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
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
C L I N C A R E / E D U C A T I O N / N U T R II T O N / P S Y C H O S O C I A L
0 Deborah T. Cirkel
1 Murray Stewart
2 Susan L. Johnson
3 for the HARMONY 3 Study Group
4 and Mark N. Feinglos
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.
OBJECTIVE
To compare the efficacy and safety of weekly albiglutide with daily sitagliptin,
daily glimepiride, and placebo.
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.
CONCLUSIONS
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.
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.
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
period (...truncated)