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Diabetes Care Volume 37, August 2014
Bo Ahrén,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
Diabetes 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 receiving metformin were randomized to albiglutide
(30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration
for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined
hyperglycemia criteria. The primary end point was change in HbA1c from baseline
at 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 was
8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide
and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104,
albiglutide significantly reduced HbA1c compared with placebo (20.9% [29.8
mmol/mol]; P < 0.0001), sitagliptin (20.4% [24.4 mmol/mol]; P = 0.0001), and
glimepiride (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: albiglutide
21.21 kg (95% CI 21.68 to 20.74), placebo 21.00 kg (95% CI 21.81 to 20.20),
sitagliptin 20.86 kg (95% CI 21.32 to 20.39), 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 compared
with 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 the
albiglutide 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.
1
Department of Clinical Sciences, Lund University, Lund, Sweden
2
Metabolic Pathways and Cardiovascular Unit,
GlaxoSmithKline, Research Triangle Park, NC
3
Metabolic Pathways and Cardiovascular Unit,
GlaxoSmithKline, Upper Merion, PA
4
RD Projects Clinical Platforms & Sciences,
GlaxoSmithKline, Stevenage, Herts, U.K.
5
Alternate Development Program, GlaxoSmithKline,
Upper Merion, PA
6
Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University
Medical Center, Durham, NC
Corresponding author: Mark N. Feinglos, mark.
[email protected].
Received 4 January 2014 and accepted 12 April
2014.
Clinical trial reg. no. NCT00838903, clinicaltrials
.gov.
CONCLUSIONS
This article contains Supplementary Data online
at http://care.diabetesjournals.org/lookup/
suppl/doi:10.2337/dc14-0024/-/DC1.
Added to metformin, albiglutide was well tolerated; produced superior reductions
in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride;
and resulted in weight loss compared with glimepiride.
© 2014 by the American Diabetes Association.
Readers may use this article as long as the work
is properly cited, the use is educational and not
for profit, and the work is not altered.
CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL
HARMONY 3: 104-Week
Randomized, Double-Blind,
Placebo- and Active-Controlled
Trial Assessing the Efficacy and
Safety of Albiglutide Compared
With Placebo, Sitagliptin, and
Glimepiride in Patients With Type 2
Diabetes Taking Metformin
2141
2142
HARMONY 3: 2-Year Albiglutide Efficacy/Safety
The management of type 2 diabetes has
become an increasingly complex practice given the number of treatments
available (1). Despite the availability of
new therapeutic agents, many patients
with type 2 diabetes continue to have
uncontrolled glycemia (2–4), and treatment adherence varies but remains relatively poor (5–9).
Among patients taking metformin but
who do not have adequately controlled
diabetes, data are limited regarding
next-step concomitant treatment (10).
As a result, extended head-to-head
comparisons of type 2 diabetes medications mirroring treatment algorithms
(i.e., combinations with metformin)
are needed to aid clinicians in making
treatment decisions (11,12). Recent
treatment guidelines have positioned
incretin-based therapies, such as GLP-1
receptor agonists (GLP-1RAs), as alternative first-line therapies in certain
clinical settings and as second-line therapies following metformin because of
their substantial effectiveness in improving glycemic control as well as
other positive effects, such as weight
loss and low hypoglycemia rates
(10,13,14).
Albiglutide is a novel, once-weekly,
long-acting GLP-1RA composed of a dipeptidyl peptidase-4 (DPP-4)2resistant
GLP-1 dimer fused to recombinant human albumin. This structure affords an
extended half-life of ;5 days and, as a
consequence, once-weekly dosing
(15,16). In a multinational phase 2b
study of type 2 diabetes, albiglutide 30 mg
once-weekly reduced HbA1c by 20.87%
(29.5 mmol/mol) and also reduced fasting plasma glucose (FPG) and weight,
with a low incidence of gastrointestinal
(GI) adverse events (AEs) (16).
The HARMONY program for albiglutide includes eight pivotal phase 3 studies designed to evaluate the efficacy and
safety of albiglutide compared with placebo, oral antidiabetes medications, insulin glargine, and another GLP-1RA
in a typical type 2 diabetic population (17,18). Here, we present 2-year
primary end point data for HARMONY
3, which is a 3-year phase 3 study
comparing the efficacy and safety of
weekly albiglutide with daily sitagliptin,
daily glimepiride, and placebo in patients with diabetes receiving metformin but not adequately controlled by
the medication.
