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Diabetes, Obesity and Metabolism 18: 317–332, 2016. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.review article
Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists Sten Madsbad Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
Currently, six glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short-acting exenatide twice daily and lixisenatide once daily; and longer-acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP-1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head-to-head trials and one large phase II study have compared the efficacy and safety of these seven GLP-1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short-acting GLP-1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer-acting agents, whereas the longer-acting compounds reduced plasma glucose throughout the 24-h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP-1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection-site reactions than liraglutide and dulaglutide. GLP-1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP-1RAs and delivery methods may further expand future treatment options. Keywords: albiglutide, dulaglutide, exenatide, GLP-1 receptor agonist, liraglutide, lixisenatide, taspoglutide, type 2 diabetes
Date submitted 25 June 2015; date of first decision 16 August 2015; date of final acceptance 22 October 2015
Introduction The early and intensive treatment of people with type 2 dia- betes (T2D) is of key importance for reducing the risk of late diabetic complications, such as microvascular disease [1]. T2D is linked to obesity [2], and the cornerstone of treatment is lifestyle changes to promote weight loss and increase exercise [3]; however, because of the progressive nature of T2D, phar- macological therapy to address hyperglycaemia becomes nec- essary in almost all patients. Pharmacological treatment is, unfortunately, often associated with side effects such as weight gain (e.g. sulphonylureas, insulin and thiazolidinediones) [4,5], hypoglycaemia (e.g. sulphonylureas and insulin) [6,7], gas- trointestinal (GI) discomfort [e.g. metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs)] and genital infec- tions [sodium-glucose co-transporter 2 (SGLT2) inhibitors] [8–10]. Notwithstanding the GI discomfort with GLP-1RAs, their introduction over the last decade has greatly improved treatment of T2D [11–14].
Human GLP-1 is a member of the incretin family of glucoregulatory hormones, and is secreted in response to
Correspondence to: Sten Madsbad, Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Kettegaards Alle, 2650 Hvidovre, Denmark. E-mail: [email protected]
This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
food ingestion [15,16]. Glucagon-like peptide-1 has multiple effects that are desirable in the treatment of T2D, includ- ing: glucose-dependent increased insulin secretion; glucose- dependent decreased glucagon secretion; delayed gastric emptying; increased satiety; and, as shown in some animal studies, protection of 𝛽-cell mass [17,18].
Unfortunately, although intravenously infused GLP-1 can normalize plasma glucose concentrations in people with T2D [19,20], it has an extremely short half-life (1–2 min) [16] that limits its therapeutic value [21]. Multiple GLP-1RAs have been developed to recapitulate the physiological effects of GLP-1 but with an extended duration of action (achieved by vari- ous changes to the molecular structure) compared with the native peptide [22].The present review examines the avail- able evidence from published head-to-head clinical trials with GLP-1RAs, and contrasts the relative clinical benefits of the short- and longer-acting agents.
Characteristics of GLP-1RAs Seven GLP-1RAs are included in the present review, all of which have been studied in phase III clinical trials. The GLP-1RAs are: exenatide twice daily (Byetta®, AstraZeneca; approved in Europe in November 2006 and 28 May 2005 in USA [23,24]); liraglutide (Victoza®, Novo Nordisk; approved in Europe in June 2009 and 25 January 2010 in USA [25,26]); exenatide once weekly (Bydureon®, AstraZeneca; approved in Europe in
review article DIABETES, OBESITY AND METABOLISM June 2011 and 26 January 2012 in USA [27,28]); lixisenatide (Lyxumia®, Sanofi; approved in Europe in February in 2013 [29] but not in the USA); albiglutide (Eperzan® and Tanzeum®, GlaxoSmithKline; approved in March 2014 in Europe and April 2014 in USA [30,31]); dulaglutide (Trulicity™, Lilly; approved in Europe in November 2014 and September 2014 in USA [32,33]); and taspoglutide (Ipsen/Roche). These have all now been approved for use in T2D, with the exception of taspoglu- tide, the development of which was halted because of serious hypersensitivity reactions and GI adverse events (AEs) during clinical trials; however, the available data for this compound are included in the present review to give a full picture of the GLP-1RA family.
As a drug class, the GLP-1RAs have proven efficacy for low- ering glycated haemoglobin (HbA1c) and decreasing weight in T2D, with a reduced risk of hypoglycaemia compared with insulin or sulphonylureas [34]. These characteristics under- lie the inclusion of GLP-1RAs in various clinical practice guidelines. Their use as dual therapy with metformin after first-line metformin and as triple therapy (in combination with metformin and a sulphonylurea/thiazolidinedione/insulin) is part of the European Association for the Study of Dia- betes/American Diabetes Association recommendations [34]. GLP-1RAs are recommended as monotherapy, dual therapy and triple therapy by the American Association of Clini- cal Endocrinologists/American College of Endocrinology guidelines [35]. Nonetheless, they differ substantially in their molecular structure and degree of homology to endogenous GLP-1, both in their chemical and physiological properties and in their durations of action (Table 1).
Several GLP-1RAs (exenatide twice daily, exenatide once weekly and lixisenatide) are based on the exendin-4 molecule, a peptide with 53% identity to native GLP-1 [36,42,43], while others, such as liraglutide, albiglutide, dulaglutide and tas- poglutide are classified as GLP-1RA analogues with 97, 95, 90 and 93% identity, respectively, to native GLP-1 [38–40]. The GLP-1RAs are, in addition, commonly considered to fall into two different classes based on their duration of receptor activation. The short-acting compounds, delivering short-lived receptor activation, comprise exenatide twice daily and lixise- natide once daily. The long-acting compounds, which activate the GLP-1 receptor continuously at their recommended dose, comprise liraglutide once daily, and the once-weekly formu- lations of exenatide, albiglutide, dulaglutide and taspoglutide (Table 1). These different durations of action largely explain variations among GLP-1RAs in their impact on fasting plasma glucose (FPG), 24-h glucose profile and postprandial plasma glucose (PPG) levels [60,61]. Delayed gastric emptying, for example, is more strongly associated with short-acting than longer-acting GLP-1RAs (Figure 1), and this may underlie the greater effects on PPG observed with short-acting GLP-1RAs. Meanwhile, the greater half-lives of the longer-acting com- pounds allow enhanced effects on the whole 24-h glucose level, including FPG. Longer-acting GLP-1RAs do not sig- nificantly affect gastric motility. Instead, they exert more of their effect via the pancreas, increasing insulin secretion and inhibiting glucagon secretion via paracrine release of somato- statin (Figure 1) [22].
Not only do GLP-1RAs differ from each other in terms of their duration of action [39,46–51], they also show varying levels of affinity for the GLP-1 receptor [62]. This difference between GLP-1RAs is also evident in their varying efficacy with regard to HbA1c reduction and weight loss, and differing tol- erability profiles and potential for immunogenicity [22,63–65]. It is important to understand these specific characteristics to appropriately tailor the choice of GLP-1RA to the individual patient. Head-to-head clinical trials are the best way to eluci- date variations in efficacy and tolerability, and a number of such studies have been conducted with GLP-1RAs in T2D.
Head-to-head Comparison Trials To date, the results from nine phase III randomized trials that directly compare different pairs of GLP-1RAs have been published [12–14,40,54–56,66,67]. An overview of the designs of these studies is provided in Table 2. One large phase II study, comparing liraglutide and lixisenatide pharmacodynamics, is also included [61].
Of the GLP1-RAs in the head-to-head trials, exenatide twice daily and liraglutide were the most common comparators (Table 2). The majority of the phase III studies included in the present review were of ∼6 months’ duration, although sev- eral also had extension phases to give trial durations up to 12 months (Table 2). All of the phase III trials examined changes in HbA1c as the primary endpoint; the phase II study by Kapitza et al. [61], however, used changes in PPG exposure as the pri- mary endpoint.
