GLP-1 Receptor Agonists in The Treatment of Type 2 Diabetes e State-Of-The-Art

Review
GLP-1 receptor agonists in the treatment of type

2 diabetes e state-of-the-art
Michael A. Nauck*, Daniel R. Quast, Jakob Wefers, Juris J. Meier
ABSTRACT
Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further
developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially
necessitating short intervals between injections (twice daily for exenatide b.i.d.).
Scope of review: To summarize current knowledge about GLP-1 receptor agonist.
Major conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly
(exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical
effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action:
augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric
emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide
b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-
term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects
on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin.
Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional
weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering
therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose
preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma
glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV
events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-
1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk
subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect
mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of
treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the
definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharma-
cogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1
diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have
become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2
diabetes and potentially other diseases.
Ó 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords Glucagon-like peptide-1 receptor agonists; Exenatide; Lixisenatide; Liraglutide; Dulaglutide; Albiglutide; Semaglutide; Type 2
diabetes; Cardiovascular disease; Body weight
1. DEVELOPMENT OF GLP-1 RAS (Copenhagen, Denmark) [1] and Joel Habener (Boston, MA, USA) [2]
were the first to correctly identify “truncated” GLP-1 (GLP-1 [7e36
The identification of gut-derived glucagon-like peptide-1 (GLP-1), amide], the amidated form [1], or GLP-1 [7e37], the glycine-extended
putatively belonging to the family of incretin hormones (i.e. gastroin- form [2]), as the product(s) of proglucagon translational processing in
testinal hormones released after nutrient intake with the ability to mammalian gut mucosa (L cells) as published in 1987. Based on the
glucose-dependently augment insulin secretory responses during proglucagon nucleotide sequence, prior assumptions regarding pro-
periods characterized by hyperglycemia) triggered the development of cessing enzymes led to an erroneous GLP-1 sequence longer by 6 N-
GLP-1 receptor agonists (GLP-1 RAs). The groups around Jens Holst terminal amino acid residues [3]. However, “truncated” GLP-1 was
Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
*Corresponding author. Head of Clinical Research, Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital (Ruhr University Bochum), Gudrunstr. 56, 44791,
Bochum, Germany. Fax: þ49 234 509 2714. E-mail: [email protected] (M.A. Nauck).
Received August 25, 2020 Revision received October 9, 2020 Accepted October 12, 2020 Available online xxx
https://doi.org/10.1016/j.molmet.2020.101102
MOLECULAR METABOLISM xxx (xxxx) xxx Ó 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1
www.molecularmetabolism.com
Review
clearly insulinotropic at much lower (picomolar) concentrations active ingredient slowly released after subcutaneous injection from a
compared to the extended GLP-1 sequence [1,2]. Initial studies with matrix dissolving over time. Thus, the onset of action was very much
rodent models indicated that GLP-1 is highly effective as an insuli- delayed, and a steady state was not reached until 8e10 weeks of
notropic agent in non-diabetic, metabolically healthy animals, but treatment [17,18]. Other approaches followed the strategy to couple
shared substantially reduced biological activity in diabetic animals with (modified) GLP-1 to large proteins such as an immunoglobulin Fc
the previously identified incretin glucose-dependent insulinotropic fragment (dulaglutide or efpeglenatide) or albumin (albiglutide). These
polypeptide (GIP) [4]. Nevertheless, studies in human subjects with compounds appear to slowly degrade, with half-lives of approximately
type 2 diabetes surprisingly showed well-preserved insulinotropic one week. After subcutaneous injection, they reach effective circu-
activity of both GLP-1 [7e36 amide] [5] and GLP-1 [7e36] that was lating concentrations relatively early, thus beginning to lower plasma
accompanied by a short-term reduction in plasma glucose in the glucose soon after initiating such treatment. Semaglutide is another
normal fasting range in patients previously characterized by persistent compound with a structure generally similar to liraglutide (GLP-1 with
hyperglycemia [6,7]. However, GLP-1 was found to be proteolytically a free fatty acid side chain) but with a much longer half-life, appar-
degraded and inactivated by the ubiquitous protease dipeptidyl ently mediated by even tighter coupling to albumin. Semaglutide is
peptidase-4 (DPP-4) [8] and both the intact GLP-1 molecule and DPP- presently available for once-weekly subcutaneous injection. More
4-generated metabolites (GLP-1 [9e36 amide] or [9e36]) were recently, semaglutide was co-formulated with sodium N-(8-(2-
subject to rapid elimination from the circulation, with an elimination hydroxybenzoyl) amino) caprylate (SNAC) for oral treatment. To ac-
half-life of approximately 2 min [9]. Therefore, GLP-1 allowed the count for the relatively low bioavailability of semaglutide when
“proof-of-principle” that GLP-1 receptor stimulation is a suitable absorbed through the gastrointestinal tract, oral semaglutide needs to
method of reducing plasma glucose in subjects with type 2 diabetes. It be administered daily. This is the first GLP-1 RA approved for oral
also helped clarify the three main mechanisms leading to reductions in administration. At equivalent doses, subcutaneous and oral sem-
plasma glucose concentrations: (a) glucose-dependent insulinotropic aglutide seem to have similar effects on HbA1c, body weight, and
actions [5], (b) suppression of glucagon hypersecretion [7] except adverse events [19]. Details regarding the molecular structures of
during episodes characterized by hypoglycemia [10], and (c) a various GLP-1 RAs and additional pharmacokinetic information were
deceleration of gastric emptying, which was found to be associated summarized by Nauck and Meier in 2019 [20].The time between
with marked effects on post-meal glycemic excursions [11]. Relatively subcutaneous (or oral) administration and the occurrence of peak
early acute changes in appetite, satiety, and prospective food con- concentrations is displayed in Figure 1.