Diabetes Care Volume 37, August 2014
RESEARCH DESIGN AND METHODS
Study Design
This was a phase 3, randomized, doubleblind, placebo- and active-controlled
parallel-group study that occurred between 17 February 2009 and 21 March
2013; the study comprised 4 study periods: screening, run-in/stabilization (4
weeks), treatment (156 weeks; 104week data are reported here), and
posttreatment follow-up (8 weeks)
(Fig. 1A); the trial is registered as
NCT00838903 at ClinicalTrials.gov. Eligible patients were stratified by HbA1c
level (,8.0% [,63.9 mmol/mol] vs.
$8.0% [$63.9 mmol/mol]), history of
myocardial infarction (MI), and age
(,65 vs. $65 years) and were randomly assigned (3:3:3:1) to receive, in
addition to their background metformin, 1 of 4 treatments at baseline: albiglutide 30 mg, sitagliptin 100 mg,
glimepiride 2 mg, or placebo. Matching
placebos for albiglutide, sitagliptin, and
glimepiride were used to maintain
blinding to treatment.
After randomization, patients with
persistent hyperglycemia qualified to
undergo dose titration and/or hyperglycemia rescue. Blinded up-titration of albiglutide from 30 to 50 mg once weekly
or glimepiride from 2 to 4 mg once daily
occurred if patients exceeded predefined FPG or HbA1c thresholds. The final
titration threshold, from week 12 until
week 143, was HbA1c 7.5% (58.5 mmol/mol);
there was no titration from week 143
to week 156. In general, 4 weeks after
up-titration, patients meeting criteria including predefined FPG or HbA1c thresholds could receive hyperglycemic rescue
therapy, in addition to study medication,
and remain in the trial. Rescue thresholds early in the trial were based
Figure 1—A: HARMONY 3 study design. QD, once daily; QW, once weekly. B: CONSORT flow diagram
of the HARMONY 3 trial through week 104. DC, discontinue; FU, follow-up; ITT, intent to treat.
care.diabetesjournals.org
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 week
12), and, later, on HbA1c ($8.5% [69.4
mmol/mol] and a #0.5% reduction
from baseline from week 12 to week
24; $8.5% [69.4 mmol/mol] from
week 24 to week 104).
Patients
Inclusion Criteria
Patients were $18 years of age, had
type 2 diabetes, and were experiencing
inadequate glycemic control while taking background metformin ($1,500 mg
or maximum tolerated dose) $3 months
before screening. They also had a baseline
HbA1c of 7.0% (53.0 mmol/mol) to 10.0%
(85.8 mmol/mol), inclusive; BMI 20 to 45
kg/m2; creatinine clearance .60 mL/min
(determined using the Cockcroft-Gault
formula); and normal thyroid-stimulating
hormone concentration or were clinically
euthyroid.
Exclusion Criteria
Major exclusion criteria were current
ongoing symptomatic biliary disease or
history of pancreatitis, recent clinically
significant cardiovascular and/or cerebrovascular disease (#2 months before
screening), treated gastroparesis, history of GI surgery thought to significantly affect upper GI function, history
of most cancers not in remission for at
least 3 years, personal or family history
of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, resting
systolic blood pressure (SBP) .160
mmHg and/or diastolic blood pressure
(DBP) .100 mmHg, lipase above the upper limit of normal (ULN), hemoglobinopathy that could affect HbA 1c , and
alanine aminotransferase or aspartate
aminotransferase more than two and a
half times the ULN.
Withdrawal Criteria
Patients withdrew or were removed from
the study drug because of loss to followup, protocol violation, noncompliance,
withdrawal of consent, or an AE or laboratory result requiring withdrawal, including QTc prolongation, elevation of liver
function test results, severe potential allergic reactions, confirmed pancreatitis,
severe or repeated hypoglycemia, and
calcitonin .100 pg/mL.
