HARMONY 3: 104-WeekRandomized, Double-Blind,Placebo- and Active-ControlledTrial Assessing the Efficacy andSafety of Albiglutide ComparedWith Placebo, Sitagliptin, andGlimepiride inPatientsWithType2Diabetes Taking MetforminDiabetes Care 2014;37:2141–2148 | DOI: 10.2337/dc14-0024

OBJECTIVE

To compare the efficacy and safety of weekly albiglutide with daily sitagliptin,daily glimepiride, and placebo.

RESEARCH DESIGN AND METHODS

Patients with type 2 diabetes receivingmetforminwere randomized to albiglutide(30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titrationfor albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefinedhyperglycemia criteria. The primary end point was change in HbA1c from baselineat week 104. Secondary end points included fasting plasma glucose (FPG), weight,and time to hyperglycemic rescue.

RESULTS

Baseline characteristics were similar among the albiglutide (n = 302), glimepiride(n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutideand glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104,albiglutide significantly reduced HbA1c compared with placebo (20.9% [29.8mmol/mol]; P < 0.0001), sitagliptin (20.4% [24.4 mmol/mol]; P = 0.0001), andglimepiride (20.3% [23.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c

were similar. Weight change from baseline for each were as follows: albiglutide21.21 kg (95% CI 21.68 to 20.74), placebo 21.00 kg (95% CI 21.81 to 20.20),sitagliptin20.86 kg (95% CI21.32 to20.39), glimepiride 1.17 kg (95% CI 0.70–1.63).The difference between albiglutide and glimepiride was statistically significant (P <

0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide comparedwith 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo,sitagliptin, and glimepiride, respectively. Rates of serious adverse events in thealbiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%,other groups 8.6–10.9%) and nausea (albiglutide 10.3%, other groups 6.2–10.9%)were generally the most frequently reported gastrointestinal events.

CONCLUSIONS

Added tometformin, albiglutidewaswell tolerated; produced superior reductionsin HbA1c and FPG at week 104 comparedwith placebo, sitagliptin, and glimepiride;and resulted in weight loss compared with glimepiride.

1Department of Clinical Sciences, Lund Univer-sity, Lund, Sweden2Metabolic Pathways and Cardiovascular Unit,GlaxoSmithKline, Research Triangle Park, NC3Metabolic Pathways and Cardiovascular Unit,GlaxoSmithKline, Upper Merion, PA4RD Projects Clinical Platforms & Sciences,GlaxoSmithKline, Stevenage, Herts, U.K.5AlternateDevelopmentProgram,GlaxoSmithKline,Upper Merion, PA6Department ofMedicine, Division of Endocrinol-ogy, Metabolism, and Nutrition, Duke UniversityMedical Center, Durham, NC

Corresponding author: Mark N. Feinglos, mark.feinglos@duke.edu.

Received 4 January 2014 and accepted 12 April2014.

Clinical trial reg. no. NCT00838903, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc14-0024/-/DC1.

© 2014 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Bo Ahren,1 Susan L. Johnson,2

Murray Stewart,3 Deborah T. Cirkel,4

Fred Yang,5 Caroline Perry,5 and

Mark N. Feinglos,6 for the HARMONY 3

Study Group

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The management of type 2 diabetes hasbecome an increasingly complex prac-tice given the number of treatmentsavailable (1). Despite the availability ofnew therapeutic agents, many patientswith type 2 diabetes continue to haveuncontrolled glycemia (2–4), and treat-ment adherence varies but remains rel-atively poor (5–9).Among patients takingmetformin but

who do not have adequately controlleddiabetes, data are limited regardingnext-step concomitant treatment (10).As a result, extended head-to-headcomparisons of type 2 diabetes medica-tions mirroring treatment algorithms(i.e., combinations with metformin)are needed to aid clinicians in makingtreatment decisions (11,12). Recenttreatment guidelines have positionedincretin-based therapies, such as GLP-1receptor agonists (GLP-1RAs), as alter-native first-line therapies in certainclinical settings and as second-line ther-apies following metformin because oftheir substantial effectiveness in im-proving glycemic control as well asother positive effects, such as weightloss and low hypoglycemia rates(10,13,14).Albiglutide is a novel, once-weekly,

long-acting GLP-1RA composed of a di-peptidyl peptidase-4 (DPP-4)2resistantGLP-1 dimer fused to recombinant hu-man albumin. This structure affords anextended half-life of ;5 days and, as aconsequence, once-weekly dosing(15,16). In a multinational phase 2bstudy of type 2 diabetes, albiglutide 30 mgonce-weekly reduced HbA1c by 20.87%(29.5 mmol/mol) and also reduced fast-ing plasma glucose (FPG) and weight,with a low incidence of gastrointestinal(GI) adverse events (AEs) (16).The HARMONY program for albiglu-