In general, baseline characteristics were similar across trial populations and between treatment groups within individual trials (Table 3). The mean age of participants ranged from 55 to 61 years across the studies, with mean duration of diabetes ranging from 6 to 9 years. Mean baseline HbA1c levels were in the range of 8.0 (64 mmol/mol) to 8.7% (72 mmol/mol) across the studies, except for the phase II study (in which HbA1c levels were lower) [61]. Glucose concentrations in the range of 9.1–9.9 mmol/l were determined in plasma and serum samples, and mean baseline weight was consistently in the range 91–102 kg, except in an Asian study, in which mean weight was lower [56] (Table 3). Differences in key study outcomes are discussed in the following sections.
Glycaemic Measurements In all of the head-to-head trials, the GLP-1RAs studied led to notable reductions in HbA1c.
These reductions ranged between 0.3 (3 mmol/mol) and 1.9% (21 mmol/mol). Although data are not comparable across studies because of differences in study design and patient cohorts, there were some important differences between treat- ment arms in the magnitude of HbA1c reductions (Figure 2). In particular, in the DURATION-1, DURATION-5 studies and the study by Ji et al. [54–56], exenatide once weekly produced both more consistent and greater reductions in HbA1c levels than did exenatide twice daily (p ≤ 0.0023). In the GetGoal-X study [12], meanwhile, exenatide twice daily showed a numeri- cally greater HbA1c reduction than lixisenatide. Liraglutide, in
318 Madsbad Volume 18 No. 4 April 2016
DIABETES, OBESITY AND METABOLISM review article
Ta bl
e 1.
C om
pa ra
tiv e
ch ar
ac te
ri st
ic s
of th
e gl
uc ag
on -l
ik e
pe pt
id e-
1 re
ce pt
or ag
on is
ts .
E xe
na ti
de tw
ic e
da il
y E
xe na
ti de
on ce
w ee
kl y
Li ra
gl ut
id e
on ce
da il
y Li
xi se
na ti
de on
ce da
il y
A lb
ig lu
ti de
on ce
w ee
kl y
D ul
ag lu
ti de
on ce
w ee
kl y
Ta sp
og lu
ti de
on ce
w ee
kl y
Pe rc
en ta
ge am
in o
ac id
se qu
en ce
si m
il ar
it y
to na
ti ve
G LP
-1
53 %
[3 6]
53 %
[3 6]
97 %
[3 7]
≈ 50
% *
95 %
[3 8]
90 %
[3 9]
93 %
[4 0]
P ro
pe rt
ie s
of th
e dr
ug R
es is
ta nt
to D
PP -4
cl ea
va ge
, la
rg el
y du
e to
th e
su bs
tit ut
io n
of al
an in
e in
po si
tio n
2 by
gl yc
in e
[4 1]
En ca
ps ul
at ed
in bi
od eg
ra da
bl e
po ly
m er
m ic
ro sp
he re
s [4
2]
C -1
6 fa
tt y
ac id
co nf
er s
al bu
m in
bi nd
in g
an d
he pt
am er
fo rm
at io
n [3
8]
B as
ed on
ex en
at id
e, bu
ti s
m od
ifi ed
by th
e de
le ti
on of
on e
pr ol
in e
re si
du e
an d
ad di
ti on
of si
x ly
si ne
re si
du es
at th
e C
-t er
m in
al [4
3]
G LP
-1 di
m er
fu se
d to
al bu
m in
[4 4]
Th e
G LP
-1 po
rt io
n of
th e
m ol
ec ul
e is
fu se
d to
an Ig
G 4
m ol
ec ul
e, lim
iti ng
re na
lc le
ar an
ce an
d pr
ol on
gi ng
ac tiv
ity [3
9]
M od
ifi ca
ti on
s de
si gn
ed to
hi nd
er cl
ea va
ge by
D PP
-4 an
d by
se ri
ne pr
ot ea
se s
an d
al so
al lo
w s
gr ea
te r
re ce
pt or
bi nd
in g
[4 5]
H al
f- lif
e 2.
4 h
[4 6]
H al
f- lif
e is
an un
pu bl
is he
d re
su lt
bu t
st ea
dy st
at e
co nc
en tr
at io
ns at
6– 7
w ee
ks [4
7]
11 –1
5 h
[4 8]
2. 7–
4. 3
h [4
9] 6–
8 da
ys [5
0] ≈
5 da
ys [3
9] 16
5 h
[5 1]
T m
ax 2.
1 h
[4 6]
2. 1–
5. 1
h du
ri ng
th e
fir st
48 h
[4 7]
≈ 9–
12 h
[4 8]
1. 25
–2 .2
5 h
[4 9]
72 –9
6 h
[5 0]
24 –7
2 h
[3 9]
4, 6
an d
8 h
at 1,
8 an
d 30
m g
do se
s, re
sp ec
tiv el
y [5
1] C
le ar
an ce
9. 1
l/ h
[5 2]
U np
ub lis
he d
re su
lts 1.
2 l/
h [5
2] 21
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8. 5
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[4 9]
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[5 3]
0. 75
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at st
ea dy
st at
e w
as 0.
07 3
an d
0. 10
7 l/
h, re
sp ec
tiv el
y [2
9]
U np
ub lis
he d
re su
lts
A nt
ib od
y fo
rm at
io n
• In
he ad
-t o-
he ad
st ud
ie s,
an tib
od ie
s w
er e
m or
e co
m m
on an
d tit
re s
w er
e hi
gh er
w ith
ex en
at id
e on
ce w
ee kl
y co
m pa
re d
w ith
ex en
at id
e tw
ic e
da ily
[5 4–
56 ].
• A
nt ib
od ie
s di
d no
tc or
re la
te w
ith ra
te s
of re
po rt
ed A
Es [5
4– 56
].
Fr om
si x
ph as
e 3
st ud
ie s,
8. 7
an d
8. 3%
of pa
rt ic
ip an
ts ha
d lo
w -t
itr e
an tib
od ie
s to
lir ag
lu ti
de 1.
2 an
d 1.
8 m
g, re
sp ec
tiv el
y, aft
er 26
w ee
ks [5
7]
A nt
ib od
ie s
de ve
lo pe
d in
: A
nt ib
od ie
s de
ve lo
pe d
in 3.
7% of
pa rt
ic ip
an ts
tr ea
te d
w ith
al bi
gl ut
id e
[1 4]
D ul
ag lu
ti de
an ti
dr ug
an tib
od ie
s in
1% of
pa rt
ic ip
an ts
an d
du la
gl ut
id e
ne ut
ra lis
in g
an ti
dr ug
an tib
od ie
s in
1% of
pa ti
en ts
[1 3]
D et
ec te
d in
49 %
of pa
rt ic
ip an
ts [4
0] •
56 –6
0% of
pa rt
ic ip
an ts
tr ea
te d
w ith
20 μg
on ce
da ily
[5 8]
• 43
% of
pa rt
ic ip
an ts
tr ea
te d
w ith
10 μg
on ce
da ily
an d
71 %
tr ea
te d
w ith
20 μg
tw ic
e da
ily [5
9]
A E,
ad ve
rs e
ev en
t; D
PP -4
,d ip
ep ti
dy lp
ep ti
da se
-4 ;G
LP -1
,g lu
ca go
n- lik
e pe
pt id
e- 1;
G LP
-1 R
A ,G
LP -1
re ce
pt or
ag on
is t;
Ig G
4, im
m un
og lo
bu lin
4; T
m ax
,t im
e to
m ax
im um
pl as
m a
co nc
en tr
at io
n. *V
al ue
ba se
d on
si m
ila ri
ty to
ex en
at id
e.