Primary and Secondary End Points
The primary end point was the change in
model-adjusted HbA1c from baseline to
Ahrén and Associates
week 104 between albiglutide and
the comparators. Secondary end points
included changes in HbA 1c , FPG, and
weight from baseline over time; the proportion of patients who achieved HbA1c
treatment goals (i.e., ,6.5% [,47.5
mmol/mol], ,7.0% [,53.0 mmol/mol],
and ,7.5% [,58.5 mmol/mol]); and
time to hyperglycemic rescue.
Safety and tolerability were assessed,
including AEs and serious AEs (SAEs);
safety events of special interest (i.e., GI
or hypoglycemic events, injection-site
reactions, pancreatitis, thyroid tumors,
potential systemic allergic reactions
[SARs], and CV events); clinical laboratory evaluations; physical examinations;
12-lead electrocardiograms; vital sign
measurements; and immunogenicity.
All major CV AEs occurring postrandomization were adjudicated by a
clinical end point committee and are
part of an ongoing meta-analysis (results
will be reported separately). An independent, blinded pancreatitis adjudication
committee (PAC) comprising three GI
specialists adjudicated AEs suggesting
pancreatitis and all laboratory elevations
of lipase and/or amylase more than or
equal to three times the ULN. The PAC
adjudicated both the probability of
events being pancreatitis (definite, probable, possible, not likely) and the likelihood of a relationship to the study drug
(definite, probable, possible, unlikely alternate etiology).
To assess any association of study medication with potential SARs, investigators
flagged AEs that were considered SARs.
Additional evaluation of the AE data for
SARs was conducted using standardized
Medical Dictionary for Regulatory Activities queries for angioedema, anaphylaxis,
and severe cutaneous reaction. Hypoglycemia was defined and assessed using
American Diabetes Association criteria
(19) and evaluated before hyperglycemic
rescue.
Statistical Methods
The planned sample size provided
.90% power to demonstrate superiority versus placebo and noninferiority
versus sitagliptin and glimepiride (noninferiority margin = 0.3%). Superiority
of albiglutide versus sitagliptin and
glimepiride was tested if noninferiority
was established. The primary efficacy end
point (intent-to-treat population/last
observation carried forward algorithm)
was analyzed using an ANCOVA model
to compare treatment effects adjusting
for region, history of previous MI, age
category, and baseline HbA1c. Patients
rescued from hyperglycemia before
week 104 had their latest HbA1c value
before rescue carried forward for primary analyses. Those patients who
achieved treatment goals were evaluated by nonparametric ANCOVA. Time
to rescue was evaluated by KaplanMeier curves and log-rank tests. For
primary end point analysis, log-rank
tests for the duration up to the primary
end point were added post hoc. A multiple comparisons adjustment strategy
was implemented for various inferential tests among the primary and key
secondary objectives; AEs were analyzed by incidence proportion and incidence density rate overall and before
rescue (with additional type 2 diabetes
medication); in this article, overall
incidence/rate is used for all events
except hypoglycemia.
Study Conduct
This study was conducted in accordance
with good clinical practice standards, all
applicable privacy requirements, and
the guiding principles of the Declaration
of Helsinki. Written informed consent
was obtained from each patient before
participation.
RESULTS
This study was conducted at 289 centers
in 10 countries. Demographics and baseline characteristics were similar among
the albiglutide (n = 302), glimepiride (n =
307), sitagliptin (n = 302), and placebo
(n = 101) treatment groups (Supplementary Table 1).The mean age for the
groups ranged from 54.3 to 56.1 years
(84.3% were ,65 years old); approximately half of patients were men and
the majority were white (63.4–74.5%).
Approximately 67.0% of the total population were moderately to severely
obese (BMI $30 kg/m2); mean weight
in all treatment groups ranged from
89.6 to 91.8 kg, and mean duration of
diabetes ranged from 5.8 to 6.7 years. In
all treatment groups at baseline, HbA1c
levels were similar (8.1–8.2% [65.0–66.1
mmol/mol]), as were FPG concentrations (9.0–9.3 mmol/L [162.8–167.4
mg/dL]).
