Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)

Efficacy and Safety of DulaglutideVersus Sitagliptin After 52Weeks in Type 2 Diabetes ina Randomized Controlled Trial(AWARD-5)Diabetes Care 2014372149ndash2158 | DOI 102337dc13-2761

OBJECTIVE

To compare the efficacy and safety of two doses of once-weekly dulaglutide aglucagon-like peptide 1 receptor agonist to sitagliptin in uncontrolled metformin-treated patients with type 2 diabetes The primary objective was to compare (fornoninferiority and then superiority) dulaglutide 15 mg versus sitagliptin in changefrom baseline in glycosylated hemoglobin A1c (HbA1c) at 52 weeks

RESEARCH DESIGN AND METHODS

This multicenter adaptive double-blind parallel-arm study randomized patients (N =1098 mean baseline age 54 years HbA1c 81 [65 mmolmol] weight 864 kgdiabetes duration 7 years) to dulaglutide 15 mg dulaglutide 075 mg sitagliptin100mg orplacebo (placebo-controlledperiod up to 26weeks) The treatmentperiodlasted 104 weeks with 52-week primary end point data presented

RESULTS

The mean HbA1c changes to 52 weeks were (least squares mean 6 SE) 2110 6

006 (2120 6 07 mmolmol) 2087 6 006 (95 6 07 mmolmol) and2039 6 006 (43 6 07 mmolmol) for dulaglutide 15 mg dulaglutide 075mg and sitagliptin respectively Both dulaglutide doseswere superior to sitagliptin(P lt 0001 both comparisons) No events of severe hypoglycemia were reportedMeanweight changes to 52weeks were greater with dulaglutide 15mg (23036022 kg) and dulaglutide 075 mg (2260 6 023 kg) compared with sitagliptin(21536 022 kg) (P lt 0001 both comparisons) The most common gastrointestinaltreatment-emergent adverse events in dulaglutide 15- and 075-mg arms werenausea diarrhea and vomiting

CONCLUSIONS

Both dulaglutide doses demonstrated superior glycemic control versus sitagliptinat 52 weeks with an acceptable tolerability and safety profile

The American Diabetes Association and European Association for the Study of Di-abetes recommend metformin for initial drug treatment of type 2 diabetes (1) Ifalternative or combination therapy is necessary other agents such as sulfonylureasthiazolidinediones dipeptidyl peptidase-4 (DPP-4) inhibitors glucagon-like peptide1 (GLP-1) receptor agonists or insulin may be used (1) DPP-4 inhibitors and GLP-1

1DiabeteszentrumBad Lauterberg Bad LauterbergGermany2Upstate Medical University Syracuse NY3Emory University Atlanta GA4Diabetology Nutrition and Metabolic Disor-ders University of Lorraine Brabois HospitalVandoeuvre-Les-Nancy France5Center of Clinical Investigation ILCV Centre Hos-pitalier Universitaire de Nancy Vandoeuvre-Les-Nancy France6Lilly Diabetes Eli Lilly and Company Indianap-olis IN7Lilly Diabetes Eli Lilly and Company ViennaAustria

Corresponding author ZvonkoMilicevicmilicevic_zvonkolillycom

Received 25 November 2013 and accepted 7March 2014

Clinical trial reg no NCT00734474 clinicaltrialsgov

This article contains Supplementary Data onlineat httpcarediabetesjournalsorglookupsuppldoi102337dc13-2761-DC1

copy 2014 by the American Diabetes AssociationReadersmay use this article as long as the work isproperly cited the use is educational and not forprofit and the work is not altered

See accompanying articles pp 2159and 2168

Michael Nauck1 Ruth S Weinstock2

Guillermo E Umpierrez3 Bruno Guerci45

Zachary Skrivanek6 and Zvonko Milicevic7

Diabetes Care Volume 37 August 2014 2149

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receptor agonists are being prescribedwith increasing frequency in thesepatients (1)Both GLP-1 receptor agonists and

DPP-4 inhibitors act via the GLP-1 path-way by increasing the interaction of na-tive GLP-1 or a respective receptoragonist with the GLP-1 receptor Treat-ment with GLP-1 receptor agonists isbased on subcutaneous administrationof exogenous peptides with differentdegrees of structural homology withnative GLP-1 Oral DPP-4 inhibitors in-crease concentrations of endogenousGLP-1 by inhibiting the rapid inactiva-tion by the DPP-4 protease (12) In-creased availability of GLP-1 or areceptor agonist stimulates insulin se-cretion in a glucose-dependent mannerand inhibits glucagon secretion (34)GLP-1 receptor agonists also slow gastricemptying and suppress appetite actionsthat can contribute to overall glucose-lowering potency (1) In recently re-ported trials GLP-1 receptor agonistsand the DPP-4 inhibitor sitagliptin havebeen compared over a 26-week treat-ment period (56) The results of thesestudies indicate greater glucose- andbody weightndashlowering effects of GLP-1receptor agonists Additional data fromlonger duration trials are important toconfirm these observations and furthercharacterize safety profiles of theseagentsDulaglutide is a long-acting human

GLP-1 receptor agonist in developmentas a once-weekly subcutaneous injec-tion for the treatment of type 2 diabetes(78) The molecule consists of two iden-tical disulfide-linked chains each con-taining an N-terminal GLP-1 analogsequence covalently linked to a modi-fied human immunoglobulin G4 heavychain by a small peptide linker (7) Incontrast to native GLP-1 dulaglutide isresistant to degradation by DPP-4 andhas a large size that slows absorptionand reduces renal clearance These mo-lecular features result in a soluble for-mulation and a prolonged half-life of5 days making it suitable for once-weekly subcutaneous administration (7)Dulaglutide exhibits GLP-1ndashmediatedeffects including glucose-dependentpotentiation of insulin secretion inhibi-tion of glucagon secretion delay of gas-tric emptying and weight loss (7ndash10)Initial clinical trials have shown that

dulaglutide treatment results in dose-

dependent reductions in fasting plasmaglucose (FPG) postprandial plasma glu-cose and glycosylated hemoglobin A1c(HbA1c) (71112) Nausea and diarrheawere the most commonly reported ad-verse events (71112) This trial Assess-ment of Weekly AdministRation ofLY2189265 [dulaglutide] in Diabetes-5(AWARD-5) evaluated multiple sets ofobjectives including selection of oneor two dulaglutide doses (from a rangeof seven doses) for further assessmentin this and other phase 3 trials (13ndash15)and safety and efficacy of selecteddulaglutide doses in comparison withsitagliptin over a period of 104 weeksand placebo up to 26 weeks in metformin-treated patients with type 2 diabetes Inthis study we present results for theselected doses and comparators up tothe primary end point at 52 weeks


