereportedwithrespecttothetimefirst or all-causemortality( comparison GLP-1 receptoragonist 52 ) ), hadsmaller, heterogeneouseffectsonMACE, The firsttrialintype2-diabeticpatientsreporting SGLT-2 inhibitorsuniformlyshowedamajorreduction 73.3 31.8 8.0 12 38 62 98.8 76.0 43.0 1744 3.2 14 752 EXSCEL ( 2 mg/week Once weekly s.c. Exenatide 21.3 15.8 49 120 ) ). Ithastobenotedthatlixisenatide 100 32.3 8.8 14 30 64 99.4 87.0 24.5 766 1.6 9463 HARMONY 50 mg/week Once weekly s.c. Albiglutide n.r. (mean:79 20.0 121 ( Outcomes mL/min) 54 ) 44 44 , Downloaded fromBioscientifica.com at09/27/202110:29:24PM 122 , , 124 124 , 123 , , 125 125 31.4 32.3 7.3 10 46 66 99.7 82.2 26.8 1257 5.5 9901 REWIND ( 1.5 mg/week Once weekly s.c. Dulaglutide ± 8.6 ). 22.0 31 , , 126 ). Thiswillcertainly 126 Table 1 181 119 :6 ). ). Heterogeneous ) ). Oneother 27.0 84.6 32.3 8.2 15 32 66 99.7 n.r. 15.3 137 1.3 3183 PIONEER-6 ( 14 mg/day Once daily Oral Semaglutide n.r. § 121 R224 ,

122 109 via freeaccess , ) European Journal of Endocrinology after suchaneventand following revascularization Biological processesdominating clinicalcomplications syndrome.of patientsshortlyafteran acutecoronary particular aspect of this ELIXA trial is the recruitment not showingsignificantdifferences. testing procedurewithanearliercomparisoninthathierarchy significance couldnotbeconcludedbasedonahierarchical confidence intervaldoesnotcrossthelineofunity),however, exenatide onceweeklyonall-causemortality(becausethe † to placebotreatment(onabackgroundofstandardcare). also shown.Asterisksindicatesignificantdifferences( DPP-4 inhibitors(DPP-4I)andSGLT-2(SGLT-2are intervals. Forcomparison,resultsfromequivalentstudieswith (C) areshownashazardratiosandtheir95%confidence A), all-causemortality(B)andhospitalizationforheartfailure care. Effectson‘majoradversecardio-vacularevents’(MACE; receptor agonistsandplaceboonabackgroundofstandard Results ofcardiovascularoutcomestrialscomparingGLP-1 Figure 5 B A C The daggermarksanapparentlysignificantinfluenceof

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pag pag pag s s s < gl gl gl gl gl gl gl gl gl lipt lipt lipt gl gl gl enatid enatid enatid ut ut ut ut ut ut ip ip ip glut glut glut lu lu lu ip ip ip 0.05) ut ut ut ozin ozin ozin ip ip ip id id id liflo liflo liflo id id id in in in ti ti ti id id id ti ti ti flozin flozin flozin ti ti ti id id id n n n ti ti ti e q. e q. e q. n n n de s.c. de s.c. de s.c. e e e e e e id id id n n n e e e zi zi zi e e e e p.o. e p.o. e p.o. n n n w. w. w. disease (basedonpreviousevents,necessityfor patients withpre-existingatheroscleroticcardiovascular stimulation throughouta24-hperiod. definition), whichprovidesubstantialGLP-1receptor characterized as long-acting compounds ( GLP-1 receptoragonistsexceptlixisenatidetestedare exception: LixisenatideintheELIXAtrial; ( was observed at leastatrendtowardsreductioninMACEevents events: Either a significant reduction (by 12–26%) or with respecttoeffectsonmajoradversecardiovascular receptor agonistsshowedasomewhatconsistentpattern as well. modification throughGLP-1receptoragonisttreatment ofatherosclerosis,andmaybelessamenabletohistory be differentfromthosecharacterizingthenatural may proceduresorbypasssurgery) (intra-coronary primary prevention canbedebated. primary demonstrated cardioprotection withdulaglutidein Therefore, theconclusion that theREWINDstudyhas reductions in MACE ( separately, bothsubgroupsdidnotshow significant to thecardiovascular system. However, whenanalysed 2-diabetic patients,independentfrompreviousdamage prevention of cardiovascular events in type for primary cardiovascular damageatbaseline,and,thus,achance be interpretedasdemonstratingeffectsinthosewithout ratios forthesesub-populations)( interaction, pre-existing cardiovascular disease (non-significant was notdifferentbetweensubgroupswithandwithout overall population.Thispercentage