Volume 18 No. 4 April 2016 doi:10.1111/dom.12596 319
review article DIABETES, OBESITY AND METABOLISM
Figure 1. Gastric-emptying effects of short-acting versus longer-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs). (A) Short-acting GLP-1RAs suppress gastric emptying, which prolongs the presence of food in the stomach and upper small intestine; the reduced transpyloric flow causes delayed intestinal glucose absorption and diminished postprandial insulin secretion. Short-acting GLP-1RAs may also directly suppress glucagon secretion. (B) Longer-acting GLP-1RAs do not significantly affect gastric motility, because of tachyphylaxis. Instead, longer-acting GLP-1RAs exert more of their effect via the pancreas, increasing insulin secretion, and inhibiting glucagon secretion via paracrine release of somatostatin. By targeting the central nervous system, both shorter- (A) and longer (B) -acting GLP-1RAs increase satiety and also may induce nausea. Adapted from Meier [22]. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology 2012;8(12):728–42, copyright 2012.
the DURATION-6 and LEAD-6 studies, led to greater HbA1c reductions than both exenatide twice daily and once weekly (p ≤ 0.02) [66,67]. Liraglutide also led to greater reductions in HbA1c than lixisenatide (p < 0.01) in the phase II study (although it was not the primary endpoint and the study dura- tion was short [61]). Likewise, in the HARMONY 7 study [14], liraglutide led to greater reductions in HbA1c than albiglutide (however, the predefined non-inferiority criteria for albiglutide were not met). In the AWARD-6 study [13], the reduction in HbA1c did not differ between liraglutide and dulaglutide after 26 weeks of treatment. In the T-emerge 2 study, taspoglutide at 10 and 20 mg led to greater reductions in HbA1c than exenatide 10 μg twice daily (p < 0.0001) [40].
In addition, PPG and FPG were assessed in many of these trials. As expected, based on the delayed gastric emptying seen with the short-acting GLP-1RAs, exenatide twice daily and lixisenatide had greater effects on PPG than the longer-acting GLP-1RAs and this improvement was observed after the meal that followed the injection. For example, in the phase II study, lixisenatide administered before breakfast was associated with significantly greater reductions in maximum PPG excursion than liraglutide (−3.9 mmol/l vs −1.4 mmol/l, respectively; p < 0.0001), resulting in PPG of 7.3 and 10.1 mmol/l, respec- tively, 2 h after starting breakfast [61]. The differential effect on PPG is evident in the 24-h plasma glucose pro- files shown in Figure 3. These data are supported by results from another phase II study, which showed that lixisenatide
had a significantly greater effect than liraglutide in reducing area under the PPG curve after a standardized solid breakfast. This difference was thought to be attributable to significant delays in gastric emptying with lixisenatide versus liraglutide, which reduced post-breakfast blood glucose exposure [68].
Similarly, in a comparison of exenatide twice daily and exe- natide once weekly, the mean change from baseline in 2-h PPG was significantly greater with the twice-daily versus the once-weekly formulation (−6.9 mmol/l vs −5.3 mmol/l, respec- tively; p = 0.0124), and the delay in gastric emptying was more pronounced with exenatide twice daily than with exenatide once weekly [54]. Furthermore, in a study conducted in Asian participants by Ji et al. [56], exenatide twice daily produced significantly greater reductions in postprandial blood glucose than exenatide once weekly based on assessments 2 h after each of the morning and evening meals (p < 0.001); however, in a sub-analysis of participants in the T-emerge 2 study, the longer-acting GLP-1RA taspoglutide had similar effects to exe- natide twice daily on postprandial metabolism, although the mechanisms underlying this effect are not entirely clear [69].
Generally, the longer-acting GLP-1RAs improve glucose control via a downward shift of the whole 24-h glucose curve, which explains the greater overall efficacy compared with the short-acting exenatide twice daily and lixisenatide once daily. While the short-acting GLP-1RAs typically have an advantage with respect to PPG, the situation is reversed with FPG. Here, the longer-acting GLP-1RAs resulted in greater improvements.
320 Madsbad Volume 18 No. 4 April 2016
DIABETES, OBESITY AND METABOLISM review article
Ta bl
e 2.
D es
ig n
of pu
bl is
he d
ph as
e II
I( an
d on
e ke
y ph
as e
II )r
an do
m iz
ed he
ad -t
o- he
ad st
ud ie
s of
gl uc
ag on
-l ik
e pe
pt id
e- 1
re ce
pt or
ag on
is ts
in ty
pe 2
di ab
et es
.
St ud
y na
m e
Tr ea
tm en
ta rm
s D
ur at
io n
In cl
us io
n cr
it er
ia P
ri m
ar y
en dp
oi nt
K ey
se co
nd ar
y en
dp oi
nt s
D U
R A
T IO
N -1
[5 4]
Ex en
at id
e on
ce w
ee kl
y vs
ex en
at id
e tw
ic e
da ily
vs 30
w ee
ks *
≥ 16
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[≤ 7.
0% (5
3 m
m ol
/m ol
), ≤
6. 5%
(4 8
m m
ol /m
ol )
an d ≤
6. 0%
(4 2
m m
ol /m
ol )]
Th er
ap y
w ith
di et
an d
ex er
ci se
,o r
w ith
1– 2
O A
D s
(m et
fo rm
in ,S
U an
d/ or
T Z
D )
C ha
ng es
in FP
G ,P
PG ,w
ei gh
t, B
P, lip
id s
an d
gl uc
ag on
H bA
1c 7.
1– 11
.0 %
FP G <
16 m
m ol
/l Ex
en at
id e
ph ar
m ac
ok in
et ic
s an
d pa
ra ce
ta m
ol ab
so rp
ti on
Sa fe
ty an
d to
le ra
bi lit
y B
M I2
5– 45
kg /m
2
D U
R A
T IO
N -5
[5 5]
Ex en
at id
e on
ce w
ee kl
y vs
ex en
at id
e tw
ic e
da ily
24 w
ee ks
≥ 18
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[< 7.
0% (5
3 m
m ol
/m ol
)a nd
≤ 6.
5% (4
8 m
m ol
/m ol
)] Tr
ea te
d w
ith di
et an
d ex
er ci
se ,o
r w
ith m
et fo
rm in
,S U
,T Z
D or
a co
m bi
na ti
on Pa
tie nt
s ac
hi ev
in g
FP G
ta rg
et (≤
7. 0
m m
ol /l
) H
bA 1c
7. 1–
11 .0
% C
ha ng
es in
FP G
,w ei
gh t,
B P
an d
lip id
s FP
G <
15 .5
m m
ol /l
Sa fe
ty an
d to
le ra
bi lit
y B
M I2
5– 45
kg /m
2
Ji et
al .[
56 ]
Ex en
at id
e on
ce w
ee kl
y vs
ex en
at id
e tw
ic e
da ily
26 w
ee ks
≥ 20
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[≤ 7.
0% (5
3 m
m ol
/m ol
), ≤
6. 5%
(4 8
m m
ol /m
ol )
an d ≤
6. 0%
(4 2
m m
ol /m
ol )]
Tr ea
te d
w ith
1– 3
O A
D s
(m et
fo rm
in ,S
U ,
T Z
D )
H bA
1c 7.
0– 11
.0 %
C ha
ng es
in FS
G ,S
M PG
,w ei
gh t,
lip id
s, H
O M
A -𝛽
an d
in su
lin se
ns iti
vi ty
Sa fe
ty an
d to
le ra
bi lit
y B
M I2
1– 35
kg /m
2
D U
R A
T IO
N -6
[6 7]
Ex en
at id
e on
ce w
ee kl
y vs
lir ag
lu ti
de on
ce da
ily 26
w ee
ks ≥
18 ye
ar s
of ag
e C
ha ng
e in
H bA
1c Pa
rt ic
ip an
ts ac
hi ev
in g
H bA
1c ta
rg et
(< 7.
0% )
Tr ea
te d
w ith
di et
an d
ex er
ci se
an d
O A
D s
(m et
fo rm
in ,S
U ,m
et fo
rm in +
SU ,o
r m
et fo
rm in +
pi og
lit az
on e)
C ha
ng es
in FS
G ,w
ei gh
t, B
P an
d lip
id s
Pa tie
nt -r
ep or
te d
ou tc
om es
H bA
1c 7.