sumption by pharmacological doses of GLP-1 were described,
resulting in a corresponding reduction in caloric intake [12], thus 2.1. Recommendations for initial up-titration (Figure 2)
increasing the motivation to develop compounds mimicking the All GLP-1 RAs developed to date have been designed for standardized
physiology of GLP-1 resistant to the proteolytic inactivation by DPP-4 dosage recommendations applicable to most if not all patients. Nausea
and with slower elimination kinetics to allow for reasonable adminis- and vomiting were noticed as common side effects, mainly occurring
tration frequencies. As a product of serendipity, the peptide exendin-4 after the initiation of injection treatment or after increasing the dose.
from the saliva of a venomous lizard (Heloderma suspectum, the Gila Peak plasma concentrations may determine the time when these
monster) was found to be homologous to mammalian GLP-1 and able symptoms most likely occur. In the early stages, a strategy of starting
to bind and activate GLP-1 receptors [13,14]. Synthetic exendin-4 was exenatide with a lower than maintenance dose, slowly increasing to
named exenatide and, without further modification, was the first GLP-1 the desired steady state, was found to reduce problems with gastro-
receptor agonist approved to treat type 2 diabetes. The detailed intestinal adverse events. Since then, recommendations have been
background of the (patho)physiology of the incretin system and the developed for such an up-titration (dose escalation) approach to induce
history of the development of incretin-based glucose-lowering medi- tolerance before patients are exposed to higher doses of GLP-1 RAs
cations have recently been reviewed [15,16]. (Figure 2). Whether or not initial up-titration has to be recommended
for a given compound/preparation depends on these agents’ phar-
2. GLP-1 RAS AVAILABLE IN 2020 AND THEIR macokinetic properties. This is not necessary for preparations such as
PHARMACOKINETIC PROPERTIES (TABLE 1) once-weekly exenatide because the protracted action is the result of
slow absorption, while the elimination of circulating exenatide follows
Following the approval of exenatide to treat type 2 diabetes (USA: the same kinetics as known for un-retarded (b.i.d.) exenatide (Table 1).
2005; Europe: 2006), several pharmaceutical companies started Among those agents that have a long duration of action mainly through
diverse developments aiming at GLP-1 receptor stimulation with their slow elimination (long elimination half-life, see Table 1), those
greater effectiveness and longer duration of action. Exenatide needs with a relatively rapid time to peak concentration (Tmax < 24 h; applies
to be injected at least twice daily, which mainly provides active to short-acting GLP-1 RAs, liraglutide, and semaglutide [20]) are those
circulating concentrations covering two major meals every day, with with recommended dose escalation schedules, while those with
low levels between the two injections. Liraglutide, approved in 2009, slower absorption (dulaglutide and albiglutide; Tmax 48 h) (Figure 1)
was designed to provide a nearly unchanged amino acid sequence can be initiated at their final dose. This could be explained by the fact
compared to mammalian GLP-1. A free fatty acid side chain was that the GLP-1 RAs characterized by a free fatty acid side chain are
coupled to the peptide, which promotes binding to albumin in plasma injected as “free” (non-albumin-bound) compounds and that it takes
and interstitial fluid. Only a minor proportion (estimated 1e2%) of some time to reach a steadyestate equilibrium for binding to albumin.
liraglutide circulates in a free (non-albumin-bound) form, ready to Only after reaching this equilibrium, most of the compound is bound to
diffuse into tissues and bind receptors. The albumin-bound bulk forms albumin, and, as such, is unable to diffuse into tissues and elicit effects
a reservoir promoting prolonged action. Overall, the elimination half- (including adverse events).
life is approximately 13 h, making it a suitable preparation for once- Choosing the appropriate initial dose escalation schedule can have
daily injection. The next step was aiming at once-weekly injections of consequences for dose selection in phase 2 of clinical development
GLP-1 RAs. Exenatide was developed as a novel preparation with the programs, since doses carried on into phase 3 and suggested for
2 MOLECULAR METABOLISM xxx (xxxx) xxx Ó 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Table 1 e Characteristics of GLP-1 RAs that have been approved to treat type 2 diabetes as of 2020.