reductionofevents disease atbaseline.MACEwasreducedby12%inthe a majority of patients without proven cardiovascular REWIND (dulaglutide)hasbeenthefirsttrialtorecruit small toallowdefiniteconclusionsforthesesubgroups. evidence ofcardiovasculardisease,asarule,weretoo damage. Theproportionsofpatientswithoutprevious events inthosewithpre-existingcardiovascular preventionofcardiovascular support theideaofsecondary proven cardiovasculardamage.Thus,theirresultsclearly mL/min (1.73 m semaglutide), chronickidneydiseasewithaneGFR (subcutaneous semaglutide),andPIONEER-6(oral risk factorsonly. InLEADER(liraglutide),SUSTAIN-6 or imaging),andasmallerproportionofpatientswith revascularization, ordefiniteresultsoffunctionaltesting comparison GLP-1 receptoragonist Most ofthesetrialsincludedahighproportion All othercardiovascularoutcomestrialstestingGLP-1 P

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0.10 for both sub-populations). , 109 , https://eje.bioscientifica.com 118 119 , 181 119 ). Thisresultmay :6 , vide supra 120 Fig. 5A ) (notable R225 ). All for < 60 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com adherence to this therapy ( 128 resides inthesubcutaneous adipose tissueforweeks( nodules asalocalreaction toinjectinganagentthat exenatide once-weeklymay producesubcutaneous selected for other GLP-1 receptor agonists. Furthermore, dose of2mgperweekmaynotbeequipotenttothose for thiscompoundoptimizingclinicaleffects( of amissedchancetocarefullyselectoptimumdosages ( The second‘outlier’seemstobeexenatideonceweekly concentrations ofthedrugforafull24-hperiod( day,every whichwill not guaranteeexposuretosignificant lixisenatide concentrations following a single injection most likelyiscausedbytheshort-livedincrements in exception of theELIXA trial with lixisenatide. The reason all GLP-1receptor agonists ( in major adverse cardiovascular events (’MACE’) with populations andchance. This appliestothereduction pharmacokinetic properties,selectionofdoses,patient in quantitativeterms,mayapplyduetodifferences responsible fortheresults.Someheterogeneity, especially biological mechanism(stimulationofGLP-1receptors) thereby suggestingthattheresultsattestofacommon on cardiovasculareventsshowacomparablepattern, of alltrialsexaminingeffectsGLP-1receptoragonists in variousways.Onedefinitioncouldbethattheresults all GLP-1receptoragonists.Thisquestioncanberaised like a‘class effect’ for cardiovascular benefits applying to HARMONY outcomes,andREWINDtrials. ( calls formorepatientsfollowedalongerperiodoftime power requiresmuchlargereventnumbers,whichinturn ratio: pointestimateandits95%CIbelow1.0).Sufficient analysis for superiority (hazard of 5%), with a secondary ruling out a 30% elevation in risk with an error margin bound ofthe95%CIhazardratioendsbelow1.3, Other trialsaimedatdefinitelyprovingsafety(upper main emphasiswasonsafety, notonprovingbenefits. during thetrialswasconsiderablylower( was shorter, andthenumberofMACEeventsaccrued margin of5%).Inthosecases,thedurationtrials 1.8 (ruling out an 80% elevation in risk with an error upper boundofthe95%CIhazardratioendsbelow (SUSTAIN-6, PIONEER-6).Thiscouldbeconcludedifthe safety ofnovelglucose-loweringdrugsbeforeapproval cardiovascular were designedtosupportpreliminary have beenquitedifferentbetweenthetrials:Sometrials Table 3 49 Review ). Informationprovidedearlier(videsupra)attests ). Thismaybeamajordeterminant ofarelativelylow A controversial question is whether there is something It isalsoimportanttonotethatthestudyobjectives ). ThisapproachappliestotheLEADER,EXSCEL, 129 Fig. 5 ), as shown by a rather M ANauckandJMeier ), with the notable Table 3 Table 1 ), asthe 17 127 ): A ). , addressing potential benefits of liraglutide treatment in addressing potentialbenefitsofliraglutidetreatmentin exclusion criteria in most studies. Dedicated clinical trials failure ( effects ontheriskforhospitalizationcongestiveheart