Overall, 67.4% of patients completed
active treatment through week 104;
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HARMONY 3: 2-Year Albiglutide Efficacy/Safety
Diabetes Care Volume 37, August 2014
rates of completion were similar among
the active treatment groups (sitagliptin
67.7%, glimepiride 68.8%, and albiglutide 68.3%) and lower for the placebo
group (59.6%). The main reasons for discontinuing active treatment were withdrawal of consent (placebo 14.4%,
sitagliptin 13.1%, glimepiride 13.2%, albiglutide 12.1%) and AEs (placebo 4.8%,
sitagliptin 3.2%, glimepiride 4.1%, albiglutide 6.3%). Patient flow is presented
in Fig. 1B.
Although all treatment groups went
through a blinded up-titration procedure, only the albiglutide and glimepiride groups actually up-titrated to 50 and
4 mg, respectively. By week 104, a
higher proportion of patients went
through the blinded up-titration process
in the placebo (;69%) and sitagliptin
(;59%) groups compared with the glimepiride (;54%) and albiglutide (;53%)
groups. Mean doses for albiglutide and
glimepiride at week 104 were 40.5 and
3.1 mg, respectively.
Primary Outcome: HbA1c
HbA1c reductions from baseline to week
104 were 20.63% (26.9 mmol/mol) for
albiglutide, 20.28% (23.1 mmol/mol)
for sitagliptin, 20.36% (23.9 mmol/mol)
for glimepiride, and +0.27% (3.0 mmol/mol)
for placebo. The model-adjusted mean
difference (albiglutide vs. comparator
treatment) demonstrated that albiglutide,
when added to metformin, was clinically
and statistically superior to placebo
(20.9% [29.8 mmol/mol]; 95% CI 21.2
to 20.7; P , 0.0001), sitagliptin (20.4%
[24.4 mmol/mol]; 95% CI 20.5 to 20.2;
P = 0.0001), and glimepiride (20.3%
[23.3 mmol/mol]; 95% CI 20.5 to
20.1; P = 0.0033) (Fig. 2A). Albiglutide
had the most durable effect, with a mean
HbA 1c of 7.5% (58.5 mmol/mol) at
week 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 at
each level (,6.5% [,47.5 mmol/mol],
,7.0% [,53.0 mmol/mol], ,7.5%
[,58.5 mmol/mol]) compared with placebo, sitagliptin, and glimepiride at
week 104 (Supplementary Fig. 1). The
difference between albiglutide and the
comparators was statistically significant
for placebo at all threshold levels (P #
0.02) and was comparable with only
Figure 2—Change in HbA1c from baseline (A), mean HbA1c (B), FPG (C), and weight (D) over
time through week 104. Intent-to-treat population data were determined using the last
observation 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.
sitagliptin and glimepiride at the
,7.5% (,58.5 mmol/mol; P # 0.04)
level. For the albiglutide group, these
treatment thresholds were met by
17.1%, 38.6%, and 58.7% of patients,
respectively. Subgroup analyses for
age, race, ethnicity, sex, baseline BMI,
and baseline HbA1c were all consistent
with the primary end point (Supplementary Fig. 2).
care.diabetesjournals.org
Ahrén and Associates
Secondary Outcomes
FPG
Changes in FPG from baseline at week
104 were consistent with the primary
end point (Fig. 2C). The treatment group
difference (albiglutide – comparator
treatment) for a model-adjusted least
squares mean decrease from baseline
to week 104 demonstrated that, when
added to metformin, albiglutide was
statistically superior to placebo (21.5
mmol/L [228 mg/dL]; P , 0.0001), sitagliptin (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 occurred
among patients taking albiglutide
(21.21 kg), placebo (21.0 kg), and sitagliptin (20.86 kg), whereas weight gain
occurred in glimepiride patients (+1.17
kg). The treatment difference between
albiglutide and glimepiride was statistically significant (P , 0.0001) (Fig. 2D).
Figure 3—Kaplan-Meier plot of time to hyperglycemic rescue (intent-to-treat population). Time
to rescue was evaluated by log-rank tests and Kaplan-Meier curves.