Eligible patients were those 18ndash75 yearsold had type 2 diabetes ($6 months)with an HbA1c value of 8 (64mmolmol) and 95 (80 mmolmol)on diet and exercise alone or $7 (53mmolmol) and 95 (80 mmolmol)on oral antihyperglycemic medication(OAM) monotherapy or combinationtherapy (metformin plus another OAM)a BMI between 25 and 40 kgm2 and astable weight during the 3-month periodbefore entering the study Patients wereexcluded if theywere takingGLP-1 recep-tor agonists during the 6 months priorto screening or were on chronic insulintherapy The protocol was approvedby local ethics review boards and allpatients provided written informedconsent The study was conducted incompliance with the Declaration ofHelsinki and the International Confer-ence on Harmonization guideline ongood clinical practices (16)

The study used an adaptive seamlessparallel-arm design (Fig 1A) to addresstwo groups of objectives 1) selection ofone or two doses for further longer-term assessment (dose-finding) (17)and 2) comparison of efficacy and safetyof selected dulaglutide doses versussitagliptin (100 mg once daily) at 52and 104 weeks and versus placebo at26 weeks (confirmatory objectives) Eli-gible patients entered a lead-in periodthat lasted up to 11 weeks Patientswere required to be treated with met-formin monotherapy (minimum dose

$1500 mgday) for $6 weeks prior torandomization to then be continuedduring the treatment period all otherOAMs were discontinued This lead-inperiod allowed patients to achieve a sta-ble dose of metformin and washout ofother OAMs Following the lead-in pe-riod patients were assigned to treatmentby one of two sequential randomizationschemes adaptive randomization duringthe dose-finding portion followed byfixed randomization after dose selection(13ndash15) A total of 230 patients wereadaptively randomized during the dose-finding portion Dulaglutide 15- and075-mg doses were selected for furtherassessment at the completion of thedose-finding portion (18) After doseselection occurred patients from nonse-lected arms were discontinued Addi-tional patients were assigned in a fixedrandomization manner to the remainingarms dulaglutide 15 mg dulaglutide075 mg sitagliptin 100 mg or placebo(replaced with sitagliptin after 26 weeksto keep blinding) in a 2221 ratio (17)The treatment period lasted 104 weeksPatients who developed persistent orworsening hyperglycemia based on pre-specified thresholds (SupplementaryTable 1) were discontinued from thestudy and an adverse event of hypergly-cemia was reported in the database

The primary outcome measure wasmean change in HbA1c from baseline to52 weeks Secondary efficacy measuresincluded change from baseline in HbA1cat other time points percentage of pa-tients with HbA1c 70 (53 mmolmol)or 65 (48 mmolmol) body weightFPG (central laboratory measure) andfasting insulin b-cell function and insulinsensitivity indices (updated homeostasismodel assessment [HOMA2]) (19) andlipids

Safety assessments included hypo-glycemic episodes vital signs electro-cardiograms laboratory parametersadverse events and dulaglutide antidrugantibodies (ADAs) Adjudication of pan-creatic events was performed by an in-dependent clinical end point committeeThe following events were adjudicatedto assess for development of pancreati-tis investigator-reported pancreatitisadverse events of serious or severe ab-dominal pain without known cause andcases of confirmed pancreatic enzymeelevations ($3 times the upper limitof normal) Laboratory analyses were

2150 Efficacy and Safety of Dulaglutide Diabetes Care Volume 37 August 2014

performed at a central laboratory (Quin-tiles Laboratories) Immunogenicity test-ing was performed by BioAgilytix

(Durham NC) andMillipore (St CharlesMO) Hypoglycemia was defined asplasma glucose 70 mgdL (39

mmolL) andor symptoms andor signsattributable to hypoglycemia (20)Severe hypoglycemia was defined as

Figure 1mdashStudy design (A) and patient disposition (B) All patients underwent a metformin run-in period that lasted up to 11 weeks to be continuedfor the duration of the study other OAMs were discontinued Seven doses of dulaglutide were evaluated in the dose-finding portion along withsitagliptin and placebo At dose selection dulaglutide 15 and 075 mg were selected for further evaluation Only patients assigned to selecteddulaglutide doses and comparators continued forward in the study Placebo-treated patients continued until week 26 and were then switched tositagliptin for blinding purposes aRandomization bPrimary end point cFinal end point dThe placebo period lasted for 26 weeks followed by a switchto sitagliptin to keep the arm blinded

carediabetesjournalsorg Nauck and Associates 2151

an episode requiring the assistance ofanother person to actively administertherapy (20)

Statistical AnalysisA sample size of 263 patients was cho-sen per arm (131 placebo) based on apredictive power calculation at dose se-lection of at least 85 to show superi-ority relative to sitagliptin at 52 weeks(14)Primary and secondary analyses were

based on the intent-to-treat (ITT) popu-lation defined as all randomized pa-tients All results presented are basedupon patients who had at least one out-come measure after initiation of treat-ment All patients randomized in thisstudy received at least one dose of studydrug The data from the placebo armwere excluded from any analysis after26 weeksThe analyses for the primary (nonin-

feriority of dulaglutide 15 mg to sita-gliptin at 52 weeks) and key secondaryefficacy objectives (HbA1c change frombaseline at 26 weeks vs placebo andat 52 weeks vs sitagliptin) used a tree-gatekeeping strategy to control thefamily-wise type 1 error rate with ad-justed P values (21) Superiority or non-inferiority (noninferioritymargin of 025)of a dulaglutide dose to a comparator

treatment was concluded if the (one-sided) adjusted P value was002

The change from baseline in HbA1c andweight at 26 and 52 weeks was analyzedusingANCOVAwith factors for treatmentcountry and baseline value as a covari-ate The last observation was carried for-ward (LOCF) in the case of missing dataAll continuous measures including sensi-tivity analyses of HbA1c and weight overtime were also analyzed using a mixed-effects repeated-measures (MMRM)analysis with additional factors for visitand treatment-by-visit interaction Leastsquares (LS) means and SEs are reportedThe percentage of patients achievingHbA1c targets (LOCF) was analyzedusing a logistic regression model Totalhypoglycemia included events that weredocumented symptomatic documentedasymptomatic probable andor severe(20) Adverse events were analyzedusing a x2 test unless there were notsufficient data to meet the assumptionsof the analysis in which case a Fisher ex-act test was conducted The two-sidedsignificance level was 5 for secondaryend points and 10 for interactions

RESULTS

The ITT population comprised 1098patients randomized to dulaglutide(15 or 075 mg) sitagliptin or placebo

arms (Fig 1A) Baseline characteristicswere balanced across arms (Table 1)The metformin dose was similar acrossarms at baseline and changes in dosewere rare The most common reasonsfor early study discontinuation wereadverse events and subject decision(Fig 1B)

EfficacyOf 1098 patients included in the ITT pop-ulation 13 did not contribute to the pri-mary analysis due to missing baseline orpostbaseline HbA1c measurements Themean HbA1c changes from baseline tothe primary end point at 52 weeks were(LS mean 6 SEs) 2110 6 006(21206 07 mmolmol) for dulaglutide15 mg 2087 6 006 (295 6 07mmolmol) for dulaglutide 075 mg and20396 006 (2436 07 mmolmol)for sitagliptin (Fig 2A) Compared withsitagliptin the LS mean changes frombaseline were significantly greater (ad-justed P 0001 both comparisons)with dulaglutide 15 mg (LS mean differ-ence2071 [278 mmolmol] nominal95 CI2087 to2055 [295 to260mmolmol]) and also with dulaglutide075 mg (2047 [251 mmolmol]2063 to 2031 [269 to 234mmolmol]) Fig 2B shows HbA1c valuesover time up to 52 weeks