and publishedcardiovascularoutcomes( body weightcontrol( GLP-1 receptoragonists,bothwithrespecttoglycaemicand the heterogeneityofresultsobtainedinclinicaltrialswith considerations orevenchance.Thisdescriptiondoesnotfit negligible, suchthatthechoiceofagentcouldbelefttocost differences betweencompoundsbelongingtoaclassare other GLP-1receptoragonists. once weekly fall short of what has been corroborated with glycaemic control; to explainwhycardiovascularoutcomes(aswellas in this‘pragmatic’trial( high rateofpatientsdiscontinuingthisdrugtreatment characterized cardiovascular risk factors (glycaemic control, characterized cardiovascular risk factors(glycaemic control, GLP-1 receptoragonistshave beneficialactionsonwell- cardiovascular endpoints receptor agonistson Potential mechanismsofactionGLP-1 case ofGLP-1RAs)mayalsobetakenintoconsideration. inhibitors versus gastrointestinal adverse events in the (predominantly genitalinfectionsinthecaseofSGLT-2 atherosclerotic disease.Potentialfrequentadverseevents be thebetterclasstopreventischaemiccomplications of chronic kidneyfailure( failure complicationsortheneedtopreventprogression of preferred ifthereisaprominentriskforcongestiveheart may bedifficultinsomepatients,SGLT-2 inhibitors willbe inhibitors foragivenpatient( made whethertopreferGLP-1receptoragonistsorSGLT-2 described forSGLT-2 inhibitors( 5 pre-existing atheroscleroticcardio-vasculardisease( recommended asapreferredtreatmentforpatientswith with theuseofGLP-1receptoragonists,thisclassis stages ofheartfailurebecausesafetyconsiderations. agonists) shouldnotbeusedinpatientswithadvanced probably indicatethatliraglutide(andotherGLP-1receptor increased mortality(notsignificant( failed toshowsuchbenefitsandrathertendedan patients withpre-existingadvancedcongestiveheartfailure comparison GLP-1 receptoragonist and GLP-1 receptor agonists have not shown any consistent GLP-1 receptoragonistshavenotshownanyconsistent Another definitionof‘classeffect’couldbethat Because ofthecardiovascularbenefitsassociated Table 3 Fig. 5B ). Advanced stages of heart failure had been ). Advancedstagesofheartfailurehadbeen ) ( 132 Fig. 3 ). Since similar benefits have been Fig. 3 132 Table 3 Downloaded fromBioscientifica.com at09/27/202110:29:24PM ) withlixisenatideandexenatide ). GLP-1receptoragonistsmay ) and concerning documented ) andconcerningdocumented ). Thus,itappearspossible Fig. 5 132 130 ). Whilethisdecision ), adecisionhastobe 181 , 131 Fig. 5 :6 )). These results )). Theseresults ). R226 Fig. via freeaccess

European Journal of Endocrinology for albiglutide( dulaglutide ( have confirmed similar effects for semaglutide ( to documentsuchrenalbenefits,morerecentstudies ( years, followingthepublicationofLEADERtrial filtration capacityhasonlybeenrecognizedinrecent by aslow, butrelentlesslyprogressivelossinrenal characterized and tointerferewiththenaturalhistory stages ofalbuminuria(micro-ormacro-albuminuria) reduce albuminuriatopreventprogressionadvanced (eGFR) have been described ( albuminuria andtheprogressivelossofkidneyfunction agonists intoclinicalpractice,beneficialeffectson Only late after the introduction of GLP-1 receptor microvascular diabeticcomplications Effects ofGLP-1receptoragonistson factor improvementthataccompaniessuchtreatment. that, in part, seem to be independent from the obvious risk GLP-1 receptoragonistsexertanti-atheroscleroticeffects recently beenreviewedextensively( and improved plaque stability ( heart tovasodilation,reducedlow-gradeinflammation, improved substrateuptakeandischemiatoleranceinthe processes inbloodvesselsandtheheart,rangingfrom lipoproteins), butalsoinfluencesamultitudeofbiological body weight,bloodpressure,fastingandpostprandial 48 Review , 118 ). Whileearliertrialsmayhavemissedachance 50 54 ), and,withatransienteffectoneGFR, ). Compositerenalendpoints(asarule Table 2 133 M ANauckandJMeier ). These