MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes?

Abstract

GLP-1, a peptide hormone secreted from the gut stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) eliminated (mainly kidneys) too fast (half-life 1-2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist have been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications. Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., albiglutide q.w., albiglutide q.w., semaglutide q.w., all for subcutaneous injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality. It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

Full text

European Journal of Endocrinology
181:6 R211–R234
M A Nauck and J J Meier GLP-1 receptor agonist
comparison
MANAGEMENT OF ENDOCRINE DISEASE
Are all GLP-1 agonists equal in the treatment
of type 2 diabetes?
MichaelANauck and JurisJMeier
Diabetes Division, St. Josef-Hospital, Ruhr-University of Bochum, Bochum, Germany
Abstract
GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was
identied as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and
eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist
has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007.
Compounds with longer duration of action (once daily, once weekly) and with increasingly better ecacy with respect
to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement,
were recommended as the rst injectable diabetes therapy after failure of oral glucose-lowering medications. Most
GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide
q.w., all for s.c. injection, and the rst oral preparation, oral semaglutide) have been examined in cardiovascular
outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease,
liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to rst major adverse cardiovascular events
(non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular
and all-cause mortality. It is the purpose of the present review to describe clinically important dierences, regarding
pharmacokinetic behaviour, glucose-lowering potency, eectiveness of reducing body weight and controlling other
cardiovascular risk factors, and of the inuence of GLP-1 receptor agonist treatment on cardiovascular outcomes in
patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive
heart failure).
Correspondence
should be addressed
to M A Nauck
Email
michael.nauck@rub.de
-19-0566
181
6
Invited Author profile
Prof. Michael Nauck MD is Head of Clinical Research at the Diabetes Division of St. Josef-Hospital
(Ruhr-University Bochum) in Bochum, Germany. He teaches at Georg-August University,Göttingen,
and Ruhr-University, Bochum, Germany. Professor Nauck has a particular research interest in the
role of gastrointestinal peptide hormones (incretins: glucose-dependent insulinotropic polypeptide,
GIP, and glucagon-like peptide-1, GLP-1) in the physiological regulation of metabolism and in
the pathophysiology of type 2 diabetes. He has contributed pivotal studies proving a therapeutic
potential of GLP-1 in type 2 diabetes. He has contributed to the development of incretin-based glucose-lowering
medications such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4. Additional areas of interest
include spontaneous hypoglycaemia (insulinomas), pancreas transplantation, cardiovascular complications
of type 2 diabetes, and the modification of cardiovascular risk in type 2-diabetic patients with glucose-lowering
pharmacotherapy. His scientific contributions have been honoured with several awards, including the Ferdinand-
Bertram Award (1993), the Werner-Creutzfeldt Award (2007) and the Paul Langerhans Medal (2012) of the German
Diabetes Association.
Review
European Journal of
Endocrinology
(2019) 181, R211–R234
Published by Bioscientifica Ltd.
https://eje.bioscientica.com
https://doi.org/10.1530/EJE-19-0566
© 2019 European Society of Endocrinology
Printed in Great Britain
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European Journal of Endocrinology
181:6 R212
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
GLP-1 receptor agonists in the treatment of
type 2 diabetes
GLP-1 in human subjects was detected in 1983 as one of
two ‘glucagon-like’ stretches of the proglucagon sequence
(i.e., at the mRNA level) (1), which left uncertainty about
details of post-translational processing and the resulting
peptide structure. GLP-1 (7-36amide) (amidated GLP-1)
and - to a lesser extent, GLP-1 (7-37) (glycine-extended
GLP-1) - were identified as the peptides produced in
intestinal L-cells in 1987 (2, 3). GLP-1 turned out to be a
potent insulinotropic agent, stimulating insulin secretion
whenever plasma glucose was higher than at fasting
concentrations, and suppressing glucagon secretion at
normo- and hyperglycaemia, but allowing its counter-
regulatory activity in the case of hypoglycaemia (4, 5).
On these premises it qualified as an incretin hormone.
Unlike the other incretin hormone, glucose-dependent
insulinotropic polypeptide (GIP, formerly called gastric
inhibitory polypeptide), GLP-1 turned out to be active in
patients with type 2 diabetes (4, 6). It was able to reduce
hyperglycaemia in fasting type 2-diabetic patients into
the normal fasting plasma glucose range, and abolished
post-meal glycaemic rises after mixed meals in proof-of-
principle studies employing exogenous synthetic GLP-1
administered intravenously (5, 7). Pre-clinical and clinical
research also indicated a potential for reducing appetite,
food intake, and body weight (8, 9). Studies employing
i.v. or s.c. administration of GLP-1 (10) also indicated that
GLP-1 is rapidly degraded and inactivated by a ubiquitous
protease, dipeptidyl peptiase-4 (DPP-4) and also eliminated
from the circulation quickly, resulting in a half-life of 1–2
min only. Consequently, s.c. administration gave rise to
short-lived peaks lasting for a maximum of 90 min, even
when applying large doses that caused side effects (5, 7).
Thus, it became evident that the original GLP-1 peptide
needed to be modified to result in peptides resistant to
DPP-4 and with slower elimination kinetics, in order to
be clinically useful glucose-lowering agents. Molecular
structures of GLP-1 receptor agonists and the parent
compound, GLP-1, are shown in Fig. 1.
The first GLP-1 receptor agonist to be approved for
the treatment of type 2 diabetes was exenatide, which
was synthetic exendin-4, a peptide from the saliva of a
Figure1
Molecular structures of GLP-1 receptor agonists used for the treatment of type 2 diabetes. For small-molecular-weight
compounds, the amino acid sequence is shown (left hand panels). Amino acids identical with mammalian (human) GLP-1 are
shown in light green, amino acids diering from the parent compound are shown in dark blue. Large-molecular weight
compounds (right hand panels) are shown schematically indicating the large protein component, spacer peptides, and modied
GLP-1 peptides. These modications concern amino acid exchanges prohibiting proteolytic attack by dipeptidyl peptidase-4
(DPP-4).
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European Journal of Endocrinology
181:6 R213
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
lizard from Arizona, Heloderma suspectum, which was
purified without any intention to be in search of a
diabetes medication (11). The similarity of the peptide
structure to GLP-1 was noticed (Fig. 1), and it was found
to stimulate GLP-1 receptors with an affinity like (or even
slightly better than) GLP-1 (12). Exenatide happened to
be DPP-4-resistant and eliminated more slowly, with a
half-life of approximately 2–3 h (7, 12). Regimens with
two or three times daily administrations were tested, and
a regimen for injecting exenatide subcutaneously before
breakfast and before dinner (twice daily) was approved.
Exenatide had a 53% sequence homology compared
to mammalian GLP-1 and, thus, was dissimilar enough
to provoke some immunogenicity leading to antibody
formation in the majority of patients, however, without
obvious consequences for its therapeutic efficacy (13, 14).
The next agent to be developed was liraglutide, the
peptide backbone of which was preserved 97% compared
to the original GLP-1 peptide (Fig. 1). Prolonged action
was achieved by attaching a free fatty acid side chain
through a linker molecule, which promotes binding
to albumin in extracellular fluid and plasma (15). Only
approximately 1–2% of liraglutide are thought to circulate
in a non-albumin-bound state, while the majority
represents a reservoir from which liraglutide can dissociate
to reach tissues and cells expressing GLP-1 receptors. The
approximate half-life is 13 h (16), and liraglutide was
approved for once daily s.c. injections in 2009.
The first compound designed for once-weekly
injections was exentide once weekly, which is exenatide
‘encaged’ in a polymer which slowly dissolves after
injections into subcutaneous adipose tissue (17, 18). The
compound that is thus slowly released into the circulation
is exenatide (identical to the un-retarded compound
injected twice daily); however, the slow absorption
of the so-called exenatide mircrospheres guarantees
steady plasma concentrations slowly rising to a steady
state within approximately 10 weeks with once weekly
injections (14, 18). This means that after discontinuing
this treatment, it will take weeks before all exenatide is
absorbed and eliminated.
A novel approach was taken in the case of dulaglutide
and albiglutide: Bigger proteins (an immunoglobulin
fragment in the case of dulaglutide (19), albumin in the
case of albiglutide (20)) were linked to two modified
(DPP-4-resistant) GLP-1 molecules, incorporated into
the linear sequence of albumin in the case of albiglutide,
peripherally attached with the help of linker molecules
in the case of dulaglutide (Fig. 1). The big ‘carrier’
proteins are typically slowly degraded/eliminated from
the circulation. Thus, these compounds have half lives in
the order of magnitude of 1 week (21, 22, 23) and can
be injected once weekly. Since the protracted action of
dulaglutide and albiglutide is mainly supported by their
slow elimination, relatively rapid absorption leads to an
earlier onset of clinically noticeable action as compared to
exenatide once weekly (24, 25).