1– 11
.0 %
B M
I≤ 45
kg /m
2
St ab
le bo
dy w
ei gh
t
Sa fe
ty an
d to
le ra
bi lit
y
LE A
D -6
[6 6]
Ex en
at id
e tw
ic e
da ily
vs lir
ag lu
ti de
on ce
da ily
26 w
ee ks
* 18
–8 0
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
re ac
hi ng
H bA
1c ta
rg et
s [<
7. 0%
(5 3
m m
ol /m
ol )a
nd ≤
6. 5%
(4 8
m m
ol /m
ol )]
Th er
ap y
w ith
m et
fo rm
in ,S
U or
bo th
H bA
1c 7.
0– 11
.0 %
C ha
ng es
in FP
G ,S
M PG
,w ei
gh t,
B P,
lip id
s, gl
uc ag
on an
d H
O M
A -𝛽
B M
I≤ 45
kg /m
2
Sa fe
ty an
d to
le ra
bi lit
y
G et
G oa
l- X
[1 2]
Ex en
at id
e tw
ic e
da ily
vs lix
is en
at id
e on
ce da
ily 24
w ee
ks 21
–8 4
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[< 7.
0% (5
3 m
m ol
/m ol
)a nd
≤ 6.
5% (4
8 m
m ol
/m ol
)] Tr
ea te
d w
ith m
et fo
rm in
H bA
1c 7.
0– 10
.0 %
C ha
ng es
in FP
G an
d w
ei gh
t Sa
fe ty
an d
to le
ra bi
lit y
Volume 18 No. 4 April 2016 doi:10.1111/dom.12596 321
review article DIABETES, OBESITY AND METABOLISM
Ta bl
e 2.
C on
ti nu
ed
St ud
y na
m e
Tr ea
tm en
ta rm
s D
ur at
io n
In cl
us io
n cr
it er
ia P
ri m
ar y
en dp
oi nt
K ey
se co
nd ar
y en
dp oi
nt s
H A
R M
O N
Y 7
[1 4]
A lb
ig lu
ti de
on ce
w ee
kl y
vs lir
ag lu
ti de
on ce
da ily
32 w
ee ks
≥ 18
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[< 7.
0% (5
3 m
m ol
/m ol
)a nd
< 6.
5% (4
8 m
m ol
/m ol
)] Tr
ea te
d w
ith m
et fo
rm in
,S U
,T Z
D or
a co
m bi
na ti
on C
ha ng
es in
FP G
an d
w ei
gh t
H bA
1c 7.
0– 10
.0 %
Sa fe
ty an
d to
le ra
bi lit
y B
M I2
0– 45
kg /m
2
A W
A R
D -6
[1 3]
D ul
ag lu
ti de
on ce
w ee
kl y
vs lir
ag lu
ti de
on ce
da ily
26 w
ee ks
≥ 18
ye ar
s of
ag e
C ha
ng e
in H
bA 1c
Pa rt
ic ip
an ts
ac hi
ev in
g H
bA 1c
ta rg
et s
[< 7.
0% (5
3 m
m ol
/m ol
)a nd
≤ 6.
5% (4
8 m
m ol
/m ol
)] Tr
ea te
d w
ith m
et fo
rm in
H bA
1c 7.
0– 10
.0 %
C ha
ng e
in FS
G ,S
M PG
,w ei
gh t,
B M
Ia nd
H O
M A
-𝛽 Sa
fe ty
an d
to le
ra bi
lit y
T -e
m er
ge 2
[4 0]
Ex en
at id
e tw
ic e
da ily
vs ta
sp og
lu tid
e on
ce w
ee kl
y 24
w ee
ks *
18 –7
5 ye
ar s
of ag
e C
ha ng
e in
H bA
1c C
ha ng
es in
FP G
an d
w ei
gh t(
as se
ss ed
ov er
52 w
ee ks
) Tr
ea te
d w
ith m
et fo
rm in
an d/
or T
Z D
C ha
ng es
in fa
st in
g pr
o- in
su lin
,f as
ti ng
pr o-
in su
lin /i
ns ul
in ra
ti o
an d
H O
M A
-𝛽 (a
ss es
se d
ov er
52 w
ee ks
) H
bA 1c
7. 0–
10 .0
% B
M I2
5– 45
kg /m
2
St ab
le bo
dy w
ei gh
t Sa
fe ty
an d
to le
ra bi
lit y
K ap
itz a
et al
.† [6
1] Li
xi se
na tid
e on
ce da
ily vs
lir ag
lu ti
de on
ce da
ily 28
da ys
37 –7
4 ye
ar s
of ag
e C
ha ng
e in
PP G
ex po
su re
C ha
ng es
in m
ax im
um PP
G ex
cu rs
io n
aft er
a st
an da
rd iz
ed br
ea kf
as tt
es tm
ea l
Tr ea
te d
w ith
m et
fo rm
in H
bA 1c
6. 5–
9. 0%
C ha
ng es
in pr
em ea
ls er
um in
su lin
,s er
um C
-p ep
ti de
an d
pl as
m a
gl uc
ag on
le ve
ls 24
-h pl
as m
a gl
uc os
e pr
ofi le
M ea
n H
bA 1c
Sa fe
ty an
d to
le ra
bi lit
y
A ll
st ud
ie s
w er
e op
en -l
ab el
. B
M I,
bo dy
m as
s in
de x;
B P,
bl oo
d pr
es su
re ;F
PG ,f
as tin
g pl
as m
a gl
uc os
e; FS
G ,f
as tin
g se
ru m
gl uc
os e;
G LP
-1 R
A ,g
lu ca
go n-
lik e
pe pt
id e-
1 re
ce pt
or ag
on is
t; H
bA 1c
,g ly
ca te
d ha
em og
lo bi
n H
O M
A -𝛽
,h om
eo st
as is
m od
el as
se ss
m en
to f𝛽
-c el
lf un
ct io
n; O
A D
,o ra
la nt
id ia
be tic
dr ug
;P PG
,p os
tp ra
nd ia
lg lu
co se
;S M
PG ,s
el f-
m ea
su re
d pl
as m
a gl
uc os
e; SU
,s ul
ph on
yl ur
ea ;T
2D ,t
yp e
2 di
ab et
es ;T
Z D
,t hi
az ol
id in
ed io
ne .
*A ls
o in
cl ud
ed an
ex te
ns io
n ph
as e
up to
52 w
ee ks
. †P
ha se
II st
ud y
(n =
14 8)
.
322 Madsbad Volume 18 No. 4 April 2016
DIABETES, OBESITY AND METABOLISM review article Ta
bl e
3. B
as el
in e
ch ar
ac te
ri st
ic s
of pa
rt ic
ip an
tp op
ul at
io ns
in pu
bl is
he d
ph as
e II
I( an
d on
e ph
as e
II )r
an do
m iz
ed he
ad -t
o- he
ad st
ud ie
s of
gl uc
ag on
-l ik
e pe
pt id
e- 1
re ce
pt or
ag on
is ts
in ty
pe 2
di ab
et es
.