GLP-1 RA First approved (date) Molecular Reference amino Other important Elimination Administration Pharmaceutical Reference
weight (Da)c acid sequence components half-life schedule company
For subcutaneous injection
Short-acting compounds
Exenatide b.i.d. 2005 (USA); 4186.6 Exendin-4 None 3.3e4.0 h Twice daily AstraZenecai [21]
2006 (Europe); Byetta
Lixisenatide 2013 (Europe); Lyxumia; 4858.5 Exendin-4 Poly-lysine tail 2.6 h Once daily Sanofi [22]
2016 (USA); Adlyxin
Long-acting compounds/preparations
Liraglutide 2009 (Europe); 3751.2 Mammalian GLP-1 Free fatty acide 12.6e14.3 h Once daily Novo Nordisk [23]
2010 (USA); Victoza
Once-weekly 2012; BYDUREONa 4186.6 Exendin-4 Active ingredient 3.3e4.0 h f
Once weekly AstraZeneca i
[21]
exenatide encapsulated in
microspheres of
poly-(D,L-lactide-co-
glycolide)
Dulaglutide 2014; Trulicity 59670.6 Mammalian GLP-1 Immunoglobulin Fc 4.7e5.5 d Once weekly Eli Lilly and Company [24]
fragment
Albiglutide 2014 (Europe); Eperzan 72971.3 Mammalian GLP-1 Albumin 5.7e6.8 d Once weekly GlaxoSmithKline [25]
Tanzeum (USA)b
Semaglutide 2017 (USA); 4113.6 Mammalian GLP-1 Free fatty acide 5.7e6.7 d Once weekly Novo Nordisk [26]
2019 (Europe); Ozempic
For oral administration
Semaglutide (long- 2020; Rybelsus 4113.6 Mammalian GLP-1 Free fatty acide 5.7e6.7 d Once daily Novo Nordisk [27]
acting)
Fixed-dose combinations
With basal insulin (for subcutaneous injection)
Liraglutide/ 2014 (Europe); 3751.2d Mammalian GLP-1 Basal insulin 12.6e14.3 h Once daily (anytimeg) Novo Nordisk [28]
insulin degludec 2016 (USA); Xultophy
(iDegLira)
Lixisenatide/ 2016 (USA); 4858.5d Exendin-4 Basal Insulin 2.6 h Once dailyh Sanofi [29]
insulin glargine Soliqua 100/33;
(iGlarLixi) 2017 (Europe); Suliqua
a
Improved once-weekly auto-injector BYDUREON BCise was approved in 2018.
b
Marketing was discontinued in 2018.
c
Mammalian GLP-1: 3297.7.
d
For the GLP-1 RA component only.
e
Promoting binding to albumin.
f
Identical to the short-acting preparation.
g
Approximately the same time every day.
h
Before meals with the highest expected glycemic excursion.
i
Previously Amylin Pharmaceuticals, Eli Lilly and Company, and Bristol Myers Squibb.
Time to reaching maximum plasma concentrations

approval have to be effective as well as tolerable and safe. Less than
after injection (oral administration) optimal up-titration regimens may lead to (avoidable) side effects and
will most likely limit the upper dose range that is considered to have a
beneficial efficacy-side effect relationship.
d
* q
w Another question related to initial up-titration is whether it is needed
d q c when switching from one agent to another (e.g., for increasing efficacy
q i d ide q d e
s
q
w q
w
e b
t id de l ut ide t id
id
e id e or avoiding side effects). This is an issue that is not normally clarified
na ati ag ut lu ut ut by dedicated clinical trials. Therefore, recommendations mainly based
ise en sem agl ag gl i gl
x x r m la b on pharmacokinetic modeling are available [30].
Li E ral Li Se Du Al
O
2.2. Injection devices (Figure 3)
All GLP-1 RAs are delivered from pre-filled, dedicated pen injection
devices developed for each particular product. However, details are
considerably different for various products. They vary with respect to
one time (mainly once-weekly GLP-1 RAs) vs multiple usage and in
0 6 12 18 24 48 72 96
their ability to deliver one predetermined dose or whether it can be
Time after injection (or oral administration *) [h] used to choose between several dose settings. For once-weekly
exenatide, the microspheres containing the active drug need to be
Figure 1: Arrows indicate the time from injection (or oral administration in the case of resuspended in buffer. Originally, this meant reconstitution of the
oral semaglutide) to peak plasma concentrations (Cmax) for GLP-1 RAs (Tmax). For active ingredient in vehicle solutions, which are stored in different
references, please see [20]. Peak plasma concentrations may determine the time when vessels. An improved dual-chamber device has simplified this pro-
nausea and vomiting are observed with GLP-1 RA treatment. The extremely slow
cedure. The dulaglutide pen injection device has received attention
absorption of once-weekly exenatide does not allow identification of a peak.
Review
Exenatide b.i.d.
Lixisenatide
Liraglutide 0.6 mg 1.2 mg 1.8 mg q.d.
Exenatide once weekly 2.0 mg q.w.