Table 1mdashBaseline characteristics and demographics of randomized patients

Variable DU 15 mg (N = 304) DU 075 mg (N = 302) SITA (N = 315) PL (N = 177)

SexMen 146 (48) 134 (44) 151 (48) 90 (51)Women 158 (52) 168 (56) 164 (52) 87 (49)

Age (years) 54 6 10 54 6 10 54 6 10 55 6 9

RaceAboriginal 0 (0) 0 (0) 1 (1) 0 (0)Black 16 (5) 12 (4) 7 (2) 9 (5)White 157 (52) 162 (54) 158 (50) 91 (51)East Asian 50 (16) 47 (16) 52 (17) 28 (16)Hispanic 54 (18) 51 (17) 67 (21) 38 (22)Native American 0 (0) 0 (0) 1 (1) 0 (0)West Asian 27 (9) 30 (10) 28 (9) 11 (6)

BMI (kgm2) 31 6 5 31 6 4 31 6 4 31 6 4

Weight (kg) 87 6 17 86 6 18 86 6 17 87 6 17

Diabetes duration (years) 7 6 6 7 6 5 7 6 5 7 6 5

HbA1c [ (mmolmol)] 81 6 11 (65 6 12) 82 6 11 (66 6 12) 81 6 11 (65 6 12) 81 6 11 (65 6 12)

Antihyperglycemic medicationa

OAM 290 (95) 284 (94) 294 (93) 167 (94)One medication class 203 (67) 193 (64) 218 (69) 114 (64)Two medication classes 83 (27) 89 (30) 76 (24) 49 (28)More than two medication classes 4 (1) 2 (1) 0 (0) 4 (2)

SBP (mmHg) 129 6 13 128 6 14 127 6 13 128 6 13

DBP (mmHg) 78 6 8 78 6 9 77 6 9 78 6 8

Data are means 6 SD or n () unless otherwise indicated DU dulaglutide PL placebo SITA sitagliptin aAt screening


The LS mean HbA1c changes frombaseline to 26 weeks were 2122 6005 (2133 6 06) 2101 6 006

(2110 6 07) 2061 6 005 (267 606) and 003 6 007 (03 6 08mmolmol) for dulaglutide 15 mg

dulaglutide 075 mg sitagliptin and pla-cebo respectively (Fig 2A) Comparedwith placebo LS mean changes from

Figure 2mdashEfficacy and safetymeasures through the treatment period A Change in HbA1c from baseline at 26 and 52weeks ANCOVA LOCF B HbA1cover time MMRM C Percentage of patients achieving HbA1c targets at 26 and 52 weeks D Change in FPG over time MMRM E Change in weightover time MMRM Data presented are LS mean6 SE daggerdaggerP 0001 superiority vs sitagliptin DaggerDaggerP 0001 superiority vs placebo P 005 vssitagliptin and placebo respectively P 0001 vs sitagliptin and placebo respectively


baseline were significantly greater (P 0001 all comparisons) with dulaglutide15 mg (LS mean difference 2126[2138 mmolmol]) dulaglutide 075mg (2105 [2115 mmolmol]) andsitagliptin (2064 [270 mmolmol])Compared with sitagliptin LS meanchanges from baseline at 26 weekswere significantly greater with bothdulaglutide doses (P 0001 bothcomparisons)After 52 weeks of treatment the per-

centage of patients attaining the targetHbA1c goal of 70 (53 mmolmol)was significantly higher in dulaglutide15-mg and dulaglutide 075-mg arms(58 and 49 respectively) comparedwith sitagliptin (33) (P 0001 bothcomparisons) (Fig 2C) At the same endpoint 42 and 29 of patients in thedulaglutide15- and075-mgarms respec-tively achieved HbA1c targets of 65(48 mmolmol) compared with 19 inthe sitagliptin arm (P 0001 both com-parisons) At 26 weeks the percentageof patients achieving HbA1c values70 (53 mmolmol) was significantlyhigherwith dulaglutide 15mg (61) anddulaglutide 075 mg (55) comparedwith sitagliptin (38) (P 0001 bothcomparisons) and placebo (21) (P 0001 both comparisons) (Fig 2C) Atthe same time point 47 and 31 of du-laglutide 15 mgndash and dulaglutide 075mgndashtreated patients respectivelyachieved HbA1c values 65 (48mmolmol) compared with 22 with si-tagliptin (P 0001 both comparisons)and 13 with placebo (P 0001 bothdulaglutide comparisons P = 0005 sita-gliptin comparison)Values of FPG significantly decreased

within 2 weeks with both dulaglutidedoses and with sitagliptin and remainedsteady thereafter while the placeboarm exhibited smaller and slower de-creases over time (Fig 2D) Comparedwith sitagliptin LS mean changes frombaseline at 52 weeks in FPG were signif-icantly greater (P 0001 both compar-isons) with dulaglutide 15 mg (LS meandifference 226 mgdL) and dulaglutide075 mg (213 mgdL) All three activearms had significantly greater changesin FPG from baseline to 26 weeks com-pared with placebo (Fig 2D)Themean changes in bodyweight from

baseline to 52 weeks were (LSmean6 SE[ANCOVA with LOCF]) significantlygreater (P 0001 both comparisons)

for dulaglutide 15 mg (2303 6 022kg) and dulaglutide 075 mg (2260 6023 kg) compared with sitagliptin(2153 6 022 kg) (LS mean difference2150 and2107 kg respectively) Bothdulaglutide doses were associated withsignificantly greater (P 0001) reduc-tions in body weight compared withplacebo and sitagliptin at 26 weeksThe effect on body weight was main-tained in all arms over time (Fig 2E)

b-Cell function estimated byHOMA2-B at 52 weeks increased nu-merically in all arms versus baseline(Supplementary Table 2) The changesobserved at 52 weeks were significantlygreater with dulaglutide doses com-pared with sitagliptin (P 0001) Nodifferences were observed among armswith respect to insulin sensitivity of theperipheral tissues estimated byHOMA2-S (Supplementary Table 2)Both dulaglutide arms were associatedwith a greater effect on HOMA2-B ver-sus placebo at 26 weeks (P 0001both comparisons) A significantly lower(P = 0026) effect on HOMA2-S wasassociatedwith dulaglutide 075mg com-pared with placebo no other differenceswere noted for change in HOMA2-Sat this time point

At 52 weeks a decrease in LDL cho-lesterol with dulaglutide 15 mg and anincrease with sitagliptin was observedresulting in significant between-treatment difference (P = 003) (Sup-plementary Table 2) At 26 weeks sig-nificantly greater decreases in totaland LDL cholesterol were observedwith dulaglutide 15 mg comparedwith placebo (P 0001 and 0007 re-spectively) No other differences wereobserved for total LDL and HDL choles-terol or triglycerides between dulaglu-tide and sitagliptin doses at 52 weeksand placebo at 26 weeks