effects have ). The potential to 117 ). Mostlikely, 134 ), ), semaglutide (significant difference) ( be therapiddropinplasmaglucoseandHbA specific ophtalmologicaltherapy)( patients hadpre-existingadvancedretinopathy(requiring (non-significant trend)( with theuseofliraglutide(non-significanttrend)( therapy, orvitrectomy)havebeenfoundincreased (need forphoto-coagulation,intra-vitrealinjection function atbaseline( as expected for populations with relatively normal renal albuminuria. Theotherendpointsonlyrarelyoccurred, ( liraglutide ( shown significant advantages for patients treated with kidney transplantation,anddeathforrenalcauses)have the stateofterminalrenalfailurerequiringdialysisor of a substantialreduction in eGFR, advancementto including progression to macro-albuminuria, a measure receptor agonists. the progression of diabetic eye disease with GLP-1 studies todecide,whetherthereisaspecificriskfor control withinshortperiodsoftime.Itwilltakemore with thepotentialtodramaticallyimproveglycaemic diagnosed andtreatedbeforeinitiatingsuchtreatment ( therapy withmultipledailyinjections or pumptherapy 1-diabetic patientsintensifyingtheirglucose-lowering been associatedwithso-called‘initialworsening’intype initiating GLP-1 receptor therapy, which has previously comparison GLP-1 receptoragonist 136 50 ), alldrivenbyamajoreffectontheprogressionto Clinical endpoints related to diabetic eye disease ). Careshouldbetakenthatdiabeticeyediseaseis 48 , 118 c now, comparativedataarelacking. administered asatablet;however, asof judged tobegoodbecausethis is absence oftachyphylaxis). effects ongastricemptying(deceleration, available. since thiscompoundisnolonger concerning albiglutidearenotconsidered, their subjectiveclinicaljudgement.Data but representtheauthors’opinionsand are derivedfrompublishedclinicaltrials, agonists. Thesemi-quantitativeestimates soon tobeapprovedGLP-1receptor effects elicitedbycurrentlyavailableand Comparison ofbeneficialandadverse Figure 6 Antibody formation. ), semaglutide( Table 3 Downloaded fromBioscientifica.com at09/27/202110:29:24PM 50 , a Mainly throughpersistent 119 ). https://eje.bioscientifica.com ). Themajorityofthese 135 134 181 52 ). Onereasonmay ), anddulaglutide ) and dulaglutide :6 b Potential 1c inducedby R227 118 via freeaccess ),

European Journal of Endocrinology https://eje.bioscientifica.com and renal (micro-vascular) endpoints. It is the purpose of events (addressingmacro-vascular diabeticcomplications) with thistherapyarethe prevention ofcardiovascular starting insulintherapy)( failure oforalglucose-lowering agents(asarule,before recommended as the first injectable therapy after the control andbodyweightreduction.Theyarenow has evolvedtoprogressivelyprovideimprovedglycaemic this classofincretin-basedglucose-loweringmedications receptor agonist, exenatide b.i.d. into clinical practice, More than 10 years after the introduction of the first GLP-1 Conclusions class ofGLP-1RAs( the conceptofindividualizedcareevenwithinbroad together, theseunequalpropertiesandeffectshighlight prevention maybeconsideredfordulaglutide.Taken whilst someevidenceforcardioprotectioninprimary prevention have been obtained for liraglutide, secondary terms ofreducingtheoverallnumbersMACEeventsin to bedetermined.Finally, themostconvincingresultsin be preferred over the weeklyinjectable therapies, is yet be administereddaily30minpriortomealingestion,will and liraglutide.Whetheroralsemaglutide,whichhasto an easy-to-usesingleusepen,followedbysemaglutides.c. use canbeattributedtodulaglutide,whichisdeliveredin effective druglevels.Thegreatestconvenienceandeaseof and exenatide,owingtotheshorterperiodsof exposure to increases appeartobelesspronouncedwithlixisenatide weekly, andhighestwithexenatideb.i.d..Heartrate found tobelowestwithalbiglutideandexenatide-once The incidenceofgastrointestinaladverseeventshasbeen semaglutide, followed