Semaglutide has a molecular structure very much
like liraglutide (Fig. 1). However, the alanine in amino
acid position 2, which is recognized and ‘attacked’ by
DPP-4, has been exchanged for α-amino butyric acid to
make the molecule entirely DPP-4-resistant (26). The
binding of the fatty acid side chain seems to be tighter,
such that elimination is even slower (27), and supports
once-weekly dosing.
Recently, an oral preparation of semaglutide has been
developed, which contains semaglutide (identical to the
compound used for s.c. injection) and an absorption
enhancer, Sodium N-(8-(2-hydroxybenzoyl) Amino)
Caprylat (SNAC), which locally raises pH, prevents
degradation of semaglutide, and facilitates absorption,
most likely through gastric mucosa (28). Note that the
bioavailability is still low, and much more peptide needs
to be ingested to achieve similar plasma concentrations
and efficacy (up to 14 mg per day as compared to 1 mg
per week in the case of semaglutide for s.c. injection,
i.e. a 98-fold difference). To compensate for low and
variable absorption, this oral preparation of semaglutide
is recommended to be taken once daily. Predictable
absorption and exposure to the drug requires it to be
taken after an overnight fast with a small volume of water.
A 30-min interval between the ingestion of the drug and
the subsequent meal is required, before more fluid, food
or other medications can be taken (28). Nevertheless, the
development of an oral drug is a remarkable achievement
and innovation.
Pharmacokinetic dierences between GLP-1
receptor agonist compounds
Important pharmacokinetic characteristics for the
individual GLP-1 receptor agonists are summarized
in Table 1. Basically, these data support the different
intervals between subsequent injections suggested, tested
and approved for various compounds belonging to the
GLP-1 receptor agonist class.
Exenatide, as a product of serendipity rather than
developed by rational drug design, had a relatively short
half-life, but was able to reduce glycated haemoglobin
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European Journal of Endocrinology
181:6 R214
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
Table 1 Molecular details, pharmacokinetic features and dosing of various GLP-1 receptor agonists approved for the treatment of type 2 diabetes.
Compound
General features
Pharmacokinetics
(single dose administration)
Structure (Fig. 1)
Molecular
weight (g/mol)*
Approved doses
(µg or mg)
Interval between injections (h
or days)
Initial up-titration
recommended?
Time to peak
(h/days)
Elimination half-life
(h/days)
Exenatide b.i.d.
(unretarded)
Natural peptide
(exendin-4) from the
saliva of the lizard
Heloderma suspectum
(53% homology)
4186.6 • 5 µg
• 10 µg
Before breakfast and
dinner (twice daily) (30)
Yes 2.1–2.2 h (33) 3.3–4.0 h (33)
Lixisenatide q.d. Exenatide plus poly-lysine
tail
4858.6 • 10 µg
• 20 µg
Before breakfast or
before the most
carbohydrate-rich meal
(once daily)
Yes ≈ 2 h (34) 2.6 h (34)
Liraglutide q.d. Slightly modied GLP-1
(97% homology) with
free fatty acid side
chain attached
3751.3 • 0.6 mg
• 1.2 mg
• 1.8 mg
Once daily (approximately
the same time every
day)
Yes 11.0–13.8 h (35) 12.6–14.3 h (35)
Exenatide once
weekly q.w.
See exenatide 4186.6 • 2 mg Once weekly No†Slow‡See exenatide
Dulaglutide q.w. Two modied GLP-1
molecules attached to
an immunoglobulin (Fc)
fragment
59669.8 • 0.75 mg
• 1.50 mg
Once weekly No 48 h (23) 4.7-5.5 day (23)
Albiglutide q.w. Two modied GLP-1
molecules amino-
terminally attached to
the linear structure of
albumin
72,970.4 • 30 mg
• 50 mg
Once weekly Yes 3–5 day (36) 5.7–6.8 day (36)
Semaglutide (for s.c.
injection) q.w.
Slightly modied GLP-1
(94% homology) with
free fatty acid side
chain attached
4113.6 • 0.5 mg
• 1.0 mg
Once weekly Yes 24 h (27) 7.6 day (27)
Semaglutide (for oral
administration)
q.d.
4113.6 • 3 mg§
• 7 mg§
• 14 mg§
30 min before breakfast║
(once daily)
Yes Early
appearance
(within 1–4 h)
(28)
See semaglutide
for s.c.
injection
*For comparison, the molecular weight of glucagon-like peptide-1is 3297.7 g/mol; ║total concentrations (including albumin-bound GLP-1 receptor agonist). Free (non-albumin-bound) concentrations
probably represent 1–2% of total concentrations; ***this was a study in healthy subjects; †due to slow absorption from s.c. depots, exenatide concentrations only rise to a steady-state within 8–10
weeks; ‡not formally assessed, since a single injection does not lead to measurable concentrations; the onset of glucose-lowering actions are seen after 4 weeks of treatment and onward; §all doses
of oral semaglutide formulated with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC).
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European Journal of Endocrinology
181:6 R215
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
and body weight with twice daily injections to a
meaningful extent, but clearly is a short-acting agent that
only transiently leads to pharmacologically active drug
exposure after each injection (for approximately 6–8 h)
(29). However, injecting exenatide three times per day did
not result in convincingly better efficacy (30). This means
that with exenatide injected twice a day, much of a 24-h
period, exenatide plasma concentrations will be too low
to fully exploit the potential of GLP-1 receptor agonists
for lowering glucose actions.
While lixisenatide is a somewhat optimized derivative
of exenatide (with a poly-lysine tail added at the
C-terminus), it still has a rather short half-life (31). It is
meant to be injected once a day, either before breakfast or
before the meal with the largest carbohydrate content (32).
With the once-daily injection, plasma concentrations will
reach an effective exposure for estimated 8 h, leaving 2/3
of the day with relatively low drug exposure (31).
Liraglutide is the only long-acting GLP-1 receptor
agonist to be injected once daily, but still leading to
steadily elevated liraglutide concentrations over a full
24-h period (16). The minor decay after reaching a
small peak after each s.c. injection of liraglutide leads to
fluctuations by approximately 30% during each day (16,
37). Approximately 1–2% of circulating liraglutide is not
albumin-bound and is able to freely diffuse into tissues
and exert biological effects (38).
Little is known about potential fluctuations in drug
exposure during a 24-h period or the week between two
injections in the case of once-weekly injected compounds.
Extending the interval between two injections of
albiglutide to 2 weeks led to fluctuations in fasting plasma
glucose reflecting lower drug exposure during the second
week, indicating that the interval needs to reflect the
elimination kinetics of a given compound (39).
Use of GLP-1 receptor agonists in
special populations
Pharmacokinetic properties may depend on renal
and hepatic function, depending on the routes of
elimination. Table 2 compiles data generated with respect
to pharmacokinetics, safety and tolerability of GLP-1
receptor agonists in subjects with impaired renal function.
Recommendations regarding their use in patients with
hepatic functional impairment are also shown.
As a rule, exenatide and related compounds like
lixisenatide are renally eliminated and should not be
used in patients with advanced stages of renal functional
impairment. Albumin-bound GLP-1 receptor agonists
(liraglutide and semaglutide) or large proteins with
GLP-1 components attached (dulaglutide, albiglutide) are
eliminated independent from renal function. Generally, in
mild or moderate chronic renal disease, no dose reduction
with lower eGFR is recommended. However, because of
limited experience, a general recommendation is to use
all GLP-1 receptor agonists with caution in patients with
chronic kidney disease and low eGFRs, and not at all
below eGFRs of 15 or 30 mL/min (1.73 m2)−1, depending
on the compound.
Finding the optimum dose for GLP-1
receptor agonists in phase 2 studies
All new drugs need to be tested in phase 2 clinical studies,
which aim at identifying dose regimens that lead to
optimized effects on target parameters (e.g. HbA1c, body
weight), while being tolerable for patients. Thus, the
balance between (wanted) effectiveness and (unwanted)
side effects is the main criterion for selecting doses for
phase 3 trials and, later, for approval. In the case of GLP-1
receptor agonists, this process can be complicated by the
fact that tolerability, in part, depends on the velocity of a
rise in exposure to the drug when starting treatment (55).
Starting with too high a dose or increasing the dose too
quickly and by major steps may provoke nausea, vomiting,
or diarrhoea (commonly called ‘gastrointestinal’ side
effects, although they probably are caused by a direct
interaction with the brain stem) (56). Careful selection
of a dose range, including ineffective and not-so-well
tolerable doses, and the choice of an initial up-titration
regimen leading to slowly rising drug levels may be
crucial for identifying optimum doses for any given GLP-1
receptor agonist.