D U
R A
T IO
N -1
(3 0
w ee
ks )
[5 4]
D U
R A
T IO
N -5
(2 4
w ee
ks )
[5 5]
Ji et
al .(
26 w
ee ks
) [5
6] D
U R
A T
IO N
-6 (2
6 w
ee ks
) [6
7] LE
A D
-6 (2
6 w
ee ks
) [6
6]
E xe
na ti
de 2
m g
on ce
w ee
kl y
(n =
14 8)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 14
7)
E xe
na ti
de 2
m g
on ce
w ee
kl y
(n =
12 9)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 12
3)
E xe
na ti
de 2
m g
on ce
w ee
kl y
(n =
34 0)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 33
8)
E xe
na ti
de 2
m g
on ce
w ee
kl y
(n =
46 1)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 45
0)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 23
1)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 23
3)
A ge
,y ea
rs 55
(1 0)
55 (1
0) 56
(1 1)
55 (1
0) 55
(1 1)
56 (1
0) 57
(9 )
57 (1
0) 57
(1 1)
56 (1
0) M
al e/
fe m
al e,
% 55
/4 5
51 /4
9 60
/4 0
55 /4
5 54
/4 6
54 /4
6 55
/4 5
54 /4
6 55
/4 5
49 /5
1
R ac
e, %
W hi
te 83
73 63
55 —
— 83
82 91
93 B
la ck
/A fr
ic an
A m
er ic
an 6
13 5
7 —
— 1
1 5
6 A
si an
/P ac
ifi c
Is la
nd er
0 1
4 4
10 0
10 0
12 13
2 <
1 O
th er
* 11
14 29
33 —
— 4
4 2
1 M
ul tip
le †
— —
— —
— —
< 1
1 —
—
Et hn
ic or
ig in
H is
pa ni
c or
La ti
n A
m er
ic an
,% 11
14 29
33 —
— 21
22 11
14 B
M I,
kg /m
2 35
(5 )
35 (5
) 34
(6 )
33 (5
) 26
(4 )
27 (3
) 32
(6 )
32 (5
) 33
(6 )
33 (6
) W
ei gh
t, kg
10 2
(1 9)
10 2
(2 1)
97 (2
1) 94
(1 9)
70 (1
2) 70
(1 2)
91 (2
0) 91
(1 9)
93 (2
0) 93
(2 0)
H bA
1c ,%
8. 3
(1 .0
) 8.
3 (1
.0 )
8. 5
(1 .1
) 8.
4 (1
.2 )
8. 7
(1 .0
) 8.
7 (1
.0 )
8. 5
(1 .0
) 8.
4 (1
.0 )
8. 1
(1 .0
) 8.
2 (1
.0 )
H bA
1c ,m
m ol
/m ol
67 (1
1) 67
(1 1)
69 (1
2) 68
(1 3)
72 (1
1) 72
(1 1)
69 (1
1) 68
(1 1)
65 (1
1) 66
(1 1)
FS G
/F P
G ,m
m ol
/l 9.
6 (2
.4 )
9. 2
(2 .3
) 9.
6 (2
.6 )
9. 3
(2 .6
) 9.
1 (2
.4 )
9. 4
(2 .7
) 9.
6 (2
.5 )
9. 8
(2 .6
) 9.
5 (2
.4 )
9. 8
(2 .5
) D
ur at
io n
of di
ab et
es ,y
ea rs
7 (6
) 6
(5 )
7 (5
) 7
(5 )
8 (5
) 9
(6 )
8 (6
) 9
(6 )
8 (6
) 9
(6 )
SB P,
m m
H g
12 8
(1 )‡
13 0
(1 )‡
13 0
(1 )‡
12 8
(1 )‡
13 1
(1 )‡
13 2
(1 )‡
13 2
(1 4)
13 4
(1 4)
13 4
(1 7)
13 2
(1 6)
D B
P, m
m H
g 78
(1 )‡
80 (1
)‡ 78
(1 )‡
77 (1
)‡ 79
(1 )‡
80 (1
)‡ 79
(9 )
80 (9
) 79
(9 )
80 (8
)
G et
G oa
l- X
(2 4
w ee
ks )
[1 2]
H A
R M
O N
Y 7
(3 2
w ee
ks )
[1 4]
A W
A R
D -6
(2 6
w ee
ks )
[1 3]
T -e
m er
ge 2
(2 4
w ee
ks )
[4 0]
K ap
it za
et al
.( 28
da ys
)§ [6
1]
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 31
6)
Li xi
se na
ti de
20 𝛍g
on ce
da il
y (n
= 31
8)
A lb
ig lu
ti de
50 m
g on
ce w
ee kl
y (n
= 40
4)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 40
8)
D ul
ag lu
ti de
1. 5
m g
on ce
w ee
kl y
(n =
29 9)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 30
0)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 37
3)
Ta sp
og lu
ti de
10 m
g on
ce w
ee kl
y (n
= 38
4)
Ta sp
og lu
ti de
20 m
g on
ce w
ee kl
y (n
= 39
2)
Li xi
se na
ti de
10 –2
0 𝛍g
on ce
da il
y (n
= 77
)
Li ra
gl ut
id e
0. 6–
1. 8
m g
on ce
da il
y (n
= 71
)
A ge
,y ea
rs 58
(1 1)
57 (9
) 55
(1 0)
56 (1
0) 57
(9 )
57 (1
0) 55
(1 0)
56 (1
0) 56
(1 0)
61 (8
) 60
(9 )
M al
e/ fe
m al
e, %
59 /4
1 48
/5 3
47 /5
3 53
/4 7
46 /5
4 50
/5 0
49 /5
1 58
/4 2
52 /4
8 64
/3 6
70 /3
0
R ac
e, %
W hi
te 92
93 N
/A N
/A 86
86 85
85 85
99 10
0 B
la ck
/A fr
ic an
A m
er ic
an 3
3 N
/A N
/A 7
5 N
/A N
/A N
/A 1
— A
si an
/P ac
ifi c
Is la
nd er
1 1
N /A
N /A
< 1
— N
/A N
/A N
/A —
— O
th er
* 3
4 N
/A N
/A 7
8 15
15 15
— —
M ul
tip le †
— —
N /A
N /A
< 1
1 N
/A N
/A N
/A —
—
Et hn
ic or
ig in
H is
pa ni
c/ La
ti n
A m
er ic
an ,%
N /A
N /A
N /A
N /A
25 24
20 18
21 N
/A N
/A B
M I,
kg /m
2 34
(7 )
34 (6
) 33
(6 )
33 (6
) 34
(5 )
34 (5
) 34
(5 )
34 (5
) 33
(5 )
31 (4
) 31
(4 )
Volume 18 No. 4 April 2016 doi:10.1111/dom.12596 323
review article DIABETES, OBESITY AND METABOLISM Ta
bl e
3. C
on ti
nu ed
.
G et
G oa
l- X
(2 4
w ee
ks )
[1 2]
H A
R M
O N
Y 7
(3 2
w ee
ks )
[1 4]
A W
A R
D -6
(2 6
w ee
ks )
[1 3]
T -e
m er
ge 2
(2 4
w ee
ks )
[4 0]
K ap
it za
et al
.( 28
da ys
)§ [6
1]
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 31
6)
Li xi
se na
ti de
20 𝛍g
on ce
da il
y (n
= 31
8)
A lb
ig lu
ti de
50 m
g on
ce w
ee kl
y (n
= 40
4)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 40
8)
D ul
ag lu
ti de
1. 5
m g
on ce
w ee
kl y
(n =
29 9)
Li ra
gl ut
id e
1. 8
m g
on ce
da il
y (n
= 30
0)
E xe
na ti
de 10
𝛍g tw
ic e
da il
y (n
= 37
3)
Ta sp
og lu
ti de
10 m
g on
ce w
ee kl
y (n
= 38
4)
Ta sp
og lu
ti de
20 m
g on
ce w
ee kl
y (n
= 39
2)
Li xi
se na
ti de
10 –2
0 𝛍g
on ce
da il
y (n
= 77
)
Li ra
gl ut
id e
0. 6–
1. 8
m g
on ce
da il
y (n
= 71
)
W ei
gh t,
kg 96
(2 3)
94 (2
0) 92
(2 1)
93 (2
2) 94
(1 8)
94 (1
9) 95
(1 9)
96 (2
0) 93
(1 9)
91 (1
5) 93
(1 7)
H bA
1c ,%
8. 0
(0 .8
) 8.
0 (0
.8 )
8. 2
(0 .9
) 8.
2 (0
.8 )
8. 1
(0 .8
) 8.
1 (0
.8 )
8. 1
(0 .9
) 8.
1 (0
.9 )
8. 1
(0 .9
) 7.