byoralsemaglutideand liraglutide. candidates. Weight losshasbeenmostpronouncedwiths.c. (once daily)orexenatide(twicemaybesuitable hyperglycaemia isakeytherapeutictarget,lixisenatide liraglutide and dulaglutide. If reductioninpostprandial more efficacious thantheoralpreparation), followedby efficacy (perhaps with the s.c. version being slightly potential, semaglutideappearstoprovidethegreatest consideration: In termsoftheoverallglucose-lowering RA foragivenpatient.Severalaspectsmaybetakeninto arises howtodetermineoptimalchoiceofaGLP-1 the fixed-ratio combinations with insulin), the question eight different GLP-1 RApreparations(even excluding In lightofthecurrentorfutureavailabilitycurrently The challengeofindividualchoices Review Fig. 6 ). 132 ). Specificbenefitsassociated M ANauckandJMeier & Dohme,NovoNordisk,NovartisandSanofi. Sharp Merck, Boehringer-Ingelheim, Co., & received Lilly Eli from has support research He Sanofi. and Nordisk Novo Dohme, & Sharp Merck, Co., Lilly& Eli Zeneca, Astra from honoraria speaker and consulting received Menarini/Berlin GlaxoSmithKline, has M J J Pharma. Sun and NovoNordisk, Dohme, & Co., Sharp Merck, Chemie, & AstraZeneca, of Lilly bureau Eli speakers’ Ingelheim, the Boehringer on Novartis served and also has Dohme, He & Pharma. Sharp Merck, Menarini/Berlin-Chemie, Co., Lilly Eli & &Dohme, from support Sharp grant received has He Versatis. Merck, and NovoNordisk, Chemie, Menarini/Berlin Roche, La Hoffman AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Fractyl, GlaxoSmithKline, M ANhasbeen member on advisory boardsorhasconsulted with Declaration ofinterest with type2diabetesmellitus. as partofanindividualizedtreatmentdecisionforpatients to supporttheselectionofmostappropriatetreatment clinical trialswithsuchagents.Thisinformationishoped the evidenceforbenefitsthathavebeendescribedin agents belongingtotheGLP-1receptoragonistclassor tohighlightdifferencesbetween the presentoverview References data presented. publication. for version final M ANistheguarantorforcontentandvouches for theaccuracyof the submit to decided have authors Both and tables,hasrevisedthemanuscriptforcriticalintellectualcontent. the first draft of the present review. J J M has provided input into the figures M ANhasdesigned the review,performedliteratureandwrote Author contributionstatement grant ME2096/8-1. (DFG), Forschungsgemeinschaft Deutsche the by supported been has M J J Funding comparison GLP-1 receptoragonist 5 6 4 2 1 3 Mojsov S, Weir GC &Habener JF. Insulinotropin:glucagon-like peptide Nauck MA, Heimesaat MM,Ørskov C, Holst JJ,Ebert R& Nauck MA &Meier JJ.Glucagon-like peptide1(GLP-1)and Nauck MA &Meier JJ.Theincretineffectinhealthyindividuals Holst JJ, Ørskov C,Vagn-Nielsen OV &Schwartz TW. Truncated Bell GI, Sanchez-Pescador R,Laybourn PJ&Najarian RC.Exon Creutzfeldt W. incretinactivityofglucagon-likepeptide Preserved regpep.2004.07.01) 2005 its derivativesinthetreatmentofdiabetes. 8587(15)00482-9) Endocrinology and responsetotherapeuticinterventions. and thosewithtype2diabetes:physiology, pathophysiology, Investigation of insulinreleaseintheperfusedratpancreas. I (7–37)co-encodedintheglucagongeneisapotentstimulator 5793(87)81430-8) gut. glucagon-like peptide1,aninsulin-releasinghormonefromthedistal Nature duplication anddivergenceinthehumanpreproglucagongene. FEBS Letters 128 1983 (Supplement)135–148. 1987 304 2016 1987 368–371. 79 4 616–619. 525–536. 211 169–174. Downloaded fromBioscientifica.com at09/27/202110:29:24PM (https://doi.org/10.1038/304368a0) (https://doi.org/10.1172/JCI112855) (https://doi.org/10.1016/S2213- (https://doi.org/10.1016/j. (https://doi.org/10.1016/0014- Lancet: Diabetesand 181 Regulatory Peptides Regulatory Journal of Clinical ofClinical Journal :6 R228 via freeaccess

European Journal of Endocrinology