SafetyTable 2 summarizes incidence of deathsoverall and serious adverse events andindividual adverse events occurring in atleast 5 of patients at 26 and 52 weeksFour patients (dulaglutide 15 mg onesitagliptin two placebo [during thesitagliptin period] one) died duringthis trial The patient treated withdulaglutide 15 mg died of a nonhemor-rhagic stroke 6 months after random-ization The incidence of adverse eventswas similar in dulaglutide arms versus

sitagliptin at 52 weeks and versus pla-cebo at 26 weeks The incidence ofgastrointestinal (GI) adverse events(nausea diarrhea and vomiting) andthe adverse event of decreased appetitewas significantly higher (P 005) withdulaglutide- compared with sitagliptin-treated patients Similar results were ob-served for comparisons betweendulaglutide- and placebo-treated pa-tients The incidence of nausea diarrheaand vomiting with dulaglutide 15 mgand dulaglutide 075 mg peaked withinthe first 2 weeks of treatment and grad-ually declined to stable levels (1ndash6 in-cidence) between 8 and 52 weeks oftreatment

The incidence of study discontinua-tion due to adverse events at 52 weekswas similar across arms (dulaglutide 15mg 33 [109] dulaglutide 075 mg 23[76] sitagliptin 30 [95]) the mostcommon adverse events causing studydiscontinuation were hyperglycemiaand nausea Discontinuation becauseof nausea was only reported with dula-glutide (dulaglutide 15 mg 8 [26]dulaglutide 075 mg 3 [10]) and themajority of these patients (6) discontin-ued within the initial 2 weeks of studydrug administration During the placebo-controlled period hyperglycemia andnausea were also the most common ad-verse events causing discontinuation Allcases of discontinuation due to nauseaduring this period (eight patients) oc-curred in dulaglutide arms There weremore patients from the placebo arm (17patients [96]) who discontinued thestudy due to hyperglycemia comparedwith active treatments (dulaglutide 15mg 4 [13] dulaglutide 075 mg1 [03] and sitagliptin 6 [19])

The incidence of total hypoglycemiaat 52 weeks was 102 for dulaglutide15 mg 53 for dulaglutide 075 mgand 48 for sitagliptin mean (SD)1-year adjusted rates (eventspatientyear) were 04 (16) 03 (26) and 01(11) respectively The incidence andrates at 26 weeks for dulaglutide- andsitagliptin-treated patients were similarto those observed at 52 weeks inci-dence and rate in the placebo arm at26 weeks were 11 and 01 (09) re-spectively There were no severe hypo-glycemic events reported during thistrial

There were three events of acutepancreatitis confirmed by adjudication


(sitagliptin two placebo [during the si-tagliptin period] one) Increases in me-dian values of serum lipase totalamylase and pancreatic amylase (p-amylase) (within the normal range)were observed with both dulaglutidedoses and sitagliptin (SupplementaryTable 2) Increase in total amylase wassignificantly greater for both dulaglutidedoses than for sitagliptin during the 52-week treatment period (P = 0016for both comparisons) increase inp-amylase for dulaglutide 15 mg wasalso significantly greater comparedwith sitagliptin (P = 0008) There wereno differences between the dulaglutideand sitagliptin arms in the incidence oftreatment-emergent (TE) high valuesduring this period All active treatmentsdemonstrated significant (P 0001) in-crease in median values of pancreaticenzymes (except sitagliptin for total am-ylase) and higher incidence of TE high

lipase values in comparison with pla-cebo during the placebo-controlledperiod (P 0001 dulaglutide 15 mgP = 0015 dulaglutide 075 mg and P =0023 sitagliptin) TE high p-amylasevalues were also more common inboth dulaglutide arms than placebo(P = 0032 dulaglutide 15 mg and P =002 dulaglutide 075 mg)

Systolic blood pressure (SBP) de-creased in all active treatment armswith the greatest reductions observedduring the first 3ndash6 months (Table 2)Decrease in SBP from baseline up to 26weeks was significantly greater withboth dulaglutide doses and sitagliptincompared with placebo (P 005)There were no differences between du-laglutide arms and sitagliptin at thistime point or at 52 weeks Changes indiastolic blood pressure (DBP) weresmall (Table 2) and there were no sig-nificant differences between active

treatments at 26 or 52 weeks An in-crease of2 to 3 bpm in LS mean pulserate was observed with both dulaglutidedoses at 26 and 52 weeks in comparisonwith no relevant changes in the sitaglip-tin and placebo arms at these timepoints (Table 2)

There were no cases of thyroid cancerduring the 52-week observational pe-riod There were no differences amongarms in calcitonin levels at 26 or 52weeks

Nine patients treated with dulaglutidehad TE dulaglutide ADAs during the treat-ment period (13) (Table 2) Dulaglutideneutralizing antibodies were present intwo of these nine patients and no patientdeveloped native-sequence GLP-1 neu-tralizing antibodies None of these pa-tients had hypersensitivity events Theincidence of hypersensitivity eventsacross the groups was very low and sim-ilar (data not shown)

Table 2mdashSafety assessments change from baseline in vital signs and TE dulaglutide ADAs through 26 and 52 weeks

Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)

Serious adverse events 17 (6) 10 (3) 11 (4) 6 (3) 26 (9) 16 (5) 17 (5)

Adverse events (patients with $1 event) 208 (68) 204 (68) 185 (59) 111 (63) 233 (77) 231 (77) 219 (70)

TE adverse events ($5 patients)SOC GI events 116 (38) 97 (32) 55 (18) 41 (23) 126 (41) 111 (37) 73 (23)Nausea 51 (17) 38 (13) 14 (4) 7 (4) 53 (17) 42 (14) 16 (5)Vomiting 36 (12) 22 (7) 6 (2) 1 (1) 39 (13) 23 (8) 7 (2)Diarrhea 39 (13) 27 (9) 8 (3) 11 (6) 44 (15) 30 (10) 9 (3)Abdominal pain 13 (4) 11 (4) 6 (2) 3 (2) 18 (6) 12 (4) 10 (3)Dyspepsia 13 (4) 14 (5) 8 (3) 2 (1) 14 (5) 18 (6) 9 (3)Abdominal distension 12 (4) 12 (4) 3 (1) 1 (1) 12 (4) 14 (5) 3 (1)

SOC infections and infestations 89 (29) 71 (24) 74 (24) 36 (20) 111 (37) 97 (32) 101 (32)Nasopharyngitis 25 (8) 24 (8) 26 (8) 13 (7) 35 (12) 35 (12) 36 (11)URI 12 (4) 12 (4) 4 (1) 2 (1) 16 (5) 16 (5) 12 (4)UTI 11 (4) 16 (5) 11 (4) 9 (5) 15 (5) 18 (6) 15 (5)