Time to Hyperglycemic Rescue
The albiglutide group had the most durable glycemic control. Per KaplanMeier estimates, fewer patients received
hyperglycemic rescue in the albiglutide
group (25.8%) compared with the placebo (59.2%), sitagliptin (36.4%), and glimepiride groups (32.7%). The difference
between baseline and time to rescue
with albiglutide was statistically significantly longer compared with sitagliptin
(P = 0.0118) and placebo (P , 0.00001)
(Fig. 3).
patient-years for placebo). Fewer patients experienced SAEs in the albiglutide
group (12.9%) than in the placebo group
(15.8%) but were comparable with those
who experienced SAEs in the sitagliptin
and glimepiride groups (9.9% and
11.7%, respectively). Overall, eight fatal
SAEs occurred through week 104 (three
each for albiglutide and glimepiride and
one each for sitagliptin and placebo);
none were considered by the investigators to be related to study medication.
General Safety and Tolerability
Events of Special Interest (Through
Week 104)
For overall safety, the proportion of patients experiencing AEs, SAEs, and AEs
leading to withdrawal while receiving
therapy was relatively balanced among
treatment groups (Table 1). Most AEs
were mild or moderate in intensity in
all treatment groups. The most frequent
AEs (occurring in .7% of patients taking
albiglutide) were upper respiratory tract
infection, diarrhea, nausea, injection-site
reaction, hypertension, nasopharyngitis, and cough. The type of AEs overall
and those occurring before rescue
(i.e., before the addition of hyperglycemic
rescue medication) were similar, and the
majority of AEs occurred before rescue
(Supplementary Table 2). The rate of
AEs was higher with albiglutide and
generally due to the higher rate
of injection-site reactions (45 of 100
patient-years for albiglutide vs. 1 of 100
GI Events
GI AEs were experienced by a similar
proportion 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 severe in intensity (1.0%, 1.3%, 1.3%, and
4.0% for placebo, sitagliptin, glimepiride, and albiglutide, respectively) or led
to withdrawal of the study drug (1.0%,
1.0%, 0.7%, and 2.0%, respectively). The
most common GI event was diarrhea in
the sitagliptin, glimepiride, and albiglutide groups and constipation in the placebo group.
At week 104, nausea event rates
were comparable between treatment
groups (7.9, 5.3, 3.7, and 9.3 events
per 100 patient-years for placebo,
sitagliptin, glimepiride, and albiglutide,
respectively), even though the incidence was highest in the placebo group
(10.9%) compared with sitagliptin
(6.6%), glimepiride (6.2%), and albiglutide (10.3%). The incidence and event
rate of vomiting over the 104 weeks
was (5.6%, 4.4 events per 100 patientyears) in the albiglutide group compared with placebo (1.0%, 0.6 events
per 100 patient-years), sitagliptin
(4.3%, 3.2 events per 100 patientyears), and glimepiride (3.6%, 2.1 events
per 100 patient-years). The per-visit prevalence of nausea/vomiting among patients receiving albiglutide was ,5% at
each time point (Supplementary Fig. 3).
Hypoglycemia
Documented symptomatic hypoglycemia (#3.9 mmol/L [#70 mg/dL]) before
rescue with albiglutide was low (3.0%)
and was similar to placebo (4.0%) and
sitagliptin (1.7%) compared with glimepiride (17.9%) (Table 1). No severe
hypoglycemic events were reported before rescue.