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comparison GLP-1 receptoragonist 48 47 50 49 56 55 54 53 52 51 58 57 Mann JFE, Orsted DD,Brown-Frandsen K,Marso SP, Poulter NR, Muskiet MHA, Tonneijck L, Huang Y, Liu M,Saremi A,Heerspink HJL Gerstein HC, Colhoun HM,Dagenais GR,Diaz R,Lakshmanan M, Holman RR, Bethel MA,Mentz RJ,Thompson VP, Lokhnygina Y, Bettge K, Kahle M,AbdElAziz MS,Meier JJ&Nauck MA.Occurrence Fineman MS, Shen LZ,Taylor K, Kim DD&Baron AD.Effectiveness Hernandez AF, Green JB,Janmohamed S,D’Agostino RB, Sr, Tuttle KR, Lakshmanan MC,Rayner B,Busch RS,Zimmermann AG, Marso SP, Bain SC,Consoli A,Eliaschewitz FG,Jodar E,Leiter LA, Tuttle KR, McKinney TD,Davidson JA,Anglin G,Harper KD& Kolterman OG, Buse JB,Fineman MS, Gaines E,Heintz S,Bicsak TA, Kendall DM, Riddle MC,Rosenstock J,Zhuang D,Kim DD, type 2diabetes. Committee andInvestigators.Liraglutiderenaloutcomesin Rasmussen S, Tornoe K, Zinman B,Buse JB&LEADERSteering S2213-8587(18)30268-7) Diabetes andEndocrinology analysis oftheELIXArandomised,placebo-controlledtrial. syndrome:anexploratory with type2diabetesandacutecoronary & vanRaalte DH.Lixisenatideandrenaloutcomesinpatients org/10.1016/j.diabres.2019.05.001) Diabetes Research andClinicalPractice diabetes mellitus:apost-hocanalysisof52-weekrandomisedtrial. compared totitratedinsulinglargineinpatientswithtype2 Exenatide twice-dailydoesnotaffectrenalfunctionoralbuminuria 131–138. the REWINDrandomised,placebo-controlledtrial. analysisof and renaloutcomesintype2diabetes:anexploratory Pais P, Probstfield J,Botros FT, Riddle MC,Ryden L (https://doi.org/10.1056/NEJMoa1612917) diabetes. of once-weeklyexenatideoncardiovascularoutcomesintype2 Buse JB, Chan JC,Choi J,Gustavson SM,Iqbal N (https://doi.org/10.1056/NEJMoa1616011) Metabolism systematic analysisofpublishedclinicaltrials. clinical trialsstudyingglucagon-likepeptide-1receptoragonists:a of nausea,vomitinganddiarrhoeareportedasadverseeventsin org/10.1002/dmrr.499) Metabolism Research andReviews dose-limiting sideeffectsinsubjectswithtype2diabetes. of progressivedose-escalationexenatide(exendin-4)inreducing 6736(18)32261-X) Lancet Outcomes): adouble-blind,randomisedplacebo-controlledtrial. patients withtype2diabetesandcardiovasculardisease(Harmony Somerville MC Granger CB, Jones NP, Leiter LA,Rosenberg AE,Sigmon KN, org/10.1016/S2213-8587(18)30104-9) Lancet: DiabetesandEndocrinology disease (AWARD-7): amulticentre,open-label,randomisedtrial. patients withtype2diabetesandmoderate-to-severechronickidney Woodward DB &Botros FT. Dulaglutide versusinsulinglarginein org/10.1056/NEJMoa1607141) ofMedicine New EnglandJournal and cardiovascularoutcomesinpatientswithtype2diabetes. Lingvay I, Rosenstock J,Seufert J,Warren ML org/10.1111/dom.12816) Diabetes, ObesityandMetabolism in patientswithtype2diabetesphaseIIandIIIclinicaltrials. Botros FT. Effectsofonce-weeklydulaglutideonkidneyfunction Taylor K, Kim D,Aisporna M,Wang Y 1083–1091. treated withmetforminandasulfonylurea. glycemic controlover30weeksinpatients withtype2diabetes Fineman MS &Baron AD.Effectsof exenatide(exendin-4)on 2018 New England Journal ofMedicine New EnglandJournal (https://doi.org/10.1016/S0140-6736(19)31150-X) 2017 (https://doi.org/10.2337/diacare.28.5.1083) 392 et al New England Journal ofMedicine New EnglandJournal 1519–1529. 19 . Albiglutideandcardiovascularoutcomesin 336–347. 2018 Downloaded fromBioscientifica.com at09/27/202110:29:24PM (https://doi.org/10.1016/S0140- (https://doi.org/10.1111/dom.12824) 2016 2004 2017 6 2018 859–869. 2019 375 20 19 et al 6 2017 411–417. 605–617. 436–441. 1834–1844. . Syntheticexendin-4 153 181 (https://doi.org/10.1016/ Diabetes Care et al 377 Diabetes, Obesityand 14–22. 2017 :6 et al . Semaglutide 1228–1239. (https://doi. et al (https://doi. (https://doi. Lancet . Effects 377 (https://doi. (https://doi. . Dulaglutide 2005 2019 839–848. Diabetes/ Lancet: R230 28 394 via freeaccess

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