The beneficial effect of slowly up-titrating GLP-1
receptor agonists was first described in the case of
exenatide b.i.d. (55), but later the dose-finding studies were
performed with a relatively narrow range of doses (57, 58).
The development of liraglutide was delayed because a
first wave of phase 2 studies did not sufficiently identify
the upper range of effective, but tolerable doses (59, 60).
A second approach was taken, using initial up-titration
to prevent excessive side effects, thus arriving at a
substantially higher, but still tolerable dose range (61).
The doses identified and up-titration regimens were
further optimized for phase 3 studies.
Dose finding for exenatide once weekly only relied
on a small study testing 0.8 and 2.0 mg per week, with
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181:6 R216
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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Table 2 Potential restrictions in the use of GLP-1 receptor agonists in patients with impaired renal and hepatic function and potential renal benets demonstrated in
clinical trials with various GLP-1 receptor agonists.
Compound Exenatide (b.i.d.) Lixisenatide (q.d.) Liraglutide (q.d.)
Exenatide
(q.w. = once weekly)
Dulaglutide (q.w.) Albiglutide (q.d.) Semaglutide (q.w.)
Route of administration s.c. s.c. s.c. s.c. s.c. s.c. s.c.
Renal elimination and safety in patients with impaired renal function
Evidence for elimination
through the kidneys
(yes/no, reference)
Yes (40) Yes (41) No (42) Yes (40)No Yes (minor)
(43)
Yes (minor, in
patients with
end-stage renal
failure) (27)
Safety/tolerability issues
in patients with severely
impaired renal function?
(yes/no, commentary)
Yes (40) Yes (41) Yes (44) Yes (40)Not reported Yes (45) No (27)
Dose reduction
recommended for mild/
moderate reductions in
renal function? (yes/no)
No (40) No (41) No (44) No (40)No No No
Approved lower limit of
eGFR [ml/min 1.73 m2]
30 30 Approved except for
terminal renal
failure
30 ≥15 30 Approved except
for terminal
renal failure
Potential renal benets
Evidence for reduction in
albuminuria?
No (46) Yes (in patients with
macro-albuminuria)
(47)
Yes (48) No (49) Yes (50, 51)Not reported Yes (52)
Slowed reduction in eGFR
over time [yes/no]
No (46) No (47) Yes (48)Not reported Yes (50, 53) Not clear (54) Not reported (52)
Evidence for benecial
inuence on clinical
renal endpoints?
(yes/no, reference)
No No Yes (48) No (49) Yes (50)Not reported Yes (52)
Use in patients with impaired hepatic function
Dose reduction
recommended in
patients with hepatic
dysfunction? (yes/no)
No (limited
experience)
No (limited experience) No (limited
experience); use
in patients with
severe hepatic
dysfunction not
recommended
No No No (limited
experience)
No (limited
experience)
Information in the present table has mainly been compiled from ocial package inserts for the medications listed. Recommendations for oral semaglutide have not been issued, since approval is
pending. They are likely to be similar to those regarding s.c. semaglutide, since the active ingredient is identical.
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European Journal of Endocrinology
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Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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the higher dose being significantly more effective (17). No
further attempts were made to define the optimum dose
range, and 2 mg per week have been used throughout the
clinical development and in all trials.
Dulaglutide dose finding was the result of a novel
approach, starting with many different doses/up-titration
regimens, selecting doses with a beneficial effectivity–
tolerability relationship, and continuing those doses
for a duration of treatment typical for phase 3 trials (an
adaptive, dose-finding, seamless phase 2/3 study) (62, 63).
Initially, both doses lower and higher than those identified
as the optimized dose range were tested and discontinued
for lack of effectiveness or intolerance.
In the case of albiglutide, the phase 2 study did
not only include once-weekly, but also bi-weekly and
monthly injections of albiglutide (39). Thus, a limited
range of doses used once-weekly was tested and carried
into phase 3.
Semaglutide doses for phase 3 were selected based on
a wide range of candidate doses, both for the s.c. (64) and
the oral (28, 65) preparations. Up-titration was optimized
for phase 3, to further reduce the risk for adverse events.
Overall, the care applied in selecting optimum doses
was highly variable from programme to programme, and
may be reflected in the efficacy and tolerability observed
in definite clinical trials (vide infra). Whether or not
the optimum dose(s) have been identified for a given
compound will be crucial for determining results of head-
to-head comparisons between different GLP-1 receptor
agonists. Generally speaking, greater clinical effectiveness
seems to be a consequence, among other determinants, of
carefully identifying the full dose range from non-effective
to non-tolerable doses, which allows the selection of doses
with an unequivocally positive benefit–risk relationship.
The experience made with fixed-dose GLP-1/insulin
combinations, such as liraglutide/insulin degludec
(66, 67) or lixisenatide/insulin glargine (68, 69) has
demonstrated that implementing even more and smaller
dose up-titration steps may further mitigate the occurrence
of GI side effects.
Injection devices, ease of administration
and adherence to GLP-1 receptor
agonist treatment
Injection devices coming with a prescription of individual
GLP-1 receptor agonists vary considerably, both regarding
their optical appearance and concerning essential
technical details (Fig. 2). Exenatide once weekly is a
suspension of polymer-’encaged’ exenatide that originally
needed to be resuspended using a dual-chamber pen
device containing the active ingredient as a powder
and a liquid solvent. Later, a single-chamber pen device
became available, containing both constituents, however,
requiring thorough shaking to reach an even suspension.
Albiglutide is soluble in an aqueous solution, but needed
to be dissolved, again using a dual-chamber pen device.
This process required approximately 15 min to guarantee
a clear solution. All other compounds are injected from
pre-filled pen devices. Some can only deliver one pre-
determined dose, the liraglutide pen allows to dial step
of 0.6, 1.2 and 1.8 mg per dose (and even in between),
which make slow and individual up-titration possible,
which may be viewed as a major benefit of this device,
potentially reducing the number of patients stopping
treatment because of side events.
For exenatide b.i.d., lixisenatide, albiglutide, and
semaglutide, the pen device has to be changed during the
initial up-titration period, when the next dose increase
is to be implemented (Fig. 2). It is often assumed that
the ease of use of pen-injection devices is an important
determinate of preferring one compound over another,
and that it contributes to adherence to treatment (keeping
the number of missed doses low) and to persistence (not
discontinuing treatment altogether). One important
factor seems to be the interval between two injections,
two injections per day resulting in the worst, and one
injection per week predicting the best indices for
adherence (70, 71, 72).
Clinical trials have been performed with an osmotic
minipump continuously delivering exenatide to
subcutaneous adipose tissue for a period of 3 or 6 months
after implantation. This ITCA 650 device (73, 74) has not
been approved so far, but has been designed to specifically
address the problem of non-adherence.
Denition of short- vs long-acting GLP-1
receptor agonists and consequences for
fasting plasma glucose, gastric emptying
and post-meal glycaemic control
Exenatide (b.i.d.) and lixisenatide (q.d.) are short-acting
GLP-1 receptor agonists, because on the recommended
injection regimen, drug concentrations rise sharply after
each injection, and, after reaching a peak, decay towards
very low levels after a few hours (29, 75). The time–drug
concentration curve, thus, is characterized by peaks and
troughs near zero concentrations, that is, intermittent
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Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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exposure is typical for short-acting GLP-1 receptor agonists.
Long-acting GLP-1 receptor agonists (liraglutide, exenatide
once weekly, dulaglutide, albiglutide, semaglutide) lead
to a more constant drug exposure, with effective GLP-1
receptor agonist concentrations maintained over a whole
24-h period, and/or over a week’s period, even if the interval
between injections is 1 day or 1 week. The consequences
are that tachyphylaxis develops for effects on gastric
emptying, which initially is decelerated with GLP-1 and
all GLP-1 receptor agonists (76, 77, 78). Gastric emptying
is a major determinant of post-meal glycaemic rises (79),
and retarded gastric emptying flattens and reduces the
rise in glucose concentrations following a carbohydrate-
containing meal (78, 80). Tachyphylaxis is observed
within hours or days and is complete after a few weeks,
when plasma glucose profiles in patients treated with long-
acting GLP-1 receptor agonists display more prominent
post-meal rises in plasma glucose concentrations than
patients treated with short-acting GLP-1 receptor agonists
(14, 81). With short-acting GLP-1 receptor agonists, no
prominent tachyphylaxis has been observed (82). On the
other hand, retardation of gastric emptying almost only
occurs after meals before which the short-acting GLP-1
receptor agonist has been administered (one meal per day
in the case of lixisenatide, two meals per day in the case
of exenatide b.i.d.). It should be noted that there usually
are residual effects on gastric emptying after sustained
GLP-1 receptor stimulation even after tachyphylaxis has
occurred (76, 77). In studies addressing tachyphylaxis
regarding the velocity of gastric emptying with long-
acting GLP-1 receptor agonists (81), less reliable methods
than scintigraphy were used. GLP-1 receptor stimulation
also leads to effects on small intestinal motility, which
may contribute to overall effects on the temporal pattern
of glucose absorption with such therapeutic agents (83).