Other adverse eventsa

Hyperglycemia 4 (1) 5 (2) 14 (4) 19 (11) 16 (5) 23 (8) 29 (9)Decreased appetite 29 (10) 16 (5) 5 (2) 3 (2) 29 (10) 17 (6) 7 (2)Back pain 12 (4) 13 (4) 10 (3) 7 (4) 15 (5) 18 (6) 15 (5)Headache 20 (7) 20 (7) 19 (6) 9 (5) 26 (9) 23 (8) 23 (7)Arthralgia 7 (2) 10 (3) 4 (1) 4 (2) 11 (4) 14 (5) 8 (3)Dizziness 3 (1) 13 (4) 8 (3) 4 (2) 5 (2) 14 (5) 10 (3)

Discontinuation due to adverse events 21 (7) 12 (4) 14 (4) 24 (14) 33 (11) 23 (8) 30 (10)

Vital signsSBP (mmHg) 217 6 07 214 6 07 219 6 07 11 6 09 208 6 07 205 6 07 205 6 07DBP (mmHg) 204 6 04 202 6 04 211 6 04 07 6 06 03 6 05 02 6 05 202 6 05Pulse rate (bpm) 26 6 05 19 6 05 201 6 05 202 6 07 24 6 05 21 6 05 203 6 05

TE dulaglutide ADAsDulaglutide ADAs 2 (1) 6 (2) 1 (1) 0 (0) 2 (1) 7 (2) 2 (1)Neutralizing dulaglutide ADAs 2 (1) 0 (0) 0 (0) 0 (0) 2 (1) 0 (0) 0 (0)

Data are n () or LS mean (6 SE) unless otherwise indicated DU dulaglutide PL placebo SITA sitagliptin SOC system organ class URI upperrespiratory infection UTI urinary tract infection P 005 vs sitagliptin and placebo respectively P 0001 vs sitagliptin and placeborespectively aMultiple SOCs


CONCLUSIONS

The results of the AWARD-5 studyshowed that in patients unable to attainglycemic targets with metformin mono-therapy addition of dulaglutide 15-mgor dulaglutide 075-mg doses providedsignificantly greater improvement inHbA1c compared with sitagliptin after52 weeks and placebo after 26 weeksAccordingly a higher percentage ofdulaglutide-treated patients attainedHbA1c targets in comparison with sita-gliptin The differences in HbA1c relativeto sitagliptin for dulaglutide 15 mg(2071 [278 mmolmol]) and dulaglu-tide 075 mg (2047 [251 mmolmol])are considered clinically relevant (22)Dulaglutide also exhibited greater weightreduction than sitagliptin GI systemndash

related adverse events were the mostcommonly reported events in patientstreated with dulaglutide and more fre-quent than with placebo or sitagliptinDiscontinuation rates across the groupsat 26 and 52 weeks were comparable tothe rates observed in similar diabetes tri-als previously reported in the medical lit-erature (23ndash25)The observed effects of dulaglutide

and sitagliptin on HbA1c in AWARD-5are similar to those reported in otherpatient populations treated with theseagents Grunberger et al (11) andUmpierrez et al (12) showed a similareffect of dulaglutide on HbA1c as add-on therapy to diet or in combinationwith OAMs In the current study theglucose-lowering effect of sitagliptinwas 2061 6 005 (267 6 06mmolmol) and 2039 6 006 (43 607 mmolmol) at 26 and 52 weeks re-spectively This decrease in HbA1c is con-sistent with results from other studieswith similar patient populations andstudy duration (62627) Greater im-provements in glycemic control withdulaglutide were also evident in thesignificantly higher percentage of pa-tients who achieved HbA1c targets of70 (53 mmolmol) and 65 (48mmolmol) than with sitagliptin In ad-dition the results of this trial showedthat the difference in glucose-loweringeffects between dulaglutide and sita-gliptin was sustained over a longer pe-riod of time (ie 52 weeks) comparedwith previously published trials thatcompared sitagliptin to a GLP-1 recep-tor agonist for up to 26 weeks (34)

One possible explanation of these dif-ferences in glucose-lowering effects re-lates to the greater degree of GLP-1receptor stimulation with receptor ago-nists than with DPP-4 inhibitors (28) Ithas been suggested that longer-actingreceptor agonists are associated withpersistently elevated GLP-1 receptor ag-onist concentrations while DPP-4 inhib-itors increase concentration of GLP-1mostly after meals (29ndash31) Assessmentof pancreatic b-cell function using theHOMA2 model may support these ex-planations Dulaglutide demonstratedgreater effects on b-cell function com-pared with sitagliptin suggesting that adrug that provides high pharmacologicallevels of exogenous GLP-1 receptor ag-onist may be more effective than a drugthat modestly increases concentrationof endogenous GLP-1 One caveat tothis comparison HOMA2 assessesb-cell function in the fasting statewhen dulaglutide levels were continu-ously elevated while during this sametime phase for patients treated with si-tagliptin endogenous GLP-1 was mostlikely in its basal range (nonndashnutrient-stimulated)

Dulaglutide-treated patients achievedan early improvement (after 2 weeks)in fasting glucose consistent with thereported pharmacokinetic characteris-tics of the drug (56) This early effectis important from a clinical perspectivein that it is a readily available measureof glycemic response allowing patientsand health care providers to gauge anindication of therapeutic effect soonafter the initiation of therapy

Themain determinants of weight gainin patients with diabetes are changes inHbA1c and type of glucose-lowering in-tervention (32) Dulaglutide treatmentresulted in significantly greater de-creases in body weight compared withsitagliptin throughout the duration ofthe treatment period despite its largereffect on HbA1c The mechanisms ofweight loss with GLP-1 receptor agonistsare probably related to their actions inthe GI andor central nervous system(3334)

Safety assessments of dulaglutide inthis trial are consistent with the knowneffects of the GLP-1 receptor agonistclass The incidence of hypoglycemicevents remained very low in both dula-glutide arms despite the robust effecton glycemic control This is consistent

with the known mechanism of actionof dulaglutide which enhances insulinsecretion in a glucose-dependent fash-ion without causing b-cell overstimula-tion and hyperinsulinemia (35)

Both dulaglutide doses were associ-ated with a higher incidence of GI ad-verse events most commonly nauseavomiting and diarrhea There were nocases of pancreatitis reported in pa-tients treated with dulaglutide The ob-served increases within the normalrange in median values of pancreatic en-zymes with dulaglutide and sitagliptinwere similar in magnitude to thechanges reported with liraglutide (36)The mechanism that causes these in-creases is unknown and there were noobserved clinical consequences of thesefindings

Cardiovascular system observationsincluded a decrease in SBP and an in-crease in pulse rate The magnitude ofthe observed changes in pulse rate wassimilar to that reported with other GLP-1 receptor agonists (62737) The inci-dence of dulaglutide ADAs was very low(13) compared with other GLP-1 re-ceptor agonists (3839) There were noassociated systemic or injection site hy-persensitivity reactions in ADA-positivepatients Additionally hypersensitivityevents overall were rare and balancedin incidence across the arms Thesedata suggest a low risk of hypersensitiv-ity reactions with dulaglutide