tide includes eight pivotal phase 3 stud-ies designed to evaluate the efficacy andsafety of albiglutide compared with pla-cebo, oral antidiabetes medications, in-sulin glargine, and another GLP-1RAin a typical type 2 diabetic popula-tion (17,18). Here, we present 2-yearprimary end point data for HARMONY3, which is a 3-year phase 3 studycomparing the efficacy and safety ofweekly albiglutide with daily sitagliptin,daily glimepiride, and placebo in pa-tients with diabetes receiving metfor-min but not adequately controlled bythe medication.

RESEARCH DESIGN AND METHODSStudy DesignThis was a phase 3, randomized, double-blind, placebo- and active-controlledparallel-group study that occurred be-tween 17 February 2009 and 21 March2013; the study comprised 4 study pe-riods: screening, run-in/stabilization (4weeks), treatment (156 weeks; 104-week data are reported here), andposttreatment follow-up (8 weeks)(Fig. 1A); the trial is registered asNCT00838903 at ClinicalTrials.gov. Eli-gible patients were stratified by HbA1clevel (,8.0% [,63.9 mmol/mol] vs.$8.0% [$63.9 mmol/mol]), history ofmyocardial infarction (MI), and age(,65 vs. $65 years) and were ran-domly assigned (3:3:3:1) to receive, inaddition to their background metfor-min, 1 of 4 treatments at baseline: albi-glutide 30 mg, sitagliptin 100 mg,

glimepiride 2 mg, or placebo. Matchingplacebos for albiglutide, sitagliptin, andglimepiride were used to maintainblinding to treatment.

After randomization, patients withpersistent hyperglycemia qualified toundergo dose titration and/or hypergly-cemia rescue. Blinded up-titration of al-biglutide from 30 to 50 mg once weeklyor glimepiride from 2 to 4 mg once dailyoccurred if patients exceeded prede-fined FPG or HbA1c thresholds. The finaltitration threshold, from week 12 untilweek143,wasHbA1c7.5%(58.5mmol/mol);there was no titration from week 143to week 156. In general, 4 weeks afterup-titration, patients meeting criteria in-cluding predefined FPG or HbA1c thresh-olds could receive hyperglycemic rescuetherapy, in addition to study medication,and remain in the trial. Rescue thresh-olds early in the trial were based

Figure 1—A: HARMONY3 study design.QD, oncedaily;QW, onceweekly.B: CONSORTflowdiagramof the HARMONY 3 trial through week 104. DC, discontinue; FU, follow-up; ITT, intent to treat.

2142 HARMONY 3: 2-Year Albiglutide Efficacy/Safety Diabetes Care Volume 37, August 2014

on FPG ($280 mg/dL [15.6 mmol/L]from week 2 to week 4, $250 mg/dL[13.9 mmol/L] from week 4 to week12), and, later, on HbA1c ($8.5% [69.4mmol/mol] and a #0.5% reductionfrom baseline from week 12 to week24; $8.5% [69.4 mmol/mol] fromweek 24 to week 104).

Patients

Inclusion Criteria

Patients were $18 years of age, hadtype 2 diabetes, and were experiencinginadequate glycemic control while tak-ing background metformin ($1,500 mgor maximum tolerated dose)$3 monthsbefore screening. They also had a baselineHbA1c of 7.0% (53.0 mmol/mol) to 10.0%(85.8 mmol/mol), inclusive; BMI 20 to 45kg/m2; creatinine clearance .60 mL/min(determined using the Cockcroft-Gaultformula); and normal thyroid-stimulatinghormone concentration or were clinicallyeuthyroid.

Exclusion Criteria

Major exclusion criteria were currentongoing symptomatic biliary disease orhistory of pancreatitis, recent clinicallysignificant cardiovascular and/or cere-brovascular disease (#2 months beforescreening), treated gastroparesis, his-tory of GI surgery thought to signifi-cantly affect upper GI function, historyof most cancers not in remission for atleast 3 years, personal or family historyof medullary thyroid carcinoma or mul-tiple endocrine neoplasia type 2, restingsystolic blood pressure (SBP) .160mmHg and/or diastolic blood pressure(DBP).100 mmHg, lipase above the up-per limit of normal (ULN), hemoglobin-opathy that could affect HbA1c, andalanine aminotransferase or aspartateaminotransferase more than two and ahalf times the ULN.