This is not to say that long-acting GLP-1 receptor
agonists do not have the ability to control post-meal
rises in glycaemia, but the mechanism is not related to
effects on gastric emptying, but rather to the stimulation
of insulin and suppression of glucagon secretion (82).
However, quantitatively, short-acting GLP-1 receptor
agonists have the more prominent effect limiting
Figure2
Pen injection devices for GLP-1 receptor agonists and xed-dose combinations of GLP-1 receptor agonists with basal insulin
preparations. The optical appearance of each pen injection device is shown as well as some essential technical characteristics
(single or multiple use, variable or pre-determined xed dosing, availability of pens delivering dierent (maximal) doses, necessity
for re-suspension (mixing dry material with a solvent for reaching a clear solution (e.g., albiglutide) or a homogeneous suspension
(e.g., exenatide once weekly))).
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181:6 R219
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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post-meal glycaemic rises after meals covered by an
injection of the agent (78, 81, 84).
On the other hand, long-acting GLP-1 receptor
agonists have more profound effects lowering overnight
and fasting plasma glucose concentrations (Fig. 2). This
is the result of higher drug concentrations maintained
during the overnight fasting period.
Dierences in adverse eects elicited by
dierent GLP-1 receptor agonists
The most common adverse events with GLP-1 receptor
agonists are nausea, vomiting and diarrhoea, which may
occur in up to 30, 15 and 15% of patients, respectively,
and may lead to discontinuation of drug treatment (56).
Usually, this occurs upon initial exposure to a GLP-1
receptor agonist, or when the dose is increased as part of
an up-titration regimen, and symptoms decay thereafter
in most patients. Perhaps, this decay is more prominent
with long-acting GLP-1 receptor agonists (85). As a rule,
such adverse events are dose dependent (for agents with
more than one approved dose) and are more prominent
on a background of metformin treatment (metformin
itself can elicit such side effects) or insulin treatment
(perhaps indicating more advanced stages of diabetes)
(56). Generally speaking, short-acting GLP-1 receptor
agonists are associated with more nausea and vomiting
(and drug discontinuations associated with such adverse
events), while long-acting GLP-1 receptor agonists are
associated with more diarrhoea (56). The exact reasons for
these differences are not known. One should be aware that
the capture of these side effects in clinical trials usually
is by self-reporting rather than by a structured, validated
questionnaire, which makes results from different studies
less comparable (86).
Comparative eectiveness of various GLP-1
receptor agonists on glycaemic control
(on a background of oral glucose-
lowering medications)
Numerous head-to-head comparisons among GLP-1
receptor agonists have been performed in patients
treated with oral glucose-lowering medications. Results
regarding glycaemic control and body weight reduction
are summarized in Fig. 3. Important adverse events
(nausea representing ‘gastrointestinal’ adverse events
and hypoglycaemia) are shown from the same studies
in Fig. 4.
There are some obvious methodological limitations
of comparative trials addressing glycaemic control,
gastrointestinal adverse effects, or body weight: The
majority of these have been ‘open-label’, with the inherent
possibility of bias. The choice of patients examined, their
background glucose-lowering medication, of comparators
and drug doses often have been guided by commercial
interests. Therefore, results from such studies should
inform, but not define, clinical practice. With such
reservations in mind, several general conclusions can be
drawn from such head-to-head comparisons:
On a background of oral glucose-lowering medications,
within the short-acting GLP-1 receptor agonists (exenatide
b.i.d. vs lixisenatide q.d.) there do not appear to be major
differences in glycaemic efficacy (Fig. 3A and D), while
body weight is reduced more by exenatide, perhaps
related to the greater temporal exposure with two rather
than 1 injection per day.
When, again on a background of oral glucose-lowering
agents, any short-acting with any long-acting GLP-1
receptor agonist were compared, there were greater effects
on glycated haemoglobin with the long-acting agent (Fig.
3B and E), mainly driven by a more substantial lowering
in fasting glucose (14, 85, 87, 88). However, there were no
clinically significant differences in body weight reduction
(14, 85, 87, 88). Thus, continuous exposure does not seem
to be a prerequisite for clinically meaningful body weight
reductions.
Given the differences in addressing fasting/preprandial
vs postprandial plasma glucose between short- and long-
acting GLP-1 receptor agonists triggered by differential
tachyphylaxis regarding a retardation of gastric emptying
(82), their effectiveness on reducing HbA1c may depend
on baseline fasting plasma glucose, since the relative
impact of postprandial glucose increments on HbA1c is
greater at lower fasting glucose concentrations (89). This
has not been specifically addressed in clinical studies,
but could offer a way to optimize drug choices based on
readily available patient factors.
Within the sub-class of long-acting GLP-1 receptor
agonists, liraglutide q.d. compared favourably to
exenatide q.w. (90) and albiglutide q.w. (91). When
these results were the only ones available, one could
have thought that going from once-daily to once-weekly
injections implied some weakening of the effectiveness
(e.g., due to potential fluctuations in drug exposure over
a 7-day period). However, dulaglutide q.w. turned out
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181:6 R220
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DHbA1c [%]
Exenatide b.i.d.
Lixisenatide q.d.
non-
inferiority
(formally
significant)
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DHbA
1c
[%]
Liraglutide q.d.
Exenatide q.w.
*
**
*
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DHbA1c [%]
Albiglutide q.w.
Dulaglutide q.w.
Semaglutide s.c. (q.w.)
Semaglutide oral (q.d.)
n.s.
non-
inferiority
n.s.c.
*
n.s.c.
*
*
not
non-
inferior
(formally
significant)
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DFastingplasmaglucose [mmol/l]
*
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DFasting plasma glucose[%]
*
*
* *
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
DFasting plasma glucose[mmol/l]
*
*
n.s. n.s.c.
**
n.s.c.
n.s.
Ro
senstock et al. 2013
-8
-7
-6
-5
-4
-3
-2
-1
0
DBodyweight[kg]
*
Buse et al. 2009
Nauck et al.2016 a
Drucker et al. 2008
Wysham et al. 1014
-8
-7
-6
-5
-4
-3
-2
-1
0
DBody weight[%]
n.s.
n.s. n.s.
n.s.
Buse et al. 2013
Pratleyet al. 2014
Dungan et al. 2014
Nauck etal. 2016 b
Ahmann et al. 2018
Pratleyet al. 2018
Davies et al. 2017
Pratleyet al. 2019
-8
-7
-6
-5
-4
-3
-2
-1
0
DBodyweight[%]
**
*
*
n.s.c.
*n.s.c.
*
Short- vs. short-
acting GLP-1 RA
Short- vs. long-
acting GLP-1 RA
Long- vs. long- acting
GLP-1 RA
C
EF
A
B
D
GH
I
Figure3
Clinical ecacy results from clinical trials comparing dierent GLP-1 receptor agonists head-to-head. Reductions in HbA1c (upper
row of panels), fasting plasma glucose (middle row of panels) and body weight (lower row of panels) are shown for trials
comparing dierent short-acting GLP-1 receptor agonists (left hand panels), for trials comparing a short- to a long-acting GLP-1
receptor agonist (middle panels) and dierent long-acting GLP-1 receptor agonists (right hand panels). Each colour represents a
specic GLP-1 receptor agonist compound (see legend). The only oral GLP-1 receptor agonist preparation studied (oral
semaglutide) is shown in the same colour (orange) as the same compound injected subcutaneously, however, not as
homogenously lled bars, but with a striped pattern. Asterisks indicate a signicant dierence (P < 0.05) for the individual
head-to-head comparison as reported in the original publication. Non-signicant dierences are marked n.s. (for not signicant).
Other conclusions (non-inferiority, non-inferiority not met) are indicated as text. If no formal statistical comparison has been
reported, this is indicated as n.s.c. (for no statistical comparison). If an original publication has reported results from several doses
for any agent, only results with the highest dose are depicted. GLP-1 receptor agonist doses from phase 2 trials (Nauck etal. (87)
comparing subcutaneous semaglutide with liraglutide and Davies etal. (65) comparing oral and subcutaneous semaglutide) were
not identical to those selected for phase 3 trials and approval. In these cases, doses coming close to those selected for phase 3
and approval have been used.