2 (0
.6 )
7. 4
(0 .8
) H
bA 1c
,m m
ol /m
ol 64
(9 )
64 (9
) 66
(1 0)
66 (9
) 65
(9 )
65 (9
) 65
(1 0)
65 (1
0) 65
(1 0)
55 (7
) 57
(9 )
FP G
/F SG
,m m
ol /l
9. 7
(2 .3
) 9.
7 (2
.0 )
N /A
N /A
9. 3
(2 .2
) 9.
2 (2
.3 )
9. 9
(2 .7
) 9.
9 (2
.6 )
9. 8
(2 .4
) N
/A N
/A D
ur at
io n
of di
ab et
es ,y
ea rs
7 (5
) 7
(6 )
8 (6
) 8
(6 )
7 (5
) 7
(5 )
7 (5
) 6
(5 )
7 (6
) 7
(N /A
) 7
(N /A
) SB
P, m
m H
g N
/A N
/A N
/A N
/A 13
2 (1
5) 13
1 (1
5) 13
1 (1
)‡ 13
2 (1
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2 (1
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For example, in DURATION-1, changes in FPG were sig- nificantly greater after 30 weeks with exenatide once weekly than with exenatide twice daily (−2.3 mmol/l vs −1.4 mmol/l, respectively; p < 0.0001) [54]. Similarly, in DURATION-5, the mean change in FPG at 24 weeks was significantly greater with exenatide once weekly than with exenatide twice daily (−1.9 mmol/l vs −0.7 mmol/l, respectively; p = 0.0008) [55]. The longer-acting GLP-1RA taspoglutide was also associated with a significantly greater reduction in FPG than short-acting exenatide twice daily at 24 weeks [40]. Accordingly, in the phase II study, changes in FPG were greater with liraglutide than with lixisenatide (−1.3 mmol/l vs −0.3 mmol/l, respec- tively; p < 0.0001) [61]. Likewise, the long-acting liraglutide once daily demonstrated greater improvements than exenatide twice daily (−1.6 mmol/l vs −0.6 mmol/l, respectively) [66]. Comparisons of once-daily liraglutide with once-weekly formulations produced a mixed pattern: liraglutide demon- strated superiority to exenatide once weekly (−2.1 mmol/l vs −1.8 mmol/l, respectively; p = 0.02) [67] and albiglutide once weekly (−1.7 mmol/l vs −1.2 mmol/l, respectively; p = 0.0048) [14] in lowering fasting serum glucose and FPG, respectively, but no significant difference compared with dulaglutide once weekly (1.90 mmol/l vs 1.93 mmol/l, respectively) [13].
Effects on Weight As a class, the GLP-1RAs have all been shown to have a weight-reduction effect (Figure 4), and this effect is significantly greater than is typically seen with most other therapeutic classes [70]. Indeed, a systematic review of clinical trials involving exe- natide twice daily, liraglutide and exenatide once weekly in par- ticipants with a body mass index (BMI) ≥25 kg/m2 (with or without T2D) found a greater reduction in weight with these compounds versus non-GLP-1RA-treated control compounds (weighted mean difference: −2.9 kg) [70].
The weight benefit varies among GLP-1RAs and studies. For example, Ji et al. [56] found that exenatide twice daily was asso- ciated with a significantly greater reduction in weight than exenatide once weekly (p < 0.001) but, in DURATION-1 and DURATION-5 [54,55], weight loss was not significantly differ- ent between the two exenatide formulations. In the T-emerge 2 study, exenatide twice daily showed a greater (non-significant) reduction in weight than taspoglutide 10 mg once weekly but showed no difference in weight loss compared with taspoglu- tide 20 mg once weekly [40]. In the LEAD-6 study, exenatide twice daily and liraglutide treatment led to similar levels of weight loss (3.2 and 2.9 kg, respectively; p = 0.2235) [66]. Exe- natide twice daily was associated with greater (non-significant) weight loss than lixisenatide in the GetGoal-X study [12], and liraglutide treatment led to greater weight loss than lixisen- atide in the study by Kapitza et al. [61] (p < 0.01; Figure 3). Other head-to-head trials revealed significantly greater reduc- tions in weight with liraglutide than the once-weekly treatments exenatide (p = 0.0005), albiglutide (p < 0.0001) and dulaglutide (p = 0.011; Figure 4) [13,14,67]. Between-treatment differences were 0.9, 1.6 and 0.7 kg, respectively [13,14,67].
In the Ji et al. [56] and DURATION-6 studies [67], the greatest weight loss was observed in participants treated with
324 Madsbad Volume 18 No. 4 April 2016
DIABETES, OBESITY AND METABOLISM review article
Figure 2. Reductions in glycated haemoglobin (HbA1c) in published phase III (and one phase II) randomized head-to-head studies of glucagon-like peptide-1 receptor agonists in type 2 diabetes. *Non-inferiority criteria met. †Non-inferiority criteria not met. ‡Phase II study. §A 1% change in HbA1c corresponds to a 10.93 mmol/mol change in The International Federation of Clinical Chemistry units.
Figure 3. Mean 24-h postprandial plasma glucose profiles at baseline and day 28. Data are mean ± standard error of the mean. Adapted from Kapitza et al. [61].
exenatide (once weekly or twice daily) or liraglutide with the highest baseline BMI. Furthermore, in a retrospective analysis of seven phase III trials from the liraglutide diabetes devel- opment programme, a slightly greater weight reduction was observed in participants treated with liraglutide, with a longer duration of GI AEs [71].
The exact mechanism by which GLP-1 exerts its anorectic effects is a matter of contention, but both peripheral and brain GLP-1 receptors seem to be involved [72,73]. It is also unclear whether the reduced weight loss with the large molecules, albiglutide and dulaglutide, compared with liraglutide can be explained by less direct activation of the GLP-1 receptors in the hypothalamic areas and brain stem. Indeed, compared
with liraglutide, the larger molecular sizes of albiglutide and dulaglutide may hinder transport across the blood–brain barrier or through fenestrated capillaries [73]. Alternatively, it may be a question of suboptimum dosing of the once-weekly GLP-1RAs; this may also may explain the differences in reduction in HbA1c level.
Cardiovascular Measurements Blood Pressure
Improvements in both systolic blood pressure (SBP) and dias- tolic blood pressure (DBP) have been reported in clinical trials
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review article DIABETES, OBESITY AND METABOLISM
Figure 4. Reductions in weight in published phase III (and one phase II) randomized head-to-head studies of glucagon-like peptide-1 receptor agonists in type 2 diabetes. *Difference was not significant at week 24, although it was significant at week 20. †Not stated if difference was significant. ‡Data shown at week 24; however, at week 52, weight loss was significantly lower in the taspoglutide 10 mg versus exenatide group (p = 0.01). §Phase II study.
of GLP-1RAs. Indeed, a meta-analysis of trials involving exe- natide once weekly, exenatide twice daily or liraglutide found that these treatments significantly decreased SBP: by −1.79 and −2.39 mmHg compared with placebo and active controls, respectively [74]. There was also a trend towards decreased DBP with GLP-1RAs, but reductions did not reach statistical signif- icance.
Head-to-head trials have not found significant differences in effects on blood pressure (BP) among different GLP-1RAs [12–14,54–56,66,67]. For example, in the DURATION-1 study [54], both SBP and DBP were reduced over 30 weeks of treatment with exenatide once weekly and exenatide twice daily (mean change in SBP −4.7 and −3.4 mmHg and in DBP: −1.7 and −1.7 mmHg, respectively). In the DURATION-5 study, larger reductions in SBP (mean change: exenatide once weekly −7.9 mmHg and exenatide twice daily −7.7 mmHg) were observed in participants with elevated baseline SBP (≥130 mmHg) but this reduction was similar in the two treat- ment arms. In the LEAD-6 trial [66], exenatide twice daily and liraglutide were associated with similar reductions in SBP and DBP at 26 weeks (mean change in SBP −2.0 and −2.5 mmHg; change in DBP −2.0 and −1.1 mmHg, respectively); however, in the extension phases of DURATION-1 and LEAD-6, which continued to 52 weeks, participants switching from exenatide twice daily to either exenatide once weekly or liraglutide experienced further reductions in SBP (−3.8 mmHg in both studies) [75,76].