Withdrawal Criteria

Patients withdrew or were removed fromthe study drug because of loss to follow-up, protocol violation, noncompliance,withdrawal of consent, or an AE or labo-ratory result requiringwithdrawal, includ-ing QTc prolongation, elevation of liverfunction test results, severe potential al-lergic reactions, confirmed pancreatitis,severe or repeated hypoglycemia, andcalcitonin .100 pg/mL.

Primary and Secondary End PointsThe primary end point was the change inmodel-adjusted HbA1c from baseline to

week 104 between albiglutide andthe comparators. Secondary end pointsincluded changes in HbA1c, FPG, andweight from baseline over time; the pro-portion of patients who achieved HbA1ctreatment goals (i.e., ,6.5% [,47.5mmol/mol], ,7.0% [,53.0 mmol/mol],and ,7.5% [,58.5 mmol/mol]); andtime to hyperglycemic rescue.

Safety and tolerability were assessed,including AEs and serious AEs (SAEs);safety events of special interest (i.e., GIor hypoglycemic events, injection-sitereactions, pancreatitis, thyroid tumors,potential systemic allergic reactions[SARs], and CV events); clinical labora-tory evaluations; physical examinations;12-lead electrocardiograms; vital signmeasurements; and immunogenicity.

All major CV AEs occurring post-randomization were adjudicated by aclinical end point committee and arepart of an ongoing meta-analysis (resultswill be reported separately). An indepen-dent, blinded pancreatitis adjudicationcommittee (PAC) comprising three GIspecialists adjudicated AEs suggestingpancreatitis and all laboratory elevationsof lipase and/or amylase more than orequal to three times the ULN. The PACadjudicated both the probability ofevents being pancreatitis (definite, prob-able, possible, not likely) and the likeli-hood of a relationship to the study drug(definite, probable, possible, unlikely al-ternate etiology).

To assess any associationof studymed-ication with potential SARs, investigatorsflagged AEs that were considered SARs.Additional evaluation of the AE data forSARs was conducted using standardizedMedical Dictionary for Regulatory Activi-ties queries for angioedema, anaphylaxis,and severe cutaneous reaction. Hypogly-cemia was defined and assessed usingAmerican Diabetes Association criteria(19) and evaluated before hyperglycemicrescue.

Statistical MethodsThe planned sample size provided.90% power to demonstrate superior-ity versus placebo and noninferiorityversus sitagliptin and glimepiride (non-inferiority margin = 0.3%). Superiorityof albiglutide versus sitagliptin andglimepiride was tested if noninferioritywas established. The primary efficacy endpoint (intent-to-treat population/lastobservation carried forward algorithm)

was analyzed using an ANCOVA modelto compare treatment effects adjustingfor region, history of previous MI, agecategory, and baseline HbA1c. Patientsrescued from hyperglycemia beforeweek 104 had their latest HbA1c valuebefore rescue carried forward for pri-mary analyses. Those patients whoachieved treatment goals were evalu-ated by nonparametric ANCOVA. Timeto rescue was evaluated by Kaplan-Meier curves and log-rank tests. Forprimary end point analysis, log-ranktests for the duration up to the primaryend point were added post hoc. A mul-tiple comparisons adjustment strategywas implemented for various inferen-tial tests among the primary and keysecondary objectives; AEs were ana-lyzed by incidence proportion and inci-dence density rate overall and beforerescue (with additional type 2 diabetesmedication); in this article, overallincidence/rate is used for all eventsexcept hypoglycemia.

Study ConductThis study was conducted in accordancewith good clinical practice standards, allapplicable privacy requirements, andthe guiding principles of the Declarationof Helsinki. Written informed consentwas obtained from each patient beforeparticipation.

RESULTS

This study was conducted at 289 centersin 10 countries. Demographics and base-line characteristics were similar amongthe albiglutide (n = 302), glimepiride (n =307), sitagliptin (n = 302), and placebo(n = 101) treatment groups (Supplemen-tary Table 1).The mean age for thegroups ranged from 54.3 to 56.1 years(84.3% were ,65 years old); approxi-mately half of patients were men andthe majority were white (63.4–74.5%).Approximately 67.0% of the total popu-lation were moderately to severelyobese (BMI $30 kg/m2); mean weightin all treatment groups ranged from89.6 to 91.8 kg, and mean duration ofdiabetes ranged from 5.8 to 6.7 years. Inall treatment groups at baseline, HbA1clevels were similar (8.1–8.2% [65.0–66.1mmol/mol]), as were FPG concentra-tions (9.0–9.3 mmol/L [162.8–167.4mg/dL]).