The AWARD-5 trial confirmed thatdulaglutide is an effective treatmentoption in metformin-treated patientswho require further treatment inten-sification Both doses were superior inglucose lowering to sitagliptin and pla-cebo Despite a greater decrease inHbA1c patients who received dulaglu-tide exhibited a decrease in weight andlow risk of hypoglycemia Dulaglutidehas a similar safety profile to that ofother agents from the GLP-1 receptoragonist class These results suggesta favorable benefitrisk profile fordulaglutide as an add-on interventionin metformin-treated type 2 diabeticpatients

Acknowledgments The authors thank theAWARD-5 team and staff for conducting thisstudy and Oralee Johnson Varnado PhD Eli Lillyand Company for writing assistanceFunding and Duality of Interest This work issponsored by Eli Lilly and Company MN


received research grants from Berlin-ChemieAGMenarini Eli Lilly and Company Merck Sharpamp Dohme Novartis Pharma AG AstraZenecaBoehringer Ingelheim GlaxoSmithKline Meta-Cure Inc Roche Pharma AG Novo Nordiskand Tolerx Inc for participation in multicenterclinical trials and received consulting fees orandhonoraria formembership in advisory boards orand honoraria for speaking fromAmylin Pharma-ceuticals Inc AstraZeneca Mjolndal Berlin-Chemie AGMenarini Boehringer IngelheimBristol-Myers Squibb Diartis PharmaceuticalsInc Eli Lilly and Company F Hoffmann-LaRoche Ltd GlaxoSmithKline Intarcia Thera-peutics Inc MannKind Corporation MerckSharp amp Dohme GmbH Merck Sharp amp DohmeNovartis Pharma AG Novo Nordisk AS NovoNordisk Pharma GmbH Sanofi Takeda Versartisand Wyeth Research including reimbursementfor travel expenses in connection with theabove-mentioned activities RSW participatedin multicenter clinical trials sponsored by Eli Lillyand Company Medtronic GlaxoSmithKlineSanofi Biodel and AstraZeneca GEU is sup-ported in part by research grants from the Amer-ican Diabetes Association (7-03-CR-35) PublicHealth Service grant UL1-RR-025008 from theClinical and Translational Science Awards Pro-gram (M01-RR-00039) National Institutes ofHealth and National Center for Research Resour-ces andby unrestricted research grants fromphar-maceutical companies (Sanofi and Merck Sharp ampDohme) to Emory University BG has receivedfees for consultancy advisory boards speakingtravel or accommodation from GlaxoSmithKlineEli Lilly and Company Merck Sharp amp DohmeAstraZeneca Bristol-Myers Squibb Pfizer NovoNordisk Sanofi Novartis Abbott LifeScanRoche Diagnostics Medtronic and MenariniZS and ZM are employees of Eli Lilly and Com-pany No other potential conflicts of interestrelevant to this article were reportedAuthor Contributions MN RSW GEUand BG researched data contributed to thediscussion and reviewed and edited the man-uscript ZS and ZM researched data andwrotethe manuscript ZM is the guarantor of thiswork and as such had full access to all the datain the study and takes responsibility for theintegrity of the data and the accuracy of thedata analysisPrior Presentation Portions of this studywere presented at the 73rd Scientific Sessionsof the American Diabetes Association ChicagoIL 21ndash25 June 2013 and the 49th Annual Euro-pean Association for the Study of DiabetesMeeting Barcelona Spain 23ndash27 September2013

References1 Inzucchi SE Bergenstal RM Buse JB et al

American Diabetes Association (ADA) Euro-

pean Association for the Study of Diabetes(EASD) Management of hyperglycemia in type

2 diabetes a patient-centered approach posi-

tion statement of the American Diabetes Asso-

ciation (ADA) and the European Association forthe Study of Diabetes (EASD) Diabetes Care

2012351364ndash13792 Holst JJ The physiology of glucagon-like pep-

tide 1 Physiol Rev 2007871409ndash1439

3 Holst JJ Orskov C Nielsen OV Schwartz TWTruncated glucagon-like peptide I an insulin-releasing hormone from the distal gut FEBSLett 1987211169ndash1744 Kreymann B Williams G Ghatei MA BloomSRGlucagon-like peptide-17-36 a physiologicalincretin in man Lancet 198721300ndash13045 Bergenstal RM Wysham C Macconell Let al DURATION-2 Study Group Efficacy andsafety of exenatide once weekly versus sitaglip-tin or pioglitazone as an adjunct to metforminfor treatment of type 2 diabetes (DURATION-2)a randomised trial Lancet 2010376431ndash4396 Pratley RE Nauck M Bailey T et al 1860-LIRA-DPP-4 Study Group Liraglutide versus sita-gliptin for patients with type 2 diabetes who didnot have adequate glycaemic control with met-formin a 26-week randomised parallel-groupopen-label trial Lancet 20103751447ndash14567 Barrington P Chien JY Tibaldi F ShowalterHD Schneck K Ellis B LY2189265 a long-actingglucagon-like peptide-1 analogue showed adose-dependent effect on insulin secretion inhealthy subjects Diabetes Obes Metab 201113434ndash4388 Glaesner W Vick AM Millican R et al Engi-neering and characterization of the long-actingglucagon-like peptide-1 analogue LY2189265an Fc fusion protein Diabetes Metab Res Rev201026287ndash2969 Data on file Eli Lilly and Company andor oneof its subsidiaries10 Baggio LL Drucker DJ Biology of incretinsGLP-1 and GIP Gastroenterology 20071322131ndash215711 Grunberger G Chang A Garcia Soria GBotros FT Bsharat R Milicevic Z Monotherapywith the once-weekly GLP-1 analogue dulaglu-tide for 12 weeks in patients with Type 2 diabe-tes dose-dependent effects on glycaemiccontrol in a randomized double-blind placebo-controlled study Diabet Med 2012291260ndash126712 Umpierrez GE Blevins T Rosenstock JCheng C Anderson JH Bastyr EJ 3rdEGO StudyGroup The effects of LY2189265 a long-actingglucagon-like peptide-1 analogue in a ran-domized placebo-controlled double-blind studyof overweightobese patients with type 2 diabe-tes the EGO study Diabetes Obes Metab 201113418ndash42513 Geiger MJ Skrivanek Z Gaydos B Chien JBerry S Berry D An adaptive dose-findingseamless phase 23 study of a long-actingglucagon-like peptide-1 analog (dulaglutide)trial design and baseline characteristics J Dia-betes Sci Tech 201261319ndash132714 Skrivanek Z Berry S Berry D et al Applica-tion of adaptive design methodology indevelopment of a long-acting glucagon-likepeptide-1 analog (dulaglutide) statistical de-sign and simulations J Diabetes Sci Tech201261305ndash131815 Spencer K Colvin K Braunecker B et alOperational challenges and solutions with im-plementation of an adaptive seamless phase 23 study J Diabetes Sci Tech 201261296ndash130416 World Medical Association World MedicalAssociation declaration of Helsinki Recommen-dations guiding physicians in biomedical re-search involving human subjects JAMA 1997277925ndash926