Reductions in SBP and DBP were also observed in the GetGoal-X trial of lixisenatide vs exenatide twice daily (mean change in SBP: −2.5 and −2.9 mmHg; change in DBP: −1.8 and −1.3 mmHg, respectively) [12], and in the AWARD-6 trial of dulaglutide vs liraglutide (mean change in SBP −3.4 and
−2.8 mmHg; change in DBP −0.2 and −0.3 mmHg, respec- tively) [13]. Again, there were no statistically significant differ- ences between treatments in either study.
Heart Rate
Increases in resting heart rate have been reported with GLP-1RAs [74]. Although the underlying physiological mechanisms have not yet been defined, the activation of the GLP-1 receptors in the sino-atrial node could play a role [77].
A meta-analysis of studies involving exenatide once weekly, exenatide twice daily or liraglutide found that these treatments increased heart rate by 1.86 beats/min (bpm) vs placebo and by 1.90 bpm vs active comparators [74]. Head-to-head trials have suggested that heart rate increases may be smaller with exenatide twice daily than exenatide once weekly or liraglutide [55,56,66]. Dulaglutide is also associated with a small increase in heart rate, of similar magnitude to that with liraglutide [13]. Lixisenatide and albiglutide did not appear to be asso- ciated with clinically relevant increases in heart rate [12,14]. Since heart rate was mostly estimated during daytime, 24-h monitoring was needed to understand the different effects of the short- and longer-acting GLP-1RAs on heart rate. In a phase II study by Meier et al. [68], liraglutide doses increased the mean ± standard error 24-h heart rate from baseline by 9 ± 1 bpm versus 3 ± 1 bpm with lixisenatide (p < 0.001) at week 8. Greater heart rate increases at week 8 with liraglutide were observed at night time, while heart rate increases with lixisenatide were greatest during the day.
Potential explanations for the increased heart rate observed in these studies could include a reflex mechanism compen- sating for vasodilation and lowering of BP [77] . Indeed, in a pooled analysis of six clinical trials, liraglutide was associated
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DIABETES, OBESITY AND METABOLISM review article with significantly greater SBP reductions than glimepiride and insulin glargine and rosiglitazone [78].
Safety and Tolerability Gastrointestinal Adverse Events
The most frequently observed AEs with GLP-1RAs are GI dis- orders, particularly nausea, vomiting and diarrhoea [11–14]. Nausea occurred less frequently with exenatide once weekly than exenatide twice daily or liraglutide [54–56,67]. Lixisen- atide also showed reduced rates of nausea compared with exe- natide twice daily [12]. Among the two most recently approved GLP-1RAs, albiglutide had lower rates of nausea than liraglu- tide [14], whereas dulaglutide had similar rates compared with liraglutide [13]; however, by far the highest rates of nausea were observed with taspoglutide: 53 and 59% with 10 and 20 mg once weekly, respectively, compared with 35% among partici- pants treated with exenatide twice daily [40]. This was one of the key reasons why the clinical development of taspoglutide was halted.
Thyroid Safety and Calcitonin Levels
In rodent models, GLP-1RAs have been linked to the release of calcitonin, and the potential formation of thyroid tumours [79], but there is no evidence of a causal relationship between GLP-1RAs and thyroid tumours in humans. Across the phase III head-to-head studies described in the present review, mean calcitonin levels were largely unchanged, and only one case of treatment-emergent thyroid cancer was observed (a papil- lary thyroid carcinoma in a patient treated with liraglutide in AWARD-6) [13].
Pancreatitis
Concerns have been raised with respect to the potential pan- creatic side effects associated with GLP-1RAs [80,81]. The 10 head-to-head studies discussed in the present review (Table 2) did not have sufficient power to detect differences between GLP-1RAs in the rates of these rare events. Indeed, in only one of these studies was there more than one case of pancreatitis: three cases were reported in the HARMONY-7 trial (one in the albiglutide group and two in the liraglutide group), from among 812 participants who received the study drug. There are lim- ited published data on the effects of GLP-1RAs on pancreatic enzymes in the head-to-head studies, and it is not possible to compare lipase level among studies because different methods have been used in their evaluation; however, in an 8-week study comparing lixisenatide 20 μg once daily with liraglutide 1.2 and 1.8 mg once daily, a greater mean increase in lipase was reported with liraglutide compared with exenatide, while amylase was within the normal range for both GLP-1RAs [68].
The US Food and Drug Administration (FDA) and the Euro- pean Medicines Agency (EMA) have agreed that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with current data; however, the FDA and the EMA have not reached
a final conclusion regarding such a causal relationship [81]. Notably, the FDA requires evidence of cardiovascular safety of new glucose-lowering agents in large clinical endpoint tri- als, and, as a by-product of these trials, clinical events related to pancreatitis and pancreatic cancer will be assessed. The first results from the Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syn- drome During Treatment With AVE0010 (Lixisenatide; ELIXA; NCT01147250) study comparing lixisenatide and placebo were presented at the American Diabetes Association 2015 Scientific Sessions. The 2-year follow-up data showed that the effect of lixisenatide compared with placebo was neutral for the primary composite endpoint: cardiovascular death, non-fatal myocar- dial infarction, non-fatal stroke or hospitalization for unstable angina (13.4% vs 13.2%). Furthermore, there was no elevation in pancreatitis and pancreas cancer with lixisenatide. Likewise, no elevation in heart rate was observed, probably explained by the short duration of action of lixisenatide given before break- fast. Lixisenatide led to a small change in HbA1c of 0.27%, in weight of 0.7 kg and in SBP of 0.8 mmHg vs placebo [82].
Following on from that study, the first results of the Liraglu- tide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation in 2015 (LEADER; NCT01179048); the Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL; NCT01144338) study, comparing exenatide once weekly and placebo; and the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND; NCT01394952) study, comparing dulaglutide and placebo, are estimated to end in 2015, 2018 and 2019, respectively.
Injection-site Reactions
It is difficult to compare injection-site reactions among the studies because of differences in methods of reporting out- comes. Overall, once-weekly GLP-1RAs appear to be associated with higher incidences of injection-site reaction than exenatide twice daily [40,54–56] or liraglutide once daily [14,67].
For example, in HARMONY-7, injection-site reactions occurred more frequently with albiglutide (13%) than with liraglutide (5%; p = 0.0002) [14]. A similar observation was made in DURATION-6 [67], in which participants treated with exenatide once weekly versus liraglutide showed higher incidences of injection-site nodules (10% vs 1%, respec- tively), injection-site pruritus (3% vs <1%, respectively) and injection-site erythema (2% vs <1%, respectively). The excep- tion appears to be dulaglutide once weekly, in AWARD-6, which was associated with low rates (<1%) of injection-site reactions, similar to those observed with liraglutide [13]. The higher rates of injection-site reactions reported in these studies is consistent with results seen with other sustained-release injectable drug formulations that undergo in vivo degradation [83,84]. In a similar pattern, in the GetGoal-X study [12], lixisenatide once daily was associated with more injection-site reactions than exenatide twice daily (8.5% vs 1.6%).
Immunogenicity
As GLP-1RAs are peptides, antibody formation could poten- tially occur that results in injection-site reactions, loss of
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review article DIABETES, OBESITY AND METABOLISM efficacy and anaphylaxis. Evidence to date, from several head-to-head trials, indicates that antibodies are formed against GLP-1RAs [13,14,40,54–57].
The development of antibodies against exenatide was reported in the drug’s clinical trial programme [85]. In head-to-head studies, anti-exenatide antibodies were more common, and titres were higher, with exenatide once weekly than with exenatide twice daily [54–56]; however, reductions in HbA1c were still significant in participants with or without antibodies, and the presence of antibodies did not correlate with reported rates of AEs [54–56].