Overall, 67.4% of patients completedactive treatment through week 104;

care.diabetesjournals.org Ahren and Associates 2143

rates of completion were similar amongthe active treatment groups (sitagliptin67.7%, glimepiride 68.8%, and albiglu-tide 68.3%) and lower for the placebogroup (59.6%). The main reasons for dis-continuing active treatment were with-drawal of consent (placebo 14.4%,sitagliptin 13.1%, glimepiride 13.2%, al-biglutide 12.1%) and AEs (placebo 4.8%,sitagliptin 3.2%, glimepiride 4.1%, albi-glutide 6.3%). Patient flow is presentedin Fig. 1B.Although all treatment groups went

through a blinded up-titration proce-dure, only the albiglutide and glimepir-ide groups actually up-titrated to 50 and4 mg, respectively. By week 104, ahigher proportion of patients wentthrough the blinded up-titration processin the placebo (;69%) and sitagliptin(;59%) groups compared with the gli-mepiride (;54%) and albiglutide (;53%)groups. Mean doses for albiglutide andglimepiride at week 104 were 40.5 and3.1 mg, respectively.

Primary Outcome: HbA1c

HbA1c reductions from baseline to week104 were20.63% (26.9 mmol/mol) foralbiglutide, 20.28% (23.1 mmol/mol)for sitagliptin, 20.36% (23.9 mmol/mol)for glimepiride, and+0.27% (3.0mmol/mol)for placebo. The model-adjusted meandifference (albiglutide vs. comparatortreatment) demonstrated that albiglutide,when added to metformin, was clinicallyand statistically superior to placebo(20.9% [29.8 mmol/mol]; 95% CI 21.2to20.7; P, 0.0001), sitagliptin (20.4%[24.4 mmol/mol]; 95% CI20.5 to20.2;P = 0.0001), and glimepiride (20.3%[23.3 mmol/mol]; 95% CI 20.5 to20.1; P = 0.0033) (Fig. 2A). Albiglutidehad themost durable effect, with ameanHbA1c of 7.5% (58.5 mmol/mol) atweek 104 compared with sitagliptin(7.8% [61.7 mmol/mol]), glimepiride(7.8% [61.7 mmol/mol]), and placebo(8.4% [68.3 mmol/mol]) (Fig. 2B).More albiglutide-treated patients

reached HbA1c treatment thresholds ateach level (,6.5% [,47.5 mmol/mol],,7.0% [,53.0 mmol/mol], ,7.5%[,58.5 mmol/mol]) compared with pla-cebo, sitagliptin, and glimepiride atweek 104 (Supplementary Fig. 1). Thedifference between albiglutide and thecomparators was statistically significantfor placebo at all threshold levels (P #0.02) and was comparable with only

sitagliptin and glimepiride at the,7.5% (,58.5 mmol/mol; P # 0.04)level. For the albiglutide group, thesetreatment thresholds were met by17.1%, 38.6%, and 58.7% of patients,

respectively. Subgroup analyses forage, race, ethnicity, sex, baseline BMI,and baseline HbA1c were all consistentwith the primary end point (Supplemen-tary Fig. 2).

Figure 2—Change in HbA1c from baseline (A), mean HbA1c (B), FPG (C ), and weight (D) overtime through week 104. Intent-to-treat population data were determined using the lastobservation carried forward method. Data in Fig. 2A denote difference (95% CI). *P ,0.0001 vs. placebo; †P , 0.0001, noninferiority of albiglutide vs. sitagliptin or glimepiride;‡P = 0.0033, superiority of albiglutide vs. glimepiride; §P = 0.0001, superiority of albiglutide vs.sitagliptin. BL, baseline.

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Secondary Outcomes

FPG

Changes in FPG from baseline at week104 were consistent with the primaryend point (Fig. 2C). The treatment groupdifference (albiglutide – comparatortreatment) for a model-adjusted leastsquares mean decrease from baselineto week 104 demonstrated that, whenadded to metformin, albiglutide wasstatistically superior to placebo (21.5mmol/L [228 mg/dL]; P, 0.0001), sita-gliptin (20.9 mmol/L [216 mg/dL]; P =0.0002), and glimepiride (20.6 mmol/L[210 mg/dL]; P = 0.0133).

Weight

At week 104, weight loss occurredamong patients taking albiglutide(21.21 kg), placebo (21.0 kg), and sita-gliptin (20.86 kg), whereas weight gainoccurred in glimepiride patients (+1.17kg). The treatment difference betweenalbiglutide and glimepiride was statisti-cally significant (P , 0.0001) (Fig. 2D).

Time to Hyperglycemic Rescue

The albiglutide group had the most du-rable glycemic control. Per Kaplan-Meier estimates, fewer patients receivedhyperglycemic rescue in the albiglutidegroup (25.8%) compared with the pla-cebo (59.2%), sitagliptin (36.4%), and gli-mepiride groups (32.7%). The differencebetween baseline and time to rescuewith albiglutide was statistically signifi-cantly longer compared with sitagliptin(P = 0.0118) and placebo (P , 0.00001)(Fig. 3).