Dulaglutide 1.5 mg q.w.a
Albiglutide 30 mg q.w.b
Semaglutide s.c. 0.25 mg q.w.c 0.50 mg q.w. 1.00 mg q.w.
Semaglutide oral 3 mg q.d. 7 mg q.d. 14 mg q.d.
0 2 4 6 8 10 12
Time after initiating treatment [weeks]
Figure 2: Recommendations issued in official package inserts regarding the necessity for slow up-titration of approved GLP-1 receptor agonists.
Figure 3: Optical appearance and properties of pen injection devices for approved GLP-1 receptor agonists (as mono substances or fixed-dose combinations with basal insulin).
Modified from Nauck and Meier 2019 [20]. *Thorough shaking was necessary to evenly resuspend the active ingredient. The ease of use was estimated semi-quantitatively based
on informal feedback from patients using these pen injection devices.
because of its single-use design and the needle, which is never visible time (Table 1). While this at first was thought to be mainly relevant with
throughout the injection procedure. Figure 3 depicts the visual respect to the injection frequency, thus representing a convenience
appearance and some essential properties as well as the authors’ issue, essential pharmacological differences were later identified that
evaluation of their ease of use of all available pen injection devices for suggested that both short- and long-acting GLP-1 RAs may have
GLP-1 RAs (free and fixed-dose combinations). specific advantages and indications [31]. By definition, short-acting
GLP-1 RAs (exenatide b.i.d. and lixisenatide) are characterized by
2.3. Classification as short- and long-acting GLP-1 RAs short-lived peaks in plasma drug concentrations following each in-
Since the parent compound of GLP-1 RAs, GLP-1, has a very short jection, with intermittent periods of near-zero concentrations. Thus, the
elimination half-life that precluded its clinical use outside settings timeeaction profile changes between periods (lasting a few hours)
characterized by continuous administration, compounds/preparations during which patients are exposed to effective circulating drug con-
with longer intervals between injections have been developed over centrations, and “resting” periods, during which GLP-1 receptors are
not activated. In contrast, long-acting GLP-1 RAs, once at a steady stimulation leads to desensitization, which probably begins early
state, are characterized by constantly elevated drug concentrations in a (within 4e24 h) and reaches its full expression after several weeks or
range leading to substantial GLP-1 receptor stimulation and only minor months [32]. Since the velocity of gastric emptying is tightly coupled to
fluctuations between injections (e.g., a 24-h period for liraglutide and a the absorption of nutrient carbohydrates, slowed gastric emptying
week-long period for semaglutide). Of note, this definition does not rest means reduced and/or delayed glycemic increases after meals. For
on the injection frequency alone but on the pharmacological kinetics. short-acting GLP-1 RAs, delayed gastric emptying is the main mech-
Consequently, once-daily lixisenatide is a short-acting compound, anism for post-meal reductions in plasma glucose rises [33]. It has
whereas once-daily liraglutide is a long-acting GLP-1 RA (Table 1). been claimed that short-acting GLP-1 RAs act preferentially on post-
One obvious consequence of the different temporal patterns of short- meal glycemic rises through their effect on gastric emptying, which
and long-acting GLP-1 RAs with reduced exposure during the night in are preserved over time [18,33,34], while there is substantial tachy-
short-acting compounds is the ability of long-acting GLP-1 RAs to more phylaxis for long-acting compounds [18,34]. First, long-acting GLP-1
profoundly lower fasting plasma glucose than short-acting GLP-1 RAs. RAs reduce post-prandial glucose as well, mainly through increasing
This was best exemplified by a study comparing un-retarded (b.i.d.) insulin and suppressing glucagon [31]. The effect on gastric emptying
and long-acting release (once-weekly) exenatide [18], although the relates only to meals, before which the short-acting GLP-1 RA has
differences were valid for the comparison of any short- and long-acting been administered (once daily with lixisenatide and twice daily with
GLP-1 RA (Figure 4). exenatide b.i.d.), with minor effects at most for other meals [33].
Another peculiarity relates to the effectiveness of GLP-1 RAs to slow Whether this translates into a net advantage is far from clear. In a
gastric emptying in light of tachyphylaxis: while intermittent stimulation recent meta-analysis comparing short- and long-acting GLP-1 RAs on
of GLP-1 receptors (short-acting GLP-1 RAs) is associated with pre- a basal insulin background, post-prandial glucose increases were not
served effects on gastric motility, even long-term continuous significantly different [35]. Conditions under which a reduction in post-
Figure 4: Comparison of approved GLP-1 RAs with respect to their effectiveness in reducing HbA1C (A), fasting plasma glucose (B), and body weight (C). A linear regression
analysis relating reductions in fasting plasma glucose to reductions in HbA1c is shown in panel D. A comparison of the reported coefficients of variation for reducing HbA1c and body
weight is displayed in panel E. All data are from clinical trials reporting head-to-head comparisons between various GLP-1 RAs (exenatide b.i.d. vs lixisenatide [36], exenatide b.i.d.
vs liraglutide [37], lixisenatide vs liraglutide [38], exenatide once-weekly vs liraglutide [39], albiglutide vs liraglutide [40], dulaglutide vs liraglutide [41], subcutaneous semaglutide
vs dulaglutide [42], and oral semaglutide vs liraglutide [43]) on a background of oral glucose-lowering agents. Data concerning the same GLP-1 RA were pooled using conventional
equations to calculate common means and their standard deviations.