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European Journal of Endocrinology
181:6 R221
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
to be equally effective compared to liraglutide q.d. (92)
with respect to the reduction in HbA1c, but displayed
a significantly reduced effect on body weight. In a
phase 2 study of various doses of semaglutide (for once
weekly s.c. injections) compared to approved doses of
liraglutide, high doses of semaglutide suggested a higher
effectiveness, both in terms of glycaemic control and
body weight reduction (64). Subcutaneous semaglutide
has proven superior versus exenatide once weekly (93)
and versus dulaglutide (94). Differences were particularly
remarkable with respect to body weight reduction. Oral
semaglutide was compared to s.c. semaglutide in a phase
2 trial: In principle, higher doses of oral semaglutide had
effects very much comparable to those of s.c. semaglutide.
However, the doses nearest (10 mg/day) to those selected
for phase 3 (up to 14 mg/day) resulted in somewhat lesser
0
10
20
30
40
50
Proportion with nausea[%]
Exenatide b.i.d.
Lixisenatide q.d.
0
10
20
30
40
50
Proportion with nausea[%]
Exenatide q.w.
Liraglutide q.d.
0
10
20
30
40
50
Proportion with nausea[%]
Albiglutide q.w.
Dulaglutide q.w.
Semaglutide s.c. (q.w.)
Semaglutide oral (q.d.)
Ro
senstock et al. 2013
0
10
20
30
40
50
Proportion with hypoglycaemia [%]
SU:
No
Buse etal. 2009
Nauck etal. 2016a
Drucker etal. 2008
Wy
sham et al. 1014
0
10
20
30
40
50
Proportion with hypoglycaemia [%]
Sulfonylureas:
YesNoYes No
Buse et al. 2013
Pratleyet al. 2014
Dungan et al. 2014
Nauck et al. 2016 b
Ahmann et al. 2018
Pratleyet al. 2018
Davies et al. 2017
Pratleyet al. 2019
0
10
20
30
40
50
Proportionwithhypoglycaemia [%]
Sulfonylureas:
YesYes No No No No NoNo
Short- vs. short-
acting GLP-1 RA
Short- vs. long-
acting GLP-1 RA
Long- vs. long- acting
GLP-1 RA
CAB
DEF
Figure4
Safety and tolerability results from clinical trials comparing dierent GLP-1 receptor agonists head-to-head. Proportion of patients
reporting nausea (upper row of panels) and proportion of patients reporting any hypoglycaemic episode (lower row of panels) are
shown for trials comparing dierent short-acting GLP-1 receptor agonists (left hand panels), for trials comparing a short- to a
long-acting GLP-1 receptor agonist (middle panels) and dierent long-acting GLP-1 receptor agonists (right hand panels). Each
colour represents a specic GLP-1 receptor agonist compound (see legend). The only oral GLP-1 receptor agonist preparation
studied (oral semaglutide) is shown in the same colour (orange) as the same compound injected subcutaneously, however, not as
homogenously lled bars, but with a striped pattern. Since the original studies usually did not report signicance of dierences,
there are no symbols indicating signicant dierences. If an original publication has reported results from several doses for any
agent, only results with the highest dose are depicted. GLP-1 receptor agonist doses from phase 2 trials (Nauck etal. (87)
comparing subcutaneous semaglutide with liraglutide and Davies etal. (65) comparing oral and subcutaneous semaglutide) were
not identical to those selected for phase 3 trials and approval. In these cases, doses coming close to those selected for phase 3
and approval have been used.
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Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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reductions in HbA1c, fasting plasma glucose, and body
weight (no formal statistical comparison was performed)
(65). Oral semaglutide compared to liraglutide (s.c., q.d.)
had similar effects on HbA1c and fasting plasma glucose,
but more profoundly lowered body weight after 26 weeks
(primary endpoint). After 52 weeks, the effect on HbA1c
was superior for oral semaglutide.
Thus, the sub-class of long-acting GLP-1 receptor
agonists have not only proven to be more effective
than short-acting GLP-1 receptor agonists, but over the
period between 2007 and today have evolved to gain
greater effectiveness with the most recently introduced
compounds, even including a novel oral preparation
of semaglutide, which turned out to be almost equally
effective compared to the subcutaneous preparation of
the same peptide agent, semaglutide.
Comparative eectiveness of various GLP-1
receptor agonists on glycaemic control
(on a background of basal insulin therapy)
GLP-1 receptor agonists have been used in addition
to basal insulin. Additive effects are expected due to
complementary mechanisms of action (95). Both short-
(96, 97, 98) and long-acting GLP-1 receptor agonists (99,
100, 101, 102) have been used in conjunction with basal
insulin as a free combination, allowing individual dosing
for both components.
The short-acting compound lixisenatide is also
available as a fixed-dose combination with insulin glargine
(called iGlarLixi or, formerly, LixiLan) (68, 69, 103), like
the long-acting compound liraglutide, which is available
as a fixed-dose combination with insulin degludec
(abbreviated IdegLira) (66, 67). These combinations
are injected from the same device, with doses of both
components being proportional (’fixed ratio’) to each
other. They have to be titrated slowly, like it is customary
for basal insulin. Compared to free combinations of the
same agents with insulin, this slow titration results in
considerably lower proportions of patients reporting
nausea, vomiting and diarrhoea (66, 67, 68, 69, 103),
underscoring the concept of a slow rise in exposure to
prevent such side effects. In studies comparing these
fixed-dose combinations with the insulin component
only, IdegLira seems to produce greater differences in
HbA1c (66, 67) than IglarLixi (68, 69), compatible with
the differences in glycaemic efficacy displayed by the two
GLP-1 receptor agonists on a background of oral glucose-
lowering agents (87). According to a meta-analysis,
IdegLira is more potent in controlling glycaemia and body
weight than iGlarLixi (104).
When used in conjunction with (basal) insulin, short-
acting GLP-1 receptor agonists have been shown to provide
superior additional post-prandial effects on top of fasting
plasma glucose being controlled by intermediate- or long-
acting insulin preparations (96, 97, 98, 105, 106). However,
the post-prandial lowering of glycaemic excursions occurs
mainly after those meals, when exenatide or lixisenatide
have been injected before. Head-to-head comparisons
to long-acting GLP-1 receptor agonists are lacking. A
recent indirect comparison performed by a meta-analysis
suggests that long-acting GLP-1 receptor agonists provide
a greater reduction in HbA1c, fasting plasma glucose,
and body weight compared to short-acting ones, mainly
driven by their more pronounced effect on fasting plasma
glucose (Huthmacher J, Meier J J, Nauck M A, unpublished
observations).
Comparative eectiveness of various GLP-1
receptor agonists on body weight reduction
All approved GLP-1 receptor agonists have the potential to
induce weight loss by decreasing appetite and increasing
satiety, that is, mainly through an interaction with GLP-1
receptors in brain areas involved in the homeostasis of
energy (food) intake, energy expenditure, and energy
balance (7). However, the quantitative impact is markedly
different for various GLP-1 receptor agonists (Fig. 3D, E
and F). Furthermore, there is substantially more inter-
individual variability regarding weight loss than there
is for glycaemic control, with some subjects treated
with GLP-1 receptor agonists not losing any weight (or
even gaining weight), while others lose up to 25 kg over
a period of half a year (14, 107, 108). Typically, a new
steady-state plateau of body weight is reached after 3–6
months of treatment. Most of this initial weight loss will
be maintained as long as the treatment is adhered to. This
is the expected consequence of lowering caloric intake
(like with an energy-restricted diet), apparently the main
mechanism how GLP-1 receptor agonists lower body
weight. If GLP-1 receptor treatment is discontinued, the
amount of weight lost with treatment will be re-gained.
In contrast to the glucose-lowering effect, head-to-
head comparisons between short- and long-acting GLP-1
receptor agonists do not systematically show superiority of
long-acting agents with respect to weight loss (Fig. 3E) (14).
This can be taken as indirect evidence that deceleration of
gastric emptying (which remains an effect of short-acting
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Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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GLP-1 receptor agonists even during long-term treatment,
while it is lost due to tachyphylaxis with long-acting
GLP-1 receptor agonists) (82) does not trigger a major loss
in appetite due to incomplete gastric emptying. Likewise,
nausea and vomiting induced in some patients does not
provide the main reason for weight loss, since it occurs to
almost the same degree in patients never complaining of
such ‘gastro-intestinal’ adverse event (14, 107).