General Safety and TolerabilityFor overall safety, the proportion of pa-tients experiencing AEs, SAEs, and AEsleading to withdrawal while receivingtherapy was relatively balanced amongtreatment groups (Table 1). Most AEswere mild or moderate in intensity inall treatment groups. The most frequentAEs (occurring in.7% of patients takingalbiglutide) were upper respiratory tractinfection, diarrhea, nausea, injection-sitereaction, hypertension, nasopharyngi-tis, and cough. The type of AEs overalland those occurring before rescue(i.e., before the addition of hyperglycemicrescue medication) were similar, and themajority of AEs occurred before rescue(Supplementary Table 2). The rate ofAEs was higher with albiglutide andgenerally due to the higher rateof injection-site reactions (45 of 100patient-years for albiglutide vs. 1 of 100

patient-years for placebo). Fewer pa-tients experienced SAEs in the albiglutidegroup (12.9%) than in the placebo group(15.8%) but were comparable with thosewho experienced SAEs in the sitagliptinand glimepiride groups (9.9% and11.7%, respectively). Overall, eight fatalSAEs occurred through week 104 (threeeach for albiglutide and glimepiride andone each for sitagliptin and placebo);none were considered by the investiga-tors to be related to study medication.

Events of Special Interest (ThroughWeek 104)

GI Events

GI AEs were experienced by a similarproportion of patients in the albiglutide(n = 110; 36.4%) and placebo groups (n =38; 37.6%) and fewer in the sitagliptin(n = 75; 24.8%) and glimepiride groups(n = 85; 27.7%). Few GI events were se-vere in intensity (1.0%, 1.3%, 1.3%, and4.0% for placebo, sitagliptin, glimepir-ide, and albiglutide, respectively) or ledto withdrawal of the study drug (1.0%,1.0%, 0.7%, and 2.0%, respectively). Themost common GI event was diarrhea inthe sitagliptin, glimepiride, and albiglu-tide groups and constipation in the pla-cebo group.

At week 104, nausea event rateswere comparable between treatmentgroups (7.9, 5.3, 3.7, and 9.3 eventsper 100 patient-years for placebo,

sitagliptin, glimepiride, and albiglutide,respectively), even though the inci-dence was highest in the placebo group(10.9%) compared with sitagliptin(6.6%), glimepiride (6.2%), and albiglu-tide (10.3%). The incidence and eventrate of vomiting over the 104 weekswas (5.6%, 4.4 events per 100 patient-years) in the albiglutide group com-pared with placebo (1.0%, 0.6 eventsper 100 patient-years), sitagliptin(4.3%, 3.2 events per 100 patient-years), and glimepiride (3.6%, 2.1 eventsper 100 patient-years). The per-visit prev-alence of nausea/vomiting among pa-tients receiving albiglutide was ,5% ateach time point (Supplementary Fig. 3).

Hypoglycemia

Documented symptomatic hypoglyce-mia (#3.9 mmol/L [#70 mg/dL]) beforerescue with albiglutide was low (3.0%)and was similar to placebo (4.0%) andsitagliptin (1.7%) compared with glime-piride (17.9%) (Table 1). No severehypoglycemic events were reported be-fore rescue.

Injection-Site Reactions

Events classified by investigators asinjection-site reactions occurred morefrequently with albiglutide (17.2%; n =52) compared with glimepiride (7.8%;n = 24), sitagliptin (6.3%; n = 19), andplacebo (5%; n = 5). Injection-site reac-tions for albiglutide were mostly mild to

Figure 3—Kaplan-Meier plot of time to hyperglycemic rescue (intent-to-treat population). Timeto rescue was evaluated by log-rank tests and Kaplan-Meier curves.

care.diabetesjournals.org Ahren and Associates 2145

moderate in intensity (98.1%), were notprogressive, and most patients (n = 32/52; 61.5%) experiencing injection-sitereactions had 1 or 2 events that lasted#1 week (median duration). These re-actions led to the withdrawal of 4 of302 patients (1.3%) at 2 years. Mostpatients (41 of 52; 79.0%) treated withalbiglutide who experienced injection-site reactions were negative for anti-albiglutide antibodies.