Antibody formation has also been reported in liraglutide clinical trials, although a meta-analysis of the LEAD studies found lower immunogenicity with liraglutide than with exe- natide twice daily and no effect of liraglutide immunogenicity on glycaemic efficacy [57].
In the GetGoal-Mono study [58], the development of anti- bodies was reported in 56–60% of participants (undergoing different treatment regimens) treated with 20 μg lixisenatide once daily as a final dose. In another monotherapy study by Ratner et al. [59], antibodies were found in 43 and 71% of par- ticipants treated with 10 μg lixisenatide once daily and 20 μg twice daily, respectively. No notable differences were reported in terms of safety and efficacy between antibody-positive and -negative participants [58,59].
Antibody formation occurred relatively rarely in phase III trials of dulaglutide and albiglutide [13,14], but no com- parison could be made with liraglutide in these studies, as anti-liraglutide antibodies were not assessed.
Finally, in the T-emerge 2 study, anti-taspoglutide antibodies were detected in 49% of participants [40]. In this trial, levels of systemic allergic reactions were also considered to be unac- ceptably high (6% of participants in each of the taspoglutide groups).
The immunogenicity reported in the trials of exenatide, lixisenatide and liraglutide would appear to have little impact on the efficacy and safety of these GLP-1RAs.
Patient Preferences and Drug Administration Patient Preference
Participant-preference data are limited within the major head-to-head trials of GLP-1RAs; however, in DURATION-1 [86], participant-assessed treatment satisfaction and quality of life improved significantly between weeks 30 and 52 among those switching from exenatide twice daily to exenatide once weekly. Meanwhile, in DURATION-6 [67], participant satis- faction and mental health were improved with both liraglutide and exenatide once weekly (p < 0.0001), with no significant differences between groups.
Survey data on patient preferences for exenatide twice daily versus liraglutide have also been collected [87]. Using a time trade-off method, 96% of respondents preferred the product profile representing liraglutide over that represent- ing exenatide. The analysis showed that efficacy (lowering of HbA1c) is the most important attribute influencing patient preference, followed by nausea, hypoglycaemia and dosing schedule [87].
The general attitude of patients to once-weekly GLP-1RA formulations has also been assessed [88]. In an online sur- vey of adults with T2D, current injection users were more likely (p < 0.001) than non-injection users to perceive potential benefits of once-weekly treatment, such as greater convenience, better medication adherence and improved quality of life [88]. A total of 47% of respondents said that they would take an injectable once-weekly medication if it was recommended by their physician; current injection users were more likely than non-injection users to respond in this way (73% vs 32%, respec- tively; p < 0.001). Concerns about once-weekly medications in this population are related to consistency of dose over time, potential forgetfulness and cost.
Drug Administration
To date, while there have been studies comparing various pre- filled insulin injection pens, there are very few data available regarding the different injection devices for the GLP-1RAs. One aspect that has been investigated is the use of narrower versus wider needles for injection devices. Both exenatide twice daily and exenatide once weekly are administered using a 23-gauge needle while liraglutide is injected using a narrower 32-gauge needle, which has been suggested to decrease injection discom- fort. In one study comparing insulin injection using two differ- ent NovoFine® needles, 58% preferred the NovoFine 32-gauge tip, 26% preferred the NovoFine 30-gauge tip, while 16% had no preference (p < 0.001 between needles) [89]. Although this study did not examine the use of GLP-1RAs, the results are nonetheless applicable to other injection devices, and suggest a strong patient preference for narrower needles.
Future Possibilities for GLP-1 RA Treatment The use of GLP-1RAs is now well established in both the early and late stages of T2D. Further research is ongoing [90], and is presently focused on several key areas.
• Further development and testing of once weekly GLP-1RAs. Both albiglutide and dulaglutide are once-weekly formula- tions that were approved in Europe and the USA in 2014; hence, additional work will be required to better understand their clinical profiles in normal clinical practice. Meanwhile, new GLP-1RAs intended for once-weekly dosing, such as semaglutide, are in phase III trials.
• Oral and inhaled formulations. All of the currently avail- able GLP-1RAs are administered by injection, but a desire to avoid needles, as noted with insulin administration, can be a barrier to starting injectable therapy in some people with T2D [91]. Alternative routes of administration, in particu- lar oral and inhaled formulations, could therefore improve the acceptability of these therapies for some patients. Work is ongoing, but the key challenge will be to ensure ade- quate absorption and prolongation of action of inhaled GLP-1RAs.
• Osmotic pump system. The ITCA 650 is another alternative route to administration, a miniature osmotic pump system that is designed to deliver zero-order, continuous subcuta- neous release of exenatide for up to 12 months with a single
328 Madsbad Volume 18 No. 4 April 2016
DIABETES, OBESITY AND METABOLISM review article placement. A recent study showed that treatment for up to 24 weeks with the ITCA 650 resulted in significant improve- ments in HbA1c, FPG and body weight in patients with T2D inadequately controlled on metformin monotherapy [92].
• Combination of GLP-1RAs with basal insulin therapy. In addition to additive glycaemic benefits, the weight loss and low hypoglycaemia risk associated with GLP-1RAs could at least partially offset the weight gains and risk of hypogly- caemia associated with insulin use [93]. Recent trials have shown the efficacy of combining insulin and GLP-1RAs in T2D [94,95]. Meanwhile, a fixed-ratio combination of insulin degludec and liraglutide has been developed as a once-daily injection, and resulted in improved glycaemic control compared with its components given alone in a phase III trial [96].
• Potential use of GLP-1RAs in T1D. There is evidence to suggest that people with T1D can achieve weight loss and improved glycaemic control on less insulin without an increase in hypoglycaemia when a GLP-1RA is added to insulin therapy [97,98]. Further studies are ongoing.
• Many other peptide hormones stimulate insulin secretion and regulate appetite by inducing satiety. Peptide YY (PYY) is produced in the intestinal L-cells and reduces appetite. Dual co-agonists developed in a single molecule and stim- ulating both the GLP-1 and PYY receptor pathways have, in preclinical investigations, reduced food intake [99]. Use of glucagon and GLP-1 co-agonists results in greater weight loss and improved glucose tolerance in obese rodents [100]. In human studies, co-administration of glucagon and GLP-1 ameliorate hyperglycaemia and increase energy expenditure in combination with a reduction in food intake [101,102]; thus, combination therapy with several hormones may open up new avenues for treatment of obesity and T2D.
Conclusions Structural differences between the various GLP-1RAs result in unique clinical profiles; these treatments, therefore, differ from each other substantially with respect to glycaemic control, effects on weight, and safety and tolerability, as demonstrated in phase III head-to-head trials in T2D. These differences should be considered when selecting a GLP-1RA for an individual patient. Patient preference should be an important element of the treatment decision. Data on patient preference for the GLP-1RAs are currently limited, although glycaemic control and AEs are likely to be key factors [87].
The present review is limited by the small number of stud- ies directly comparing the different GLP-1RAs. Indeed, most of these studies have an open-label design and have a relatively short duration of treatment in highly selected populations with- out major diabetes complications; therefore, long-term end- point studies are needed that assess safety and efficacy, and include larger numbers of patients treated with polypharmacy; these data would help to define the place of GLP-1RAs in the T2D treatment algorithm.
The importance of the GLP-1RA therapeutic class seems poised to increase in the treatment of T2D. Meanwhile, ongoing assessments of novel GLP-1RAs and new delivery methods may lead to an even greater number of options in future.
Acknowledgements The author thanks Watermeadow Medical for assistance with preparation of this manuscript (funded by Novo Nordisk).
Conflict of Interest S. M. has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Novartis Pharma, Novo Nordisk and Sanofi-Aventis; received fees for speaking from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Sharp & Dohme, Novartis Pharma, Novo Nordisk and Sanofi-Aventis; and received grants research from Novo Nordisk. S.M. researched, approved and wrote the paper.
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