Average weight loss with exenatide b.i.d., lixisenatide
q.d., liraglutide q.d., and dulaglutide q.w. is 2–4 kg,
with considerable inter-individual variation, while it
appears to be less with albiglutide (54, 91) (treatment
with which is associated with less nausea/vomiting as
well), and more with semaglutide, both concerning the
once weekly subcutaneous preparation (65, 93, 94) and
the once-daily oral preparation (co-formulated with an
absorption enhancer) (109, 110, 111, 112). Differences
in uptake across the blood–brain barrier (or in brain
access through subfornical organs) have been postulated
as an explanation. However, convincing direct evidence
is lacking. Effects of GLP-1 receptor agonists on body
weights are depicted in Fig. 3 D, E and F.
Comparative eects on antibody formation
Exenatide (both the b.i.d. and the once-weekly
preparation) has prompted antibody formation, even in
the majority of patients (14, 113), probably due to the
low sequence homology to mammalian GLP-1 (Fig. 1).
However, this was of uncertain functional consequences,
since even high titres were not obviously associated with
a reduced effectiveness (14, 113). With liraglutide (114),
dulaglutide (115), albiglutide (116) and semaglutide (94),
antibody formation is only rarely observed.
Comparative eectiveness of various GLP-1
receptor agonists on other cardiovascular
risk factors (blood pressure, lipoproteins,
heart rate)
All GLP-1 receptor agonists lower systolic blood pressure
by 2–5 mmHg, with less consistent effects on diastolic
blood pressure (117). At the same time, an average
increase in pulse rate of 2–5 beats per min has been noted
in patients treated with GLP-1 receptor agonists (117),
the duration of which within a 24-h period matching
the exposure to effective GLP-1 receptor stimulation
with the various agents (i.e. continuous with long-acting
agents, intermittent with short-acting agents) (81). 24-h
electrocardiographic monitoring detects more acceleration
of heart rate than occasional pulse rate measurements
(81). In addition to body weight reduction, and lowering
in systolic blood pressure, all GLP-1 receptor agonists
slightly, but favourably modify lipoprotein concentrations
(lowering of LDL cholesterol and triglycerides) (117).
The acceleration in pulse rate does not seem to prevent
cardio-vascular benefits of GLP-1 receptor agonists, even
in patients in whom a prominent heart rate response was
observed.
Cardiovascular outcomes studies with
dierent GLP-1 receptor agonists:
technical aspects
Since the first positive report on the LEADER trial
examining liraglutide effects on cardiovascular outcomes
in high-risk type 2-diabetic patients (118), a body of
evidence has accumulated on the potential cardio-
vascular benefits elicited by GLP-1 receptor agonists (49,
52, 54, 109, 119, 120). Originally, such trials had become
mandatory for all new diabetes drugs after 2008 to prove
their cardiovascular safety. Thus, the original aim was
to show that outcomes were not worse (‘non-inferior’)
with the active drug as compared to placebo. Typically,
populations with pre-existing definite cardio-vascular
damage (e.g., previous cardio-vascular events) were
studied, (a) because such patients were considered to be a
highly most vulnerable population, and (b) because high
cardio-vascular event rates could be expected, leading to
smaller sample sizes and shorter study durations while
still achieving numbers of events providing the necessary
power to achieve the study objectives. After several
studies had shown positive effects in such populations
with pre-existing atherosclerotic cardio-vascular disease,
supporting the idea of secondary prevention of cardio-
vascular events with GLP-1 receptor agonists, the question
arose, whether similar benefits could be demonstrated in
lower-risk patients without definite pre-existing cardio-
vascular damage. Thus, the proportion of patients with
either previous cardio-vascular events or definite cardio-
vascular ischemia is a major important variable differing
between studies. Other parameters with potential impact
on outcomes are the proportion of patients with chronic
kidney disease (significant albuminuria and/or reduced
glomerular filtration rate), patient and event numbers,
duration, and variables indicating adherence to treatment
(or discontinuation of the study drug, respectively).
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Table 3 displays patient and study characteristics in cardio-
vascular outcomes trials with GLP-1 receptor agonists.
Cardiovascular outcomes studies with
dierent GLP-1 receptor agonists:
cardiovascular outcomes
Key findings of cardiovascular outcomes trials comparing
treatment with a GLP-1 receptor agonist to placebo on
a background of standard of care are shown in Fig. 5:
(red symbols). For comparison, results of similar studies
employing SGLT-2 (sodium-glucose transporter-2)
inhibitors (blue symbols) (121, 122, 123) and DPP-4
(dipeptidyl peptidase-4) inhibitors (green symbols)
(44, 124, 125, 126) are shown as well. Changes in time
to major adverse cardiovascular events (’MACE’: first
non-fatal acute myocardial infarction, non-fatal stroke,
or cardiovascular death), all-and cause mortality, or
hospitalization for congestive heart failure are shown.
None of the DPP-4 inhibitors significantly changed the
number of major adverse cardiovascular (MACE) events
or all-cause mortality (44, 124, 125, 126). Heterogeneous
results were reported with respect to the time to first
hospitalization for heart failure: As significantly increased
risk was reported for saxagliptin, a similar trend with
alogliptin, no change with sitagliptin, and a beneficial
trend with linagliptin (44, 124, 125, 126).
SGLT-2 inhibitors uniformly showed a major reduction
in hospitalization for congestive heart failure (121, 122,
123), had smaller, heterogeneous effects on MACE,
and differed widely with respect to all-cause mortality
(substantial and highly significant for empagliflozin,
trends without significance in the case of canagliflozin
and dapagliflozin) (121, 122, 123).
The first trial in type 2-diabetic patients reporting
results with a GLP-1 receptor agonist, lixisenatide
(ELIXA trial), did not describe any noticeable effect
on MACE, all-cause mortality, or hospitalization for
heart failure (120). It has to be noted that lixisenatide
is a rather short-acting GLP-1 receptor agonists and its
recommended use is once daily (31). This will certainly
not lead to drug levels sufficient to stimulate GLP-1
receptors for a whole 24-h period (Table 1). One other
Table 3 Cardio-vascular outcomes trials with GLP-1 receptor agonists: study and patient characteristics.
Compound Lixisenatide Liraglutide Semaglutide Exenatide Albiglutide Dulaglutide Semaglutide
Details of treatment
Route of administration s.c. s.c. s.c. s.c. s.c. s.c. Oral
Interval between
administrations
Once daily Once daily Once weekly Once weekly Once weekly Once weekly Once daily
Dose/interval 20 µg/day 1.8 mg/day 0.5/1.0 mg/week 2 mg/week 50 mg/week 1.5 mg/week 14 mg/day
Study acronym, reference ELIXA (120) LEADER (118) SUSTAIN-6 (52) EXSCEL (49)HARMONY
Outcomes
(54)
REWIND (119) PIONEER-6 (109)
Study characteristics
Patient number 6068 9340 3297 14 752 9463 9901 3183
Study duration*2.1 3.8 2.1 3.2 1.6 5.5 1.3
MACE† endpoints 805 1302 254 1744 766 1257 137
Premature discontinuation (%) 27.5 n.r. 19.9/22.6 43.0 24.5 26.8 15.3
Exposition to drug (%)‡90.5 84.0 86.5 76.0 87.0 82.2 n.r.§
Vital state known (%) 98.8 99.7 99.6 98.8 99.4 99.7 99.7
Baseline patient characteristics
Age (years) 60 64 65 62 64 66 66
Sex: % female 30 36 39 38 30 46 32
Diabetes duration (years) 913 14 12 14 10 15
HbA1c (%) 7.7 8.7 8.7 8.0 8.8 7.3 8.2
BMI (kg/m2) 30.1 32.5 n.r.*31.8 32.3 32.3 32.3
Pre-existing
cardio-vascular disease (%)
100 98.2 72.2 73.3 100 31.4 84.6
Pre-existing heart
failure (%)
22.5 17.9 23.1 15.8 20.0 8.6 n.r.
eGFR <60 mL/min (%) n.r. (mean: 77
mL/min)
±23.9 30.2/26.7 21.3 n.r. (mean: 79
mL/min)
±22.0 27.0
If the original publication did not report details for all patients (treated with active drug or placebo), data on patients treated with the study drug are
reported in this table.
*Median; †Mean body weight 92.3 kg; ‡Expressed as individual percentage of the duration of observation with full adherence to randomized drug;
§75% of the patients took study drug for >1 year.
n.r., not reported.
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Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
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particular aspect of this ELIXA trial is the recruitment
of patients shortly after an acute coronary syndrome.
Biological processes dominating clinical complications
after such an event and following revascularization
(intra-coronary procedures or bypass surgery) may
be different from those characterizing the natural
history of atherosclerosis, and may be less amenable to
modification through GLP-1 receptor agonist treatment
as well.