Injection-Site Reactions
Events classified by investigators as
injection-site reactions occurred more
frequently with albiglutide (17.2%; n =
52) compared with glimepiride (7.8%;
n = 24), sitagliptin (6.3%; n = 19), and
placebo (5%; n = 5). Injection-site reactions for albiglutide were mostly mild to
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HARMONY 3: 2-Year Albiglutide Efficacy/Safety
Diabetes Care Volume 37, August 2014
Table 1—AEs while receiving therapy, to week 104
Placebo + metformin Sitagliptin + metformin Glimepiride + metformin Albiglutide + metformin
(n = 101)
(n = 302)
(n = 307)
(n = 302)
Overall safety to week 104
Any AEs
SAEs
Related AEs
AEs leading to withdrawal
Most common AEs (.7% with albiglutide)
Upper respiratory tract infection
Diarrhea
Nausea
Injection-site reaction
Hypertension
Nasopharyngitis
Cough
Hypoglycemia before rescue*
Severe
Documented symptomatic
Asymptomatic
79.2/283.0
12.9/10.7
20.8/24.4
5.0/3.1
79.1/250.2
8.9/5.6
17.9/30.6
3.6/2.1
83.1/261.1
9.4/6.5
17.6/19.4
4.6/2.6
83.8/350.7
11.9/10.1
31.1/101.4
6.6/3.8
9.9/7.3
10.9/7.3
10.9/7.9
2.0/1.2
5.0/3.1
7.9/4.9
5.9/4.3
9.3/7.0
8.6/6.1
6.6/5.3
1.7/1.0
8.6/5.3
9.3/7.6
6.3/4.6
8.5/6.5
9.1/6.5
6.2/3.7
2.6/1.7
6.5/4.3
9.1/6.5
7.5/4.9
16.2/12.4
12.6/9.1
10.3/9.3
9.6/48.1
7.9/4.6
7.6/7.0
7.3/4.6
0
4 (4.0)/3.6
1 (1.0)/1.8
0
5 (1.7)/2.8
4 (1.3)/1.4
0
55 (17.9)/60.7
3 (1.0)/0.7
0
9 (3.0)/2.6
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 albiglutide
proportion in the overall data. *Patients with more than one hypoglycemic event were counted in all severity categories reported. Percentages are
based on the number of patients in each treatment group for the study being summarized. Severity was derived using the American Diabetes
Association guidelines for categorization of hypoglycemic events, as follows: severe = required assistance of another person; documented
symptomatic = typical symptoms accompanied by a plasma glucose concentration of #3.9 mmol/L; and asymptomatic = no symptoms but plasma
glucose concentration #3.9 mmol/L.
moderate in intensity (98.1%), were not
progressive, and most patients (n = 32/
52; 61.5%) experiencing injection-site
reactions had 1 or 2 events that lasted
#1 week (median duration). These reactions led to the withdrawal of 4 of
302 patients (1.3%) at 2 years. Most
patients (41 of 52; 79.0%) treated with
albiglutide who experienced injectionsite reactions were negative for antialbiglutide antibodies.
Pancreatitis
Six patients (albiglutide, n = 4; glimepiride, n = 2) were evaluated by a blinded,
independent PAC because of a reported
AE or a lipase/amylase concentration
more than or equal to three times the
ULN. Adjudication determined that neither patient from the glimepiride group
had pancreatitis. Among the four patients receiving albiglutide, adjudication
determined that one event was unlikely
to reflect pancreatitis, one event was
considered to reflect possible pancreatitis (laboratory elevations alone) unlikely related to the study drug, and
two events were probable pancreatitis
(laboratory elevations and suggestive
symptoms), and both were considered
possibly related to the study drug.
Thyroid Cancer
One patient treated with albiglutide developed follicular cancer on day 243.
Two patients receiving sitagliptin developed thyroid cancer: one experienced
follicular papillary carcinoma on day 48
and the other papillary thyroid cancer
on day 549. In these three patients, thyroid cancer diagnoses were considered
by the investigator to be not related to
the study drug, and calcitonin concentrations were not abnormal.
Potential SARs
A search of the standardized Medical
Dictionary for Regulatory Activities
queries identified two patients (placebo, n = 1; glimepiride, n = 1) who experienced angioedema as an SAE. The
investigator considered neither to be related to the study drug but instead related to ACE inhibitor therapy. Both
patients remained in the study after
discontinuing ACE inhibitor therapy.
Neither patient had positive antialbiglutide antibodies, and no other cases
of angioedema, anaphylaxis, pharyngeal
edema, or laryngeal edema occurred.
The investigators did not flag any additional events of interest.
Immunogenicity
Antialbiglutide antibody incidence
among albiglutide-treated subjects was
7.0% (21 of 302 subjects), and included
1 subject (0.4%) with preexisting antibodies (positive at baseline). Antibodies
were nonneutralizing and showed
reactivity with GLP-1 in 16 of the 21
antibody-positive subjects and with albumin in 5 antibody-positive subjects.
No samples tested positive for antialbiglutide IgE antibodies, and no SARs were
reported for antibody-positive subjects.
Cardiovascular Parameters
At baseline, lipids and blood pressure
were well controlled and mean values
were similar across the four treatment
groups (Supplementary Table 3). There
were no clinically meaningful mean
changes to lipids throughout the study.