Pancreatitis

Six patients (albiglutide, n = 4; glimepir-ide, n = 2) were evaluated by a blinded,independent PAC because of a reportedAE or a lipase/amylase concentrationmore than or equal to three times theULN. Adjudication determined that nei-ther patient from the glimepiride grouphad pancreatitis. Among the four pa-tients receiving albiglutide, adjudicationdetermined that one event was unlikelyto reflect pancreatitis, one event wasconsidered to reflect possible pancrea-titis (laboratory elevations alone) un-likely related to the study drug, andtwo events were probable pancreatitis(laboratory elevations and suggestivesymptoms), and both were consideredpossibly related to the study drug.

Thyroid Cancer

One patient treated with albiglutide de-veloped follicular cancer on day 243.

Two patients receiving sitagliptin devel-oped thyroid cancer: one experiencedfollicular papillary carcinoma on day 48and the other papillary thyroid canceron day 549. In these three patients, thy-roid cancer diagnoses were consideredby the investigator to be not related tothe study drug, and calcitonin concen-trations were not abnormal.

Potential SARs

A search of the standardized MedicalDictionary for Regulatory Activitiesqueries identified two patients (pla-cebo, n = 1; glimepiride, n = 1) who ex-perienced angioedema as an SAE. Theinvestigator considered neither to be re-lated to the study drug but instead re-lated to ACE inhibitor therapy. Bothpatients remained in the study afterdiscontinuing ACE inhibitor therapy.Neither patient had positive antialbi-glutide antibodies, and no other casesof angioedema, anaphylaxis, pharyngealedema, or laryngeal edema occurred.The investigators did not flag any addi-tional events of interest.

Immunogenicity

Antialbiglutide antibody incidenceamong albiglutide-treated subjects was7.0% (21 of 302 subjects), and included1 subject (0.4%) with preexisting anti-bodies (positive at baseline). Antibodieswere nonneutralizing and showed

reactivity with GLP-1 in 16 of the 21antibody-positive subjects and with al-bumin in 5 antibody-positive subjects.No samples tested positive for antialbi-glutide IgE antibodies, and no SARs werereported for antibody-positive subjects.

Cardiovascular Parameters

At baseline, lipids and blood pressurewere well controlled and mean valueswere similar across the four treatmentgroups (Supplementary Table 3). Therewere no clinically meaningful meanchanges to lipids throughout the study.Minor changes in SBP and DBP, respec-tively, from baseline occurred in all treat-ment groups at week 104: placebo (2.2and 0 mmHg), sitagliptin (0.2 and 0.2mmHg), glimepiride (1.5 and 1.0mmHg), albiglutide (21.0 and 20.7mmHg). Treatment differences in SBPand DBP at week 104 between albiglutideand the three comparators were not sta-tistically significant. Similarly, there wereno meaningful changes from baseline atweek 104 inmean heart rate: placebo, 2.3bpm; sitagliptin, 0.8 bpm; glimepiride,20.5 bpm; albiglutide, 1.3 bpm.

CONCLUSIONS

When added to metformin, albiglutideproduced clinically and statistically su-perior and more sustained reduction inHbA1c at week 104 compared with

Table 1—AEs while receiving therapy, to week 104

Placebo + metformin(n = 101)

Sitagliptin + metformin(n = 302)

Glimepiride + metformin(n = 307)

Albiglutide + metformin(n = 302)

Overall safety to week 104Any AEs 79.2/283.0 79.1/250.2 83.1/261.1 83.8/350.7SAEs 12.9/10.7 8.9/5.6 9.4/6.5 11.9/10.1Related AEs 20.8/24.4 17.9/30.6 17.6/19.4 31.1/101.4AEs leading to withdrawal 5.0/3.1 3.6/2.1 4.6/2.6 6.6/3.8

Most common AEs (.7% with albiglutide)Upper respiratory tract infection 9.9/7.3 9.3/7.0 8.5/6.5 16.2/12.4Diarrhea 10.9/7.3 8.6/6.1 9.1/6.5 12.6/9.1Nausea 10.9/7.9 6.6/5.3 6.2/3.7 10.3/9.3Injection-site reaction 2.0/1.2 1.7/1.0 2.6/1.7 9.6/48.1Hypertension 5.0/3.1 8.6/5.3 6.5/4.3 7.9/4.6Nasopharyngitis 7.9/4.9 9.3/7.6 9.1/6.5 7.6/7.0Cough 5.9/4.3 6.3/4.6 7.5/4.9 7.3/4.6

Hypoglycemia before rescue*Severe 0 0 0 0Documented symptomatic 4 (4.0)/3.6 5 (1.7)/2.8 55 (17.9)/60.7 9 (3.0)/2.6Asymptomatic 1 (1.0)/1.8 4 (1.3)/1.4 3 (1.0)/0.7 4 (1.3)/1.3

Data are incidence (percentage of patients with event) and event rate (events per 100 person-years). The order of AEs is based on albiglutideproportion in the overall data. *Patients with more than one hypoglycemic event were counted in all severity categories reported. Percentages arebased on the number of patients in each treatment group for the study being summarized. Severity was derived using the American DiabetesAssociation guidelines for categorization of hypoglycemic events, as follows: severe = required assistance of another person; documentedsymptomatic = typical symptoms accompanied by a plasma glucose concentration of#3.9 mmol/L; and asymptomatic = no symptoms but plasmaglucose concentration #3.9 mmol/L.