17 Skrivanek ZCJ Gaydos B Heathman MGeiger M Milicevic Z Eds Dose-Finding Resultsin an Adaptive Trial of Dulaglutide Combinedwith Metformin in Type 2 Diabetes (AWARD-5) Chicago IL American Diabetes Association201318 Skrivanek Z Chien JY Gaydos B HeathmanM Geiger MJ Milisevic Z Dose finding results inan adaptive trial of dulaglutide combined withmetformin in type 2 diabetes (AWARD-5) Dia-betologia 201356(Suppl 1)S40219 Wallace TM Levy JCMatthews DR Use andabuse of HOMA modeling Diabetes Care 2004271487ndash149520 Workgroup on Hypoglycemia American Di-abetes Association Defining and reporting hypo-glycemia in diabetes a report from the AmericanDiabetes Association Workgroup on Hypoglyce-mia Diabetes Care 2005281245ndash124921 Dmitrienko A Tamhane AC Wiens BL Gen-eral multistage gatekeeping procedures Biom J200850667ndash67722 Stratton IM Adler AI Neil HA et al Associ-ation of glycaemia with macrovascular and mi-crovascular complications of type 2 diabetes(UKPDS 35) prospective observational studyBMJ 2000321405ndash41223 Zinman B Gerich J Buse JB et al LEAD-4Study Investigators Efficacy and safety of thehuman glucagon-like peptide-1 analog liraglu-tide in combination with metformin and thiazo-lidinedione in patients with type 2 diabetes(LEAD-4 Met+TZD) Diabetes Care 2009321224ndash123024 NauckM Frid A Hermansen K et al LEAD-2Study Group Efficacy and safety comparison ofliraglutide glimepiride and placebo all in com-bination withmetformin in type 2 diabetes theLEAD (liraglutide effect and action in diabetes)-2study Diabetes Care 20093284ndash9025 Garber A Henry R Ratner R et al LEAD-3(Mono) Study Group Liraglutide versus glime-piride monotherapy for type 2 diabetes (LEAD-3Mono) a randomised 52-week phase IIIdouble-blind parallel-treatment trial Lancet2009373473ndash48126 Chapell R Gould AL Alexander CM Base-line differences in A1C explain apparent differ-ences in efficacy of sitagliptin rosiglitazone andpioglitazone Diabetes Obes Metab 2009111009ndash101627 Pratley RE Nauck MA Bailey T et al 1860-LIRA-DPP-4 Study Group Efficacy and safety ofswitching from the DPP-4 inhibitor sitagliptin tothe human GLP-1 analog liraglutide after 52weeks in metformin-treated patients with type2 diabetes a randomized open-label trial Di-abetes Care 2012351986ndash199328 DeFronzo RA Okerson T Viswanathan PGuan X Holcombe JH MacConell L Effects ofexenatide versus sitagliptin on postprandial glu-cose insulin and glucagon secretion gastricemptying and caloric intake a randomizedcross-over study Curr Med Res Opin 2008242943ndash295229 Aschner P Kipnes MS Lunceford JKSanchez M Mickel C Williams-Herman DE Si-tagliptin Study 021 Group Effect of the dipep-tidyl peptidase-4 inhibitor sitagliptin asmonotherapy on glycemic control in patientswith type 2 diabetes Diabetes Care 2006292632ndash2637


30 Degn KB Juhl CB Sturis J et al One weekrsquostreatment with the long-acting glucagon-likepeptide 1 derivative liraglutide (NN2211) mark-edly improves 24-h glycemia and alpha- andbeta-cell function and reduces endogenous glu-cose release in patients with type 2 diabetesDiabetes 2004531187ndash119431 Herman GA Stevens C Van Dyck K et alPharmacokinetics and pharmacodynamics ofsitagliptin an inhibitor of dipeptidyl peptidaseIV in healthy subjects results from two ran-domized double-blind placebo-controlledstudies with single oral doses Clin PharmacolTher 200578675ndash68832 Fonseca V McDuffie R Calles J et alACCORD Study Group Determinants of weight

gain in the Action to Control Cardiovascular Riskin Diabetes Trial Diabetes Care 2013362162ndash216833 Flint A Raben A Astrup A Holst JJ Glucagon-like peptide 1 promotes satiety and suppressesenergy intake in humans J Clin Invest 1998101515ndash52034 Kieffer TJ Habener JF The glucagon-likepeptides Endocr Rev 199920876ndash91335 Drucker DJ Nauck MA The incretin systemglucagon-like peptide-1 receptor agonists anddipeptidyl peptidase-4 inhibitors in type 2 dia-betes Lancet 20063681696ndash170536 Buse JB Nauck M Forst T et al Exenatideonce weekly versus liraglutide once daily in pa-tients with type 2 diabetes (DURATION-6)

a randomised open-label study Lancet 2013381117ndash12437 Blevins T Pullman JMalloy J et al DURATION-5 exenatide once weekly resulted in greaterimprovements in glycemic control comparedwith exenatide twice daily in patients withtype 2 diabetes J Clin Endocrinol Metab 2011961301ndash131038 Russell-Jones D The safety and tolerabilityof GLP-1 receptor agonists in the treatment oftype-2 diabetes Int J Clin Pract 2010641402ndash141439 Schellekens H Factors influencing theimmunogenicity of therapeutic proteinsNephrol Dial Transplant 200520(Suppl 6)vi3ndashvi9


receptor agonists are being prescribedwith increasing frequency in thesepatients (1)Both GLP-1 receptor agonists and

DPP-4 inhibitors act via the GLP-1 path-way by increasing the interaction of na-tive GLP-1 or a respective receptoragonist with the GLP-1 receptor Treat-ment with GLP-1 receptor agonists isbased on subcutaneous administrationof exogenous peptides with differentdegrees of structural homology withnative GLP-1 Oral DPP-4 inhibitors in-crease concentrations of endogenousGLP-1 by inhibiting the rapid inactiva-tion by the DPP-4 protease (12) In-creased availability of GLP-1 or areceptor agonist stimulates insulin se-cretion in a glucose-dependent mannerand inhibits glucagon secretion (34)GLP-1 receptor agonists also slow gastricemptying and suppress appetite actionsthat can contribute to overall glucose-lowering potency (1) In recently re-ported trials GLP-1 receptor agonistsand the DPP-4 inhibitor sitagliptin havebeen compared over a 26-week treat-ment period (56) The results of thesestudies indicate greater glucose- andbody weightndashlowering effects of GLP-1receptor agonists Additional data fromlonger duration trials are important toconfirm these observations and furthercharacterize safety profiles of theseagentsDulaglutide is a long-acting human