All other cardiovascular outcomes trials testing GLP-1
receptor agonists showed a somewhat consistent pattern
with respect to effects on major adverse cardiovascular
events: Either a significant reduction (by 12–26%) or
at least a trend towards a reduction in MACE events
was observed (49, 52, 54, 109, 118, 119, 120) (notable
exception: Lixisenatide in the ELIXA trial; Fig. 5A). All
GLP-1 receptor agonists except lixisenatide tested are
characterized as long-acting compounds (vide supra for
definition), which provide substantial GLP-1 receptor
stimulation throughout a 24-h period.
Most of these trials included a high proportion of
patients with pre-existing atherosclerotic cardiovascular
disease (based on previous events, necessity for
revascularization, or definite results of functional testing
or imaging), and a smaller proportion of patients with
risk factors only. In LEADER (liraglutide), SUSTAIN-6
(subcutaneous semaglutide), and PIONEER-6 (oral
semaglutide), chronic kidney disease with an eGFR <60
mL/min (1.73 m2)−1 was taken as a risk equivalent to
proven cardiovascular damage. Thus, their results clearly
support the idea of secondary prevention of cardiovascular
events in those with pre-existing cardiovascular
damage. The proportions of patients without previous
evidence of cardiovascular disease, as a rule, were too
small to allow definite conclusions for these subgroups.
REWIND (dulaglutide) has been the first trial to recruit
a majority of patients without proven cardiovascular
disease at baseline. MACE was reduced by 12% in the
overall population. This percentage reduction of events
was not different between subgroups with and without
pre-existing cardiovascular disease (non-significant
interaction, P = 0.97, for a difference between hazard
ratios for these sub-populations) (119). This result may
be interpreted as demonstrating effects in those without
cardiovascular damage at baseline, and, thus, a chance
for primary prevention of cardiovascular events in type
2-diabetic patients, independent from previous damage
to the cardiovascular system. However, when analysed
separately, both subgroups did not show significant
reductions in MACE (P > 0.10 for both sub-populations).
Therefore, the conclusion that the REWIND study has
demonstrated cardioprotection with dulaglutide in
primary prevention can be debated.
0.40.5 0.60.7 0.80.9 1.01.1 1.21.3 1.41.5
CARMELINA
TECOS
EXAMINE
SAVOR-TIMI 53
DECLARE-TIMI 58
CANVAS program
EMPAREG-Outcomes
PIONEER 6
REWIND
HARMONY Outcomes
EXSCEL
SUSTAIN-6
LEADER
ELIXA
MACE
Hazard ratio (95 % confidence interval)
Study
DPP-4 I
GLP-1 RA
SGLT-2 I
Saxagliptin
Dapaflozin
Canagliflozin
Empagliflozin
Semaglutid
e p.o.
Dulaglutide
Albiglutide
Exenatide q.w.
Semglutide s.c.
Liraglutide
Lixisenatide
Sitagliptin
Alogliptin
Linagliptin
*
*
**
*
*
0.40.5 0.60.7 0.80.9 1.01.1 1.21.3 1.41.5
CARMELINA
TECOS
EXAMINE
SAVOR-TIMI 53
DECLARE-TIMI 58
CANVAS program
EMPAREG-Outcomes
PIONEER 6
REWIND
HARMONY Outcomes
EXSCEL
SUSTAIN-6
LEADER
ELIXA
All cause death
Hazard ratio (95 % confidence interval)
Study
DPP-4 I
GLP-1 RA
SGLT-2 I
Saxagliptin
Dapaflozin
Canagliflozin
Empagliflozin
Semaglutid
e p.o.
Dulaglutide
Albiglutide
Exenatide q.w.
Semglutide s.c.
Liraglutide
Lixisenatide
Sitagliptin
Alogliptin
Linagliptin
*
*
0.40.5 0.60.7 0.80.9 1.01.1 1.21.3 1.41.5
CARMELINA
TECOS
EXAMINE
SAVOR-TIMI 58
DECLARE
CANVAS program
EMPAREG-Outcomes
PIONEER 6
REWIND
HARMONY Outcomes
EXSCEL
SUSTAIN-6
LEADER
ELIXA
Hospitalization for heart failure
Hazard ratio (95 % confidence interval)
Study
DPP-4 I
GLP-1 RA
SGLT-2 I
Saxagliptin
Dapaflozin
Canagliflozin
Empagliflozin
Semaglutid
e p.o.
Dulaglutide
Albiglutide
Exenatide q.w.
Semglutide s.c.
Liraglutide
Lixisenatide
Sitagliptin
Alogliptin
Linagliptin
not reported
*
**
*
A
B
C
Figure5
Results of cardiovascular outcomes trials comparing GLP-1
receptor agonists and placebo on a background of standard of
care. Eects on ‘major adverse cardio-vacular events’ (MACE;
A), all-cause mortality (B) and hospitalization for heart failure
(C) are shown as hazard ratios and their 95% condence
intervals. For comparison, results from equivalent studies with
DPP-4 inhibitors (DPP-4 I) and SGLT-2 inhibitors (SGLT-2 I) are
also shown. Asterisks indicate signicant dierences (P < 0.05)
to placebo treatment (on a background of standard of care).
†The dagger marks an apparently signicant inuence of
exenatide once weekly on all-cause mortality (because the
condence interval does not cross the line of unity), however,
signicance could not be concluded based on a hierarchical
testing procedure with an earlier comparison in that hierarchy
not showing signicant dierences.
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European Journal of Endocrinology
181:6 R226
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
It is also important to note that the study objectives
have been quite different between the trials: Some trials
were designed to support preliminary cardiovascular
safety of novel glucose-lowering drugs before approval
(SUSTAIN-6, PIONEER-6). This could be concluded if the
upper bound of the 95% CI of the hazard ratio ends below
1.8 (ruling out an 80% elevation in risk with an error
margin of 5%). In those cases, the duration of the trials
was shorter, and the number of MACE events accrued
during the trials was considerably lower (Table 3), as the
main emphasis was on safety, not on proving benefits.
Other trials aimed at definitely proving safety (upper
bound of the 95% CI of the hazard ratio ends below 1.3,
ruling out a 30% elevation in risk with an error margin
of 5%), with a secondary analysis for superiority (hazard
ratio: point estimate and its 95% CI below 1.0). Sufficient
power requires much larger event numbers, which in turn
calls for more patients followed for a longer period of time
(Table 3). This approach applies to the LEADER, EXSCEL,
HARMONY outcomes, and REWIND trials.
A controversial question is whether there is something
like a ‘class effect’ for cardiovascular benefits applying to
all GLP-1 receptor agonists. This question can be raised
in various ways. One definition could be that the results
of all trials examining effects of GLP-1 receptor agonists
on cardiovascular events show a comparable pattern,
thereby suggesting that the results attest of a common
biological mechanism (stimulation of GLP-1 receptors)
responsible for the results. Some heterogeneity, especially
in quantitative terms, may apply due to differences in
pharmacokinetic properties, selection of doses, patient
populations and chance. This applies to the reduction
in major adverse cardiovascular events (’MACE’) with
all GLP-1 receptor agonists (Fig. 5), with the notable
exception of the ELIXA trial with lixisenatide. The reason
most likely is caused by the short-lived increments in
lixisenatide concentrations following a single injection
every day, which will not guarantee exposure to significant
concentrations of the drug for a full 24-h period (Table 1).
The second ‘outlier’ seems to be exenatide once weekly
(49). Information provided earlier (vide supra) attests
of a missed chance to carefully select optimum dosages
for this compound for optimizing clinical effects (17): A
dose of 2 mg per week may not be equipotent to those
selected for other GLP-1 receptor agonists. Furthermore,
exenatide once-weekly may produce subcutaneous
nodules as a local reaction to injecting an agent that
resides in the subcutaneous adipose tissue for weeks (127,
128). This may be a major determinant of a relatively low
adherence to this therapy (129), as shown by a rather
high rate of patients discontinuing this drug treatment
in this ‘pragmatic’ trial (Table 3). Thus, it appears possible
to explain why cardiovascular outcomes (as well as
glycaemic control; Fig. 3) with lixisenatide and exenatide
once weekly fall short of what has been corroborated with
other GLP-1 receptor agonists.
Another definition of ‘class effect’ could be that
differences between compounds belonging to a class are
negligible, such that the choice of agent could be left to cost
considerations or even chance. This description does not fit
the heterogeneity of results obtained in clinical trials with
GLP-1 receptor agonists, both with respect to glycaemic and
body weight control (Fig. 3) and concerning documented
and published cardiovascular outcomes (Fig. 5).