2146 HARMONY 3: 2-Year Albiglutide Efficacy/Safety Diabetes Care Volume 37, August 2014

placebo, sitagliptin, and glimepiride.The sustained treatment effect of albi-glutide also is supported by the time tohyperglycemic rescue, which showedthat fewer subjects taking albiglutide re-quired rescue by week 104 comparedwith patients treated with placebo, sita-gliptin, and glimepiride; the differencewas statistically significant for albiglu-tide versus placebo and sitagliptin. In-terestingly, the reduction in HbA1c wassimilar during the early treatment pe-riod (;4 weeks). This might not havebeen anticipated given the longer timeto a steady state for the once-weeklyalbiglutide and the quick mechanism ofaction of sulfonylureas. Similar clinicallyand statistically superior results with al-biglutide compared with all other treat-ment arms were observed for change inFPG from baseline and the proportion ofpatients meeting clinically relevantHbA1c treatment goals. In addition, pa-tients receiving albiglutide, sitagliptin,and placebo lost weight through week104, whereas patients treated with gli-mepiride gained weight; the differencebetween albiglutide and glimepiridewas statistically significant (P, 0.0001).The sustained effect of diabetes ther-

apy is a critical clinical issue. Previoustype 2 diabetes comparator trials havedemonstrated the superiority or nonin-feriority of GLP-1RAs with or withoutmetformin but have been shorter 26-week trials (20–22). The Diabetes Ther-apy Utilization: Researching Change inA1C,Weight, and Other Factors ThroughIntervention with Exenatide Once-Weekly (DURATION)-2 and LiraglutideEffect Action in Diabetes (LEAD)-2 trials,which included metformin in all treat-ment arms, demonstrated the superior-ity of exenatide over sitagliptin andpioglitazone and of liraglutide over pla-cebo, respectively, with regard to HbA1creductions (20–22). In another 26-weekstudy (HARMONY 8), once-weekly albi-glutide provided superior glycemic im-provement, similar tolerability, andbetter patient compliance comparedwith sitagliptin therapy in patients withtype 2 diabetes and renal impairment(21). Understanding the long-term ef-fects on type 2 diabetes of differentcombination therapies has led to the5-year Glycemia Reduction Approachesin Diabetes: A Comparative Effective-ness (GRADE) study. This trial is compar-ing the efficacy and durability of four

classes of medications (DPP-4, sulfonyl-ureas, GLP-1RAs, and long-acting insulin)in patients with type 2 diabetes who arereceiving metformin (11). The results re-ported here may give a window to theeventual results of that trial.

Albiglutide was generally well toler-ated; the albiglutide group showed ratesof SAEs and AEs leading to withdrawalsimilar to those of the comparatorgroups. The percentage of patients re-porting AEs while receiving therapy wassimilar for albiglutide, sitagliptin, andglimepiride and slightly lower for pla-cebo. The types of AEs noted for albiglu-tide are generally consistent with thetype 2 diabetic population and theknown profile of GLP-1RAs (23,24).

The 104-week incidence of nausea/vomiting with albiglutide (10.6%/5.6%)was lower than values observed in pre-vious studies using other GLP-1RAs, par-ticularly in the early weeks of therapy. Inclinical practice, GI AEs occurring early inthe course of treatment with GLP-1RAsmay contribute to the discontinuationrates seen with this class, and agentswith reduced GI effects may improvepatient adherence. With respect to hy-poglycemia, albiglutide had rates similarto sitagliptin and placebo and lower ratescompared with glimepiride. Injection-sitereactions were more common in thealbiglutide-treated subjects, although afew (1.3%) withdrew because of reac-tions during the 104-week period. Theproportion of patients developing anti-albiglutide antibodies was low, andnone were nonneutralizing.

HARMONY 3 is a long-term, 3-year tri-al with unique design features that mustbe considered when interpreting re-sults. First, up-titration was based onglucose thresholds established by pro-tocol: the time point of titration wasnot prescribed or standardized, reflect-ing up-titration methods in clinical prac-tice; thus, the efficacy and safety datareflect a mixture of 30- and 50-mg albi-glutide doses and 2- and 4-mg glimepir-ide doses. In addition, there was noincreased dose for placebo and sitaglip-tin despite patients who underwent theblinded up-titration procedure. Becauseof this design feature, many patientsrandomized to glimepiride and albiglu-tide were not receiving the maximumdose, as evidenced by the mean dosesof each drug. Therefore, the maximumeffect in these arms may not have been

achieved, depending on the dose curvefor each agent, and there is a possibilitythat the relationship between the armsmay have shifted at higher doses.