Minor changes in SBP and DBP, respectively, from baseline occurred in all treatment groups at week 104: placebo (2.2
and 0 mmHg), sitagliptin (0.2 and 0.2
mmHg), glimepiride (1.5 and 1.0
mmHg), albiglutide (21.0 and 20.7
mmHg). Treatment differences in SBP
and DBP at week 104 between albiglutide
and the three comparators were not statistically significant. Similarly, there were
no meaningful changes from baseline at
week 104 in mean heart rate: placebo, 2.3
bpm; sitagliptin, 0.8 bpm; glimepiride,
20.5 bpm; albiglutide, 1.3 bpm.
CONCLUSIONS
When added to metformin, albiglutide
produced clinically and statistically superior and more sustained reduction in
HbA 1c at week 104 compared with
care.diabetesjournals.org
placebo, sitagliptin, and glimepiride.
The sustained treatment effect of albiglutide also is supported by the time to
hyperglycemic rescue, which showed
that fewer subjects taking albiglutide required rescue by week 104 compared
with patients treated with placebo, sitagliptin, and glimepiride; the difference
was statistically significant for albiglutide versus placebo and sitagliptin. Interestingly, the reduction in HbA1c was
similar during the early treatment period (;4 weeks). This might not have
been anticipated given the longer time
to a steady state for the once-weekly
albiglutide and the quick mechanism of
action of sulfonylureas. Similar clinically
and statistically superior results with albiglutide compared with all other treatment arms were observed for change in
FPG from baseline and the proportion of
patients meeting clinically relevant
HbA1c treatment goals. In addition, patients receiving albiglutide, sitagliptin,
and placebo lost weight through week
104, whereas patients treated with glimepiride gained weight; the difference
between albiglutide and glimepiride
was statistically significant (P , 0.0001).
The sustained effect of diabetes therapy is a critical clinical issue. Previous
type 2 diabetes comparator trials have
demonstrated the superiority or noninferiority of GLP-1RAs with or without
metformin but have been shorter 26week trials (20–22). The Diabetes Therapy Utilization: Researching Change in
A1C, Weight, and Other Factors Through
Intervention with Exenatide OnceWeekly (DURATION)-2 and Liraglutide
Effect Action in Diabetes (LEAD)-2 trials,
which included metformin in all treatment arms, demonstrated the superiority of exenatide over sitagliptin and
pioglitazone and of liraglutide over placebo, respectively, with regard to HbA1c
reductions (20–22). In another 26-week
study (HARMONY 8), once-weekly albiglutide provided superior glycemic improvement, similar tolerability, and
better patient compliance compared
with sitagliptin therapy in patients with
type 2 diabetes and renal impairment
(21). Understanding the long-term effects on type 2 diabetes of different
combination therapies has led to the
5-year Glycemia Reduction Approaches
in Diabetes: A Comparative Effectiveness (GRADE) study. This trial is comparing the efficacy and durability of four
Ahrén and Associates
classes of medications (DPP-4, sulfonylureas, GLP-1RAs, and long-acting insulin)
in patients with type 2 diabetes who are
receiving metformin (11). The results reported here may give a window to the
eventual results of that trial.
Albiglutide was generally well tolerated; the albiglutide group showed rates
of SAEs and AEs leading to withdrawal
similar to those of the comparator
groups. The percentage of patients reporting AEs while receiving therapy was
similar for albiglutide, sitagliptin, and
glimepiride and slightly lower for placebo. The types of AEs noted for albiglutide are generally consistent with the
type 2 diabetic population and the
known 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 previous studies using other GLP-1RAs, particularly in the early weeks of therapy. In
clinical practice, GI AEs occurring early in
the course of treatment with GLP-1RAs
may contribute to the discontinuation
rates seen with this class, and agents
with reduced GI effects may improve
patient adherence. With respect to hypoglycemia, albiglutide had rates similar
to sitagliptin and placebo and lower rates
compared with glimepiride. Injection-site
reactions were more common in the
albiglutide-treated subjects, although a
few (1.3%) withdrew because of reactions during the 104-week period. The
proportion of patients developing antialbiglutide antibodies was low, and
none were nonneutralizing.