GLP-1 receptor agonist in developmentas a once-weekly subcutaneous injec-tion for the treatment of type 2 diabetes(78) The molecule consists of two iden-tical disulfide-linked chains each con-taining an N-terminal GLP-1 analogsequence covalently linked to a modi-fied human immunoglobulin G4 heavychain by a small peptide linker (7) Incontrast to native GLP-1 dulaglutide isresistant to degradation by DPP-4 andhas a large size that slows absorptionand reduces renal clearance These mo-lecular features result in a soluble for-mulation and a prolonged half-life of5 days making it suitable for once-weekly subcutaneous administration (7)Dulaglutide exhibits GLP-1ndashmediatedeffects including glucose-dependentpotentiation of insulin secretion inhibi-tion of glucagon secretion delay of gas-tric emptying and weight loss (7ndash10)Initial clinical trials have shown that

dulaglutide treatment results in dose-

dependent reductions in fasting plasmaglucose (FPG) postprandial plasma glu-cose and glycosylated hemoglobin A1c(HbA1c) (71112) Nausea and diarrheawere the most commonly reported ad-verse events (71112) This trial Assess-ment of Weekly AdministRation ofLY2189265 [dulaglutide] in Diabetes-5(AWARD-5) evaluated multiple sets ofobjectives including selection of oneor two dulaglutide doses (from a rangeof seven doses) for further assessmentin this and other phase 3 trials (13ndash15)and safety and efficacy of selecteddulaglutide doses in comparison withsitagliptin over a period of 104 weeksand placebo up to 26 weeks in metformin-treated patients with type 2 diabetes Inthis study we present results for theselected doses and comparators up tothe primary end point at 52 weeks


Eligible patients were those 18ndash75 yearsold had type 2 diabetes ($6 months)with an HbA1c value of 8 (64mmolmol) and 95 (80 mmolmol)on diet and exercise alone or $7 (53mmolmol) and 95 (80 mmolmol)on oral antihyperglycemic medication(OAM) monotherapy or combinationtherapy (metformin plus another OAM)a BMI between 25 and 40 kgm2 and astable weight during the 3-month periodbefore entering the study Patients wereexcluded if theywere takingGLP-1 recep-tor agonists during the 6 months priorto screening or were on chronic insulintherapy The protocol was approvedby local ethics review boards and allpatients provided written informedconsent The study was conducted incompliance with the Declaration ofHelsinki and the International Confer-ence on Harmonization guideline ongood clinical practices (16)

The study used an adaptive seamlessparallel-arm design (Fig 1A) to addresstwo groups of objectives 1) selection ofone or two doses for further longer-term assessment (dose-finding) (17)and 2) comparison of efficacy and safetyof selected dulaglutide doses versussitagliptin (100 mg once daily) at 52and 104 weeks and versus placebo at26 weeks (confirmatory objectives) Eli-gible patients entered a lead-in periodthat lasted up to 11 weeks Patientswere required to be treated with met-formin monotherapy (minimum dose

$1500 mgday) for $6 weeks prior torandomization to then be continuedduring the treatment period all otherOAMs were discontinued This lead-inperiod allowed patients to achieve a sta-ble dose of metformin and washout ofother OAMs Following the lead-in pe-riod patients were assigned to treatmentby one of two sequential randomizationschemes adaptive randomization duringthe dose-finding portion followed byfixed randomization after dose selection(13ndash15) A total of 230 patients wereadaptively randomized during the dose-finding portion Dulaglutide 15- and075-mg doses were selected for furtherassessment at the completion of thedose-finding portion (18) After doseselection occurred patients from nonse-lected arms were discontinued Addi-tional patients were assigned in a fixedrandomization manner to the remainingarms dulaglutide 15 mg dulaglutide075 mg sitagliptin 100 mg or placebo(replaced with sitagliptin after 26 weeksto keep blinding) in a 2221 ratio (17)The treatment period lasted 104 weeksPatients who developed persistent orworsening hyperglycemia based on pre-specified thresholds (SupplementaryTable 1) were discontinued from thestudy and an adverse event of hypergly-cemia was reported in the database

The primary outcome measure wasmean change in HbA1c from baseline to52 weeks Secondary efficacy measuresincluded change from baseline in HbA1cat other time points percentage of pa-tients with HbA1c 70 (53 mmolmol)or 65 (48 mmolmol) body weightFPG (central laboratory measure) andfasting insulin b-cell function and insulinsensitivity indices (updated homeostasismodel assessment [HOMA2]) (19) andlipids

Safety assessments included hypo-glycemic episodes vital signs electro-cardiograms laboratory parametersadverse events and dulaglutide antidrugantibodies (ADAs) Adjudication of pan-creatic events was performed by an in-dependent clinical end point committeeThe following events were adjudicatedto assess for development of pancreati-tis investigator-reported pancreatitisadverse events of serious or severe ab-dominal pain without known cause andcases of confirmed pancreatic enzymeelevations ($3 times the upper limitof normal) Laboratory analyses were













RESULTS






SexMen 146 (48) 134 (44) 151 (48) 90 (51)Women 158 (52) 168 (56) 164 (52) 87 (49)

Age (years) 54 6 10 54 6 10 54 6 10 55 6 9


BMI (kgm2) 31 6 5 31 6 4 31 6 4 31 6 4

Weight (kg) 87 6 17 86 6 18 86 6 17 87 6 17


HbA1c [ (mmolmol)] 81 6 11 (65 6 12) 82 6 11 (66 6 12) 81 6 11 (65 6 12) 81 6 11 (65 6 12)



SBP (mmHg) 129 6 13 128 6 14 127 6 13 128 6 13

DBP (mmHg) 78 6 8 78 6 9 77 6 9 78 6 8




























Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS









































RESULTS






SexMen 146 (48) 134 (44) 151 (48) 90 (51)Women 158 (52) 168 (56) 164 (52) 87 (49)

Age (years) 54 6 10 54 6 10 54 6 10 55 6 9


BMI (kgm2) 31 6 5 31 6 4 31 6 4 31 6 4

Weight (kg) 87 6 17 86 6 18 86 6 17 87 6 17


HbA1c [ (mmolmol)] 81 6 11 (65 6 12) 82 6 11 (66 6 12) 81 6 11 (65 6 12) 81 6 11 (65 6 12)



SBP (mmHg) 129 6 13 128 6 14 127 6 13 128 6 13

DBP (mmHg) 78 6 8 78 6 9 77 6 9 78 6 8




























Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS




































RESULTS






SexMen 146 (48) 134 (44) 151 (48) 90 (51)Women 158 (52) 168 (56) 164 (52) 87 (49)

Age (years) 54 6 10 54 6 10 54 6 10 55 6 9


BMI (kgm2) 31 6 5 31 6 4 31 6 4 31 6 4

Weight (kg) 87 6 17 86 6 18 86 6 17 87 6 17


HbA1c [ (mmolmol)] 81 6 11 (65 6 12) 82 6 11 (66 6 12) 81 6 11 (65 6 12) 81 6 11 (65 6 12)



SBP (mmHg) 129 6 13 128 6 14 127 6 13 128 6 13

DBP (mmHg) 78 6 8 78 6 9 77 6 9 78 6 8




























Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS























































Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS


















































Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS





































Variable

26 weeks 52 weeks

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

PL(N = 177)

DU 15 mg(N = 304)

DU 075 mg(N = 302)

SITA(N = 315)

Death 1 (1) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 2 (1)












CONCLUSIONS






























CONCLUSIONS


















































Documents

Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5)