GLP-1 receptor agonists have not shown any consistent
effects on the risk for hospitalization for congestive heart
failure (Fig. 5B). Advanced stages of heart failure had been
exclusion criteria in most studies. Dedicated clinical trials
addressing potential benefits of liraglutide treatment in
patients with pre-existing advanced congestive heart failure
failed to show such benefits and rather tended to show an
increased mortality (not significant (130, 131)). These results
probably indicate that liraglutide (and other GLP-1 receptor
agonists) should not be used in patients with advanced
stages of heart failure because of safety considerations.
Because of the cardiovascular benefits associated
with the use of GLP-1 receptor agonists, this class is
recommended as a preferred treatment for patients with
pre-existing atherosclerotic cardio-vascular disease (Fig.
5 and Table 3) (132). Since similar benefits have been
described for SGLT-2 inhibitors (Fig. 5), a decision has to be
made whether to prefer GLP-1 receptor agonists or SGLT-2
inhibitors for a given patient (132). While this decision
may be difficult in some patients, SGLT-2 inhibitors will be
preferred if there is a prominent risk for congestive heart
failure complications or the need to prevent progression of
chronic kidney failure (132). GLP-1 receptor agonists may
be the better class to prevent ischaemic complications of
atherosclerotic disease. Potential frequent adverse events
(predominantly genital infections in the case of SGLT-2
inhibitors versus gastrointestinal adverse events in the
case of GLP-1 RAs) may also be taken into consideration.
Potential mechanisms of action of GLP-1
receptor agonists on
cardiovascular endpoints
GLP-1 receptor agonists have beneficial actions on well-
characterized cardiovascular risk factors (glycaemic control,
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European Journal of Endocrinology
181:6 R227
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
body weight, blood pressure, fasting and postprandial
lipoproteins), but also influences a multitude of biological
processes in blood vessels and the heart, ranging from
improved substrate uptake and ischemia tolerance in the
heart to vasodilation, reduced low-grade inflammation,
and improved plaque stability (133). These effects have
recently been reviewed extensively (117). Most likely,
GLP-1 receptor agonists exert anti-atherosclerotic effects
that, in part, seem to be independent from the obvious risk
factor improvement that accompanies such treatment.
Eects of GLP-1 receptor agonists on
microvascular diabetic complications
Only late after the introduction of GLP-1 receptor
agonists into clinical practice, beneficial effects on
albuminuria and the progressive loss of kidney function
(eGFR) have been described (Table 2). The potential to
reduce albuminuria to prevent progression to advanced
stages of albuminuria (micro- or macro-albuminuria)
and to interfere with the natural history characterized
by a slow, but relentlessly progressive loss in renal
filtration capacity has only been recognized in recent
years, following the publication of the LEADER trial
(48, 118). While earlier trials may have missed a chance
to document such renal benefits, more recent studies
have confirmed similar effects for semaglutide (134),
dulaglutide (50), and, with a transient effect on eGFR,
for albiglutide (54). Composite renal endpoints (as a rule
including progression to macro-albuminuria, a measure
of a substantial reduction in eGFR, advancement to
the state of terminal renal failure requiring dialysis or
kidney transplantation, and death for renal causes) have
shown significant advantages for patients treated with
liraglutide (48, 118), semaglutide (134), and dulaglutide
(50), all driven by a major effect on the progression to
albuminuria. The other endpoints only rarely occurred,
as expected for populations with relatively normal renal
function at baseline (Table 3).
Clinical endpoints related to diabetic eye disease
(need for photo-coagulation, intra-vitreal injection
therapy, or vitrectomy) have been found increased
with the use of liraglutide (non-significant trend) (118),
semaglutide (significant difference) (52) and dulaglutide
(non-significant trend) (50, 119). The majority of these
patients had pre-existing advanced retinopathy (requiring
specific ophtalmological therapy) (135). One reason may
be the rapid drop in plasma glucose and HbA1c induced by
initiating GLP-1 receptor therapy, which has previously
been associated with so-called ‘initial worsening’ in type
1-diabetic patients intensifying their glucose-lowering
therapy with multiple daily injections or pump therapy
(136). Care should be taken that diabetic eye disease is
diagnosed and treated before initiating such treatment
with the potential to dramatically improve glycaemic
control within short periods of time. It will take more
studies to decide, whether there is a specific risk for
the progression of diabetic eye disease with GLP-1
receptor agonists.
Figure6
Comparison of benecial and adverse
eects elicited by currently available and
soon to be approved GLP-1 receptor
agonists. The semi-quantitative estimates
are derived from published clinical trials,
but represent the authors’ opinions and
their subjective clinical judgement. Data
concerning albiglutide are not considered,
since this compound is no longer
available. aMainly through persistent
eects on gastric emptying (deceleration,
absence of tachyphylaxis). bPotential
judged to be good because this is
administered as a tablet; however, as of
now, comparative data are lacking.
cAntibody formation.
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European Journal of Endocrinology
181:6 R228
Review M A Nauck and J J Meier GLP-1 receptor agonist
comparison
https://eje.bioscientica.com
The challenge of individual choices
In light of the current or future availability of currently
eight different GLP-1 RA preparations (even excluding
the fixed-ratio combinations with insulin), the question
arises how to determine to optimal choice of a GLP-1
RA for a given patient. Several aspects may be taken into
consideration: In terms of the overall glucose-lowering
potential, semaglutide appears to provide the greatest
efficacy (perhaps with the s.c. version being slightly
more efficacious than the oral preparation), followed by
liraglutide and dulaglutide. If reduction in postprandial
hyperglycaemia is a key therapeutic target, lixisenatide
(once daily) or exenatide (twice daily) may be suitable
candidates. Weight loss has been most pronounced with s.c.
semaglutide, followed by oral semaglutide and liraglutide.
The incidence of gastrointestinal adverse events has been
found to be lowest with albiglutide and exenatide-once
weekly, and highest with exenatide b.i.d.. Heart rate
increases appear to be less pronounced with lixisenatide
and exenatide, owing to the shorter periods of exposure to
effective drug levels. The greatest convenience and ease of
use can be attributed to dulaglutide, which is delivered in
an easy-to-use single use pen, followed by semaglutide s.c.
and liraglutide. Whether oral semaglutide, which has to
be administered daily 30 min prior to meal ingestion, will
be preferred over the weekly injectable therapies, is yet
to be determined. Finally, the most convincing results in
terms of reducing the overall numbers of MACE events in
secondary prevention have been obtained for liraglutide,
whilst some evidence for cardioprotection in primary
prevention may be considered for dulaglutide. Taken
together, these unequal properties and effects highlight
the concept of individualized care even within the broad
class of GLP-1 RAs (Fig. 6).
Conclusions
More than 10 years after the introduction of the first GLP-1
receptor agonist, exenatide b.i.d. into clinical practice,
this class of incretin-based glucose-lowering medications
has evolved to progressively provide improved glycaemic
control and body weight reduction. They are now
recommended as the first injectable therapy after the
failure of oral glucose-lowering agents (as a rule, before
starting insulin therapy) (132). Specific benefits associated
with this therapy are the prevention of cardiovascular
events (addressing macro-vascular diabetic complications)
and renal (micro-vascular) endpoints. It is the purpose of
the present overview to highlight differences between
agents belonging to the GLP-1 receptor agonist class or
the evidence for benefits that have been described in
clinical trials with such agents. This information is hoped
to support the selection of the most appropriate treatment
as part of an individualized treatment decision for patients
with type 2 diabetes mellitus.
Declaration of interest
M A N has been member on advisory boards or has consulted with
AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Fractyl, GlaxoSmithKline,
Homan La Roche, Menarini/Berlin Chemie, Merck, Sharp & Dohme,
NovoNordisk, and Versatis. He has received grant support from Eli Lilly
& Co., Menarini/Berlin-Chemie, Merck, Sharp & Dohme, and Novartis
Pharma. He has also served on the speakers’ bureau of AstraZeneca,
Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Menarini/Berlin
Chemie, Merck, Sharp & Dohme, NovoNordisk, and Sun Pharma. J J M has
received consulting and speaker honoraria from Astra Zeneca, Eli Lilly&
Co., Merck, Sharp & Dohme, Novo Nordisk and Sano. He has received
research support from Eli Lilly & Co., Boehringer-Ingelheim, Merck, Sharp
& Dohme, Novo Nordisk, Novartis and Sano.
Funding
J J M has been supported by the Deutsche Forschungsgemeinschaft (DFG),
grant ME 2096/8-1.
Author contribution statement
M A N has designed the review, performed the literature review, and wrote
the rst draft of the present review. J J M has provided input into the gures
and tables, and has revised the manuscript for critical intellectual content.
Both authors have decided to submit the nal version for publication.
M A N is the guarantor for the content and vouches for the accuracy of
data presented.
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Received 22 July 2019
Revised version received 11 September 2019
Accepted 9 October 2019
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