Review
meal glycemic excursions through a lasting deceleration of gastric 2.4. Comparison between GLP-1 RA and insulin therapy
emptying cause an obvious advantage of short-over long-acting GLP-1 According to current recommendations, recently diagnosed type 2
RAs still need to be defined. diabetes should be treated with patient education instructing in
The effectiveness of short- and long-acting GLP-1 RAs for controlling favor of a healthy lifestyle including nutrition avoiding excess cal-
fasting plasma glucose and HbA1c in patients with type 2 diabetes ories and rapidly absorbed carbohydrates and physical exercise. At
otherwise treated with oral glucose-lowering agents was compared in this early stage or later, single (mostly metformin) or combination
relatively large head-to-head comparison trials conducted in patients therapy with oral glucose-lowering agents is recommended until
receiving oral glucose-lowering medications as background therapy. injectable therapy with more effective drugs (insulin or GLP-1 re-
Figure 5 shows representative data from these clinical trials. The ceptor agonists) becomes necessary. It was surprising that when
reduction in fasting plasma glucose was systematically more pro- meta-analyzing studies directly comparing insulin treatment (mainly
nounced with long-acting compounds. Consequently, HbA1c values basal insulin combined with oral agents) with any of the GLP-1
were reduced significantly more by long-acting GLP-1 RAs (since the receptor agonists, there was, at most, a minor difference in gly-
overnight period represented one-third of the 24 h period). Efficacy cemic effectiveness [44,45]. If anything, GLP-1 receptor agonist had
regarding reductions in fasting plasma glucose and HbA1c were highly a slightly better effect on reducing HbA1c. In addition, they uniformly
correlated (Figure 4D), underscoring the importance of controlling led to some weight loss, and were only associated with hypogly-
fasting plasma glucose to achieve acceptable overall glycemic control cemic episodes when combined with sulfonylureas or insulin. As a
based on commonly recommended target ranges. Similar conclusions factor contributing to more convenience, GLP-1 RAs can be
were derived from specifically assessing 4 head-to-head clinical trials employed using more or less standardized dosing instructions
comparing short- and long-acting GLP-1 RAs (depicted in Nauck and (including initial up-titration), while insulin needs to be individually
Meier 2019 [20]). titrated, with effective doses spread across a wide range. Some
features of (basal) insulin and GLP-1 RA therapy in combination with
oral glucose-lowering agents are summarized in Table 2. Of note,
basal insulin and GLP-1 RAs are similarly effective in patients
starting at very high baseline HbA1c values (although patients
selected by this criterion often fail to reach conventional target
ranges for HbA1c) [46]. Overall, these reasons form the basis of the
ADA/EASD recommendation to preferentially use GLP-1 RAs in type
2 diabetes patients failing on oral agents alone [47]. Exceptions are
circumstances suggesting type 1 diabetes or latent autoimmune
diabetes in adults (LADA) with severe insulin deficiency.
2.5. Combination with (basal) insulin therapy

Therapy with basal insulin may fail because it may be successful in
controlling fasting plasma glucose but does not sufficiently limit post-
prandial glycemic excursions. Treatment intensification can mean
adding one to three prandial insulin injections per day or adding a GLP-
1 RA to ongoing insulin treatment. Nevertheless, GLP-1 RA therapy
with a background of oral glucose-lowering medications may fail to
achieve glycemic targets as well. In this case, combining it with insulin
(mainly basal insulin) is a well-documented method of improving
fasting, post-prandial, and overall (HbA1c) glycemic control [51e57].
The combination of (basal) insulin with a GLP-1 RA is a highly effective
treatment even for advanced stages of type 2 diabetes. It should only
be used in patients needing a combination of two injectable treat-
ments, especially considering the costs of such a combination.
When a GLP-1 RA is added to (basal) insulin, the combination is as
effective as an intensified (basal bolus) insulin regime in terms of
HbA1c control, but with a much lower risk of hypoglycemia and weight
gain [58].