Second, rescue medications wereused in the program to permit patientsto remain in the studies while receivinga blinded investigational product or con-trol through 3 years. This represents amore “real-life” situation, where addi-tional medications are added to regi-mens that are not meeting treatmentgoals. While the primary efficacy assess-ment was based on end points beforerescue, the main safety assessment in-cluded data after rescue. These designfeatures, however, may have compli-cated the interpretation of some results.Finally, interpretation of the proportionof patients reaching the treatment goalwas complex; up-titration occurred at7.5% and not 7.0%, and the full benefitof 50 mg may not be seen since the endpoint contains a mix of patients taking30- and 50-mg albiglutide.

In conclusion, when added to metfor-min, albiglutide produced clinically andstatistically significant reductions inHbA1c and FPG at week 104 comparedwith placebo, sitagliptin, and glimepir-ide. Patients receiving albiglutide, sita-gliptin, and placebo lost body weightthrough week 104, whereas patientstaking glimepiride gained weight; thedifference between albiglutide and gli-mepiride was statistically significant. Al-biglutide was generally well tolerated,and rates of SAEs were similar acrosstreatment groups. The most frequentAEs for albiglutidewere largely consistentwith the known profile for GLP-1RAs.

Acknowledgments. The authors thank DouglasL. Wicks, MPH, CMPP, of GlaxoSmithKline, formanaging manuscript development. Editorialsupport was provided by Leonard Lionnet, PhD,of PharmaWrite, LLC (assistance with the pro-duction of a draft outline and the first draft ofthe manuscript, assembling tables and figures,and collating author comments); Diana Talag,ELS, of PharmaWrite, LLC (assistance withcopyediting and fact-checking); and ShanaCambareri of PharmaWrite, LLC (art direction).Duality of Interest. B.A. received honoraria forlecturing and holds advisory board membershipfor Bristol-Myers Squibb, GlaxoSmithKline,Lilly, Novartis, Novo Nordisk, Merck, and Sanofi,which all are companies producing GLP-1RAsor DPP-4 inhibitors. S.L.J., M.S., D.T.C., F.Y., andC.P. are employed by and shareholders ofGlaxoSmithKline. M.N.F. has received researchsupport and has served either as an investigator

care.diabetesjournals.org Ahren and Associates 2147

or principal investigator for Amylin, AstraZeneca,Eli Lilly and Company, GlaxoSmithKline, Merck &Co., Inc., Medtronic Inc., Novo Nordisk, Proctor &Gamble Co., Prodigy Diabetes Care, Sanofi, andTethys, some of which are companies producingGLP-1RAs or DPP-4 inhibitors. M.N.F. also hasserved as a consultant for GlaxoSmithKline, Pfizer,and Proctor & Gamble Co. No other potentialconflicts of interest relevant to this article werereported.

The sponsor of the study participated in thestudy design, data collection, data review, dataanalysis, and writing of the report. All authorshad full access to all the data in the study. M.N.F.reviewed the trial report (signatory investigator),had full access to all data in the study, and hadfinal responsibility for the decision to submit forpublication.Author Contributions. B.A. and M.N.F. pro-vided study patients. S.L.J., M.S., D.T.C., F.Y.,and C.P. analyzed and interpreted data. B.A.,S.L.J., D.T.C., F.Y., and M.N.F. wrote and revisedthe manuscript. F.Y. performed the statisticalanalysis. All authors revised the manuscript,reviewed the final manuscript, and approvedthe manuscript for submission. M.N.F. is theguarantor of this work and, as such, had fullaccess to all the data in the study and takesresponsibility for the integrity of the data andthe accuracy of the data analysis.Prior Presentation. Data from this article werepresented at the 73rd Scientific Sessions of theAmerican Diabetes Association, Chicago, IL, 21–25 June 2013, and published in Diabetes2013;62(Suppl. 1A):LB14 (Abstract 52-LB).Data also were presented via oral presentationat the 49th Annual Meeting of the EuropeanAssociation for the Study of Diabetes, Barcelona,Spain, 23–27 September 2013, and published inDiabetologia 2013;56(Suppl. 1):S8.

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2148 HARMONY 3: 2-Year Albiglutide Efficacy/Safety Diabetes Care Volume 37, August 2014