HARMONY 3 is a long-term, 3-year trial with unique design features that must
be considered when interpreting results. First, up-titration was based on
glucose thresholds established by protocol: the time point of titration was
not prescribed or standardized, reflecting up-titration methods in clinical practice; thus, the efficacy and safety data
reflect a mixture of 30- and 50-mg albiglutide doses and 2- and 4-mg glimepiride doses. In addition, there was no
increased dose for placebo and sitagliptin despite patients who underwent the
blinded up-titration procedure. Because
of this design feature, many patients
randomized to glimepiride and albiglutide were not receiving the maximum
dose, as evidenced by the mean doses
of each drug. Therefore, the maximum
effect in these arms may not have been
achieved, depending on the dose curve
for each agent, and there is a possibility
that the relationship between the arms
may have shifted at higher doses.
Second, rescue medications were
used in the program to permit patients
to remain in the studies while receiving
a blinded investigational product or control through 3 years. This represents a
more “real-life” situation, where additional medications are added to regimens that are not meeting treatment
goals. While the primary efficacy assessment was based on end points before
rescue, the main safety assessment included data after rescue. These design
features, however, may have complicated the interpretation of some results.
Finally, interpretation of the proportion
of patients reaching the treatment goal
was complex; up-titration occurred at
7.5% and not 7.0%, and the full benefit
of 50 mg may not be seen since the end
point contains a mix of patients taking
30- and 50-mg albiglutide.
In conclusion, when added to metformin, albiglutide produced clinically and
statistically significant reductions in
HbA1c and FPG at week 104 compared
with placebo, sitagliptin, and glimepiride. Patients receiving albiglutide, sitagliptin, and placebo lost body weight
through week 104, whereas patients
taking glimepiride gained weight; the
difference between albiglutide and glimepiride was statistically significant. Albiglutide was generally well tolerated,
and rates of SAEs were similar across
treatment groups. The most frequent
AEs for albiglutide were largely consistent
with the known profile for GLP-1RAs.
Acknowledgments. The authors thank Douglas
L. Wicks, MPH, CMPP, of GlaxoSmithKline, for
managing manuscript development. Editorial
support was provided by Leonard Lionnet, PhD,
of PharmaWrite, LLC (assistance with the production of a draft outline and the first draft of
the manuscript, assembling tables and figures,
and collating author comments); Diana Talag,
ELS, of PharmaWrite, LLC (assistance with
copyediting and fact-checking); and Shana
Cambareri of PharmaWrite, LLC (art direction).
Duality of Interest. B.A. received honoraria for
lecturing and holds advisory board membership
for Bristol-Myers Squibb, GlaxoSmithKline,
Lilly, Novartis, Novo Nordisk, Merck, and Sanofi,
which all are companies producing GLP-1RAs
or DPP-4 inhibitors. S.L.J., M.S., D.T.C., F.Y., and
C.P. are employed by and shareholders of
GlaxoSmithKline. M.N.F. has received research
support and has served either as an investigator
2147
2148
HARMONY 3: 2-Year Albiglutide Efficacy/Safety
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, and
Tethys, some of which are companies producing
GLP-1RAs or DPP-4 inhibitors. M.N.F. also has
served as a consultant for GlaxoSmithKline, Pfizer,
and Proctor & Gamble Co. No other potential
conflicts of interest relevant to this article were
reported.
The sponsor of the study participated in the
study design, data collection, data review, data
analysis, and writing of the report. All authors
had 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 had
final responsibility for the decision to submit for
publication.
Author Contributions. B.A. and M.N.F. provided 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 revised
the manuscript. F.Y. performed the statistical
analysis. All authors revised the manuscript,
reviewed the final manuscript, and approved
the manuscript for submission. M.N.F. is the
guarantor of this work and, as such, had full
access to all the data in the study and takes
responsibility for the integrity of the data and
the accuracy of the data analysis.
Prior Presentation. Data from this article were
presented at the 73rd Scientific Sessions of the
American Diabetes Association, Chicago, IL, 21–
25 June 2013, and published in Diabetes
2013;62(Suppl. 1A):LB14 (Abstract 52-LB).
Data also were presented via oral presentation
at the 49th Annual Meeting of the European
Association for the Study of Diabetes, Barcelona,
Spain, 23–27 September 2013, and published in
Diabetologia 2013;56(Suppl. 1):S8.
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