When insulin is added to a GLP-1 RA, it helps control fasting plasma
glucose. In combination with post-prandial effects of GLP-1 RAs
(through decelerating gastric emptying, stimulating insulin, or sup-
pressing glucagon secretion [31]), this provides excellent chances to
achieve the target ranges for fasting, post-prandial, and overall (HbA1c)
glycemic control. In studies comparing basal insulin and GLP-1 RAs
Figure 5: Meta-analysis comparing effects of short- and long-acting GLP-1 receptor alone and in combination with each other, the combination achieved
agonists added to basal insulin in HbA1c (A), HbA1c target (7.0%) achievement (B), the lowest HbA1c or highest HbA1c reduction and a body weight
fasting plasma glucose (C), and body weight (D). For each variable, the results were
transformation in between GLP-1 RA alone (lowest) and insulin alone
significantly better for long-acting compounds (liraglutide, once-weekly exenatide,
dulaglutide, and semaglutide based on 6 studies) compared to short-acting compounds
(highest) [59]. There is a risk of hypoglycemic episodes with this
(exenatide b.i.d. and lixisenatide based on 8 studies). Both studies with free and fixed- combination, which is higher than treating with GLP-1 RAs alone, but
dose combinations were analyzed. Modified from [50]. lower compared to insulin treatment alone [59].
The fact that a combination of a GLP-1 RA with basal insulin is a highly
Table 2 e Comparison of injectable treatments for type 2 diabetes with
basal insulin or GLP-1 receptor agonists (based on meta-analyses of head-
efficacious glucose-lowering treatment regime for advanced stages of
to-head comparisons [44,45]). type 2 diabetes has led to the development of fixed-dose combina-
tions. GLP-1 RAs that are usually injected once daily (liraglutide or
Criterion Treatment with Commentary
lixisenatide) were combined with basal insulin designed for once-daily
Basal insulin GLP-1 receptor injection (insulin degludec or insulin glargine), resulting in the fixed-
agonists
dose combinations iDegLira [28,59] and iGlarLixi [60,61]. Since in-
Glycemic control sulin must be titrated slowly as part of the dose-finding process, the
Fasting plasma After meticulous Substantial reduction An exception is
GLP-1 RA component of these fixed-dose combinations is titrated
glucose (FPG) titration, FPG can be achieved. semaglutide for once-
concentrations in Overall, slightly less weekly injection, slowly as well. This approach for introducing GLP-1 RA therapy has
the target range (for effective than insulin which lowered FPG resulted in fewer problems with nausea, vomiting, or diarrhea.
example, 80 more than insulin Apparently smaller steps of increasing GLP-1 RA exposure better
e110 mg/dl) can glargine [48] support an adaptation process increasing patients’ tolerance to such
often be reached
Prandial Can be reduced Reduced through Short-acting GLP-1
adverse reactions.
glycemic with appropriately deceleration of gastric RAs maintain their It has been postulated that short-acting GLP-1 RAs are particularly
excursions dosed basal insulin emptying (short-acting effect on gastric suited for combination with basal insulin because the strength of long-
GLP-1 RAs) and the emptying with acting compounds, a greater effect on fasting plasma glucose, is not
influence on insulin continued
needed in this combination since the role of basal insulin would be to
and/or glucagon administration, while
secretion [31] there is tachyphylaxis control fasting plasma glucose. However, the effect of slowing gastric
over days/weeks with emptying leading to slower absorption of nutrients (which is preserved
long-acting GLP-1 RAs over time with short-acting GLP-1 RAs) is a mechanism limiting post-
[18] meal glycemic excursion [31]. Notably, with short-acting GLP-1 RAs,
HbA1c Substantial Substantial reduction, A slightly better
reduction, often into often into the target reduction was shown
this effect only applies to the meal before which the agent has been
the target range range with GLP-1 RAs, injected. A recent meta-analysis described the advantages of
which might have combining long-acting GLP-1 RAs (compared to short-acting GLP-1
been caused by RAs) with basal insulin [50]. This applied to free combinations (dosage
insufficient titration of
determined separately for the GLP-1 RAs and basal insulin) as well as
basal insulin; long-
acting GLP-1 RAs fixed-dose combinations [50]. As depicted in Figure 5, not only HbA1c
achieve lower HbA1c was lowered significantly more and HbA1c targets were achieved in a
concentrations [44] higher proportion of patients, but also fasting plasma glucose con-
Dosing By titration, often Standard dosage Hypoglycemia may be centrations and body weight were controlled better with long-acting
starting with recommendations are dose-limiting for
approximately 10 available for individual insulin, while nausea
GLP-1 RAs [50]. In addition, the risk of hypoglycemic episodes and
IU/d. Effective GLP-1 RAs (often and vomiting may gastrointestinal side effects was slightly, but significantly lower with
doses are including some slow suggest using lower long-acting GLP-1 RAs [50].
somewhere up-titration during the doses than generally
between 15 and initial period) recommended for
2.6. Weight loss induced by GLP-1 RAs
200 IU/d and GLP-1 RAs
cannot be precisely Intracerebroventricular [62] and peripheral administration of GLP-1
predicted based on [12] and GLP-1 RAs [20,63] reduces appetite and prospective food
clinical consumption, increases satiety and a feeling of abdominal fullness,
characteristics (for and limits caloric intake under conditions of ad libitum feeding. All GLP-
example, BMI)a
Frequency Usually once daily Between twice daily Variable for GLP-1 RAs
1 RAs after longer-term treatment lead to weight loss but in varying
(“bedtime” insulin) (exenatide b.i.d.) and because of their degrees (Figure 4). Thus, GLP-1 RAs are unique in promoting weight
once weekly differing elimination loss while reducing the glycemia level, which in turn limits glucosuria
kinetics (energy lost through urinary glucose excretion) and therefore should be
Changes in body Increases by 1 Decreases by 2e6 kg Within the range
associated with weight gain. Most other glucose-lowering agents,
weight e2.5 kg on average on average typical for each GLP-1
RA, individual weight except for sodium/glucose cotransporter-2 (SGLT-2) inhibitors, usually
loss is highly variable lead to some weight gain (sulfonylureas, insulin, or thiazolidinediones)
Risk of Hypoglycemic Hypoglycemic Clinically meaningful or are weight neutral (metformin, DPP-4 inhibitors, or a-glucosidase
hypoglycemic episodes are episodes are reported hypoglycemia with inhibitors) [47]. Liraglutide (at doses somewhat higher than used to
episodes reported in in approximately 23% GLP-1 RAs heavily
approximately 43% of patients, very much depends on a co-
treat diabetes mellitus) is also approved for pharmacological obesity
of patients, in part depending on the medication with therapy [64,65]. Semaglutide, the GLP-1 RA with the highest efficacy
depending on the proportion receiving sulfonylureas [44] regarding weight loss in clinical trials of type 2 diabetes patients
proportion receiving sulfonylurea treatment (Figure 4), is also undergoing evaluation as a weight-loss agent in
sulfonylurea [44]
obese subjects without diabetes mellitus [66e68].
treatment [44]
Nausea and Rare Nausea (up to 20%) Gastrointestinal side The quantitative differences in body weight reduction typically ach-
vomiting as and vomiting (up to effects lead to ieved with different GLP-1 RAs critically depend on the respective
adverse events 10%) mainly occur medication withdrawal doses selected in phase 2 studies. Since the primary indication for
after initiating in approximately 5 using GLP-1 RAs is type 2 diabetes, dose selection has mainly
treatment or e10% [49]
associated with
addressed glycemic control (HbA1c reduction). Some data suggest that
increases in dosage while HbA1c reduction plateaus at relatively lower doses, higher doses
a
Algorithms are available that aid the titration process.
may still be more effective for weight loss [69,70]. This is one
Review
important reason for testing higher doses, for example, dulaglutide

Table 3 e Mechanisms involved in GLP-1 RA-associated appetite and
[71], to seek approval for more effective, higher doses of GLP-1 RAs for weight reduction as reported in a recently published comprehensive study
those who tolerate them. focusing on the effects of semaglutide (compared to liraglutide) on diet-
The fact that some GLP-1 RAs have particularly weak effects with induced obesity in mice (based on Secher et al., 2014 and [72] and Gabery
respect to body weight (e.g., albiglutide), whereas other compounds et al., 2020 [73]).
seem to have more pronounced effects (e.g., semaglutide) even if their Aspects of the Findings Explanation/
glucose-lowering effects are similar, has sparked interest in charac- mechanism of GLP-1 commentary
terizing the mechanism of action. It is obvious that appetite-and RA-induced weight
weight-reducing effects involve uptake into specific brain regions loss
and interaction with CNS neural circuits involved in the homeostatic or Access of peripherally No transport across the Absence of GLP-1 Rs in
hedonic [77] regulation of energy household and food intake. Table 3 circulating GLP-1 RAs bloodebrain barrier (BBB) brain endothelial cells
into the central Uptake of liraglutide and Uptake of liraglutide and
summarizes recent insights gained from comprehensive studies
nervous system semaglutide into selected semaglutide into
characterizing semaglutide’s (and liraglutide) effects on diet-induced brain areas: (a) not protected selected brain areas is
obesity in rodents [72,73]. These findings point to a role of the by the BBB (circum- similar, but not fully
arcuate nucleus within the hypothalamus, area postrema (AP), and ventricular organs); (b) pro- identical (e.g., sem-
nucleus tractus solitarii (NTS) for the influence of systemically tected by the BBB: for aglutide had a distribu-
example, nucleus arcuatus tion extending more
administered GLP-1 RAs on appetite, satiety, calorie intake, and body (hypothalamus), area post- laterally and into poste-
weight as schematically summarized in Figure 6. In this model, GLP-1 rema, nucleus tractus sol- rior portions of the nu-
RAs seem to be effective at preventing meal initiation by suppressing itarii, and dorsal motor cleus arcuatus)
the activity of NPY/agouti-related peptide (AgRP) producing neurons in nucleus of the vagus nerve
(brain stem)
the arcuate nucleus and inducing meal termination in the lateral
A potential role of tanycytes
parabrachial nucleus (PB). Signals reaching the PB originate from the in mediating uptake of sem-
arcuate nucleus of the hypothalamus and brain stem (AP and NTS). aglutide into some brain
POMC/CART neurons expressing GLP-1 receptors activate PB neurons areas
and directly or indirectly suppress NPY/AgRP neurons [72,73], leading Access of GLP-1 RAs to Brain areas with a high up- Uptake of fluorescently
GLP-1 receptors in take of semaglutide are labeled semaglutide is
to disinhibition of suppressive signals to the PB (Figure 6). Recent data the brain equipped with GLP-1 substantially reduced in
indicated subtle differences in how the brain interacts with liraglutide receptors (mainly in the GLP-1 R/- animals
and semaglutide [73], which may help explain why these two GLP-1 hypothalamus and hindbrain)
RAs differ in their efficacy to reduce body weight (Figure 4). This in- Direct effects of GLP-1 POMC/CART neurons are As previously shown for
RAs on the depolarized (stimulated); liraglutide
formation may guide the design of GLP-1 RAs or related pharmaco-
hypothalamus NPY/AgRP neurons are
logical agents with even more pronounced weight loss efficacy. It still (nucleus arcuatus) hyperpolarized (inhibited)
remains unclear why albiglutide has a weaker weight-lowering effi- Neuronal activation in C-Fos activation observed in Immediate consequence
cacy than other GLP-1 RAs (Figure 4). brain areas accessible the area postrema and nu- of GLP-1 R engagement
Human studies have confirmed the ability of GLP-1 RAs to influence for GLP-1 RAs cleus tractus solitarii (brain
stem)
food choices (toward a selection of less energy-dense healthier foods) Neuronal activation in C-Fos activation in the bed These are brain regions
[66,78]. However, in contrast to some recent findings in rodents [73], brain areas not nuclei of the stria terminalis, that have been identified
studies in human subjects did not observe any interference of sem- directly accessible for central amygdala nucleus, as part of an appetite-
aglutide treatment with a reduction in energy expenditure that usually GLP-1 RAs midline group of the dorsal regulation pathway
(“secondary thalamus, parasubthalamic related to meal
accompanies weight loss (as one important mechanism for main-
activation”) nucleus, and parabrachial termination [74]
taining body weight close to a pre-determined “set point”) [66,79]. nucleus (CGRP-expressing
Twelve weeks may not be sufficient to reach a steady state of weight neurons)
reduction and possibly compensatory mechanisms. Of interest are the Food intake and body Reduced (strong initial effect Reduced caloric intake
results of questionnaires indicating that obese subjects had fewer food weight and some attenuation over is the main mechanism
time); substantial weight leading to weight loss
cravings and could better resist food cravings while treated with reduction compared to pla- with GLP-1 RAs
semaglutide [66]. The answers point to the fact that eating was cebo treatment
considered less pleasurable during treatment with semaglutide [66]. Food preference Semaglutide reduced intake These results suggest
This could be in line with functional magnetic resonance imaging of chocolate bars in favor of that GLP-1 RAs may
chow promote healthier food
showing that GLP-1 R activation decreases anticipatory food reward
choices
(the anticipated pleasure of eating certain meals) and increases Energy expenditure Weight loss induced by Interferes with an
consummatory food reward (the pleasure offered by eating a meal) caloric restriction leads to a effective compensatory
[80]. The regulation of energy intake thus is not only subject to ho- compensatory reduction in mechanism counter-
meostatic regulation (nervous system circuits attempting to maintain energy expenditure acting weight loss;
Weight loss induced by needs to be confirmed in
unchanged body weight), but also interacts with the brain reward semaglutide only transiently human studies
system [80e84]. did so: energy expenditure
The robust effects of GLP-1 RAs to reduce body weight, usually by 2e returned to baseline levels
7 kg (or % of initial body weight) on average in type 2 diabetes, have within a week
led to the exploration of GLP-1 RAs as a novel pharmacological BBB: bloodebrain barrier, GLP-1 R: glucagon-like peptide-1 receptor, GLP-1 RA: GLP-
treatment in obese but non-diabetic subjects often with impaired 1 receptor agonist, POMC/CART: proopiomelanocortin/cocaine- and amphetamine-
fasting glucose or glucose tolerance (“prediabetes”). Based on the regulated transcript, NPY/AgRP: neuropeptide Y/agouti-related peptide.
observation that doseeresponse relationships have shown a plateau

for glycemic control at lower doses than for body weight reduction,
Figure 6: Schematic diagram demonstrating how various methods of GLP-1 or GLP-1 RA administration into the general circulation can reach and influence brain areas involved in
the regulation of energy intake and expenditure [72,73]. (A) Evidence also suggests that GLP-1 receptors in the hepatoportal region [75] (B) and on afferent parasympathetic nerve
endings in the intestinal mucosa (C) [76] may generate central nervous system signals influencing insulin secretion and metabolism. Stimulatory signals (þ) are shown in green,
inhibitory () signals are depicted in red, and afferent parasympathetic (vagal) signals are denoted in blue. See the text for a more detailed explanation of the mechanisms.
Review
higher doses have been employed to treat obese subjects. Daily doses some patients feel motivated for further attempts to improve their
up to 3.0 mg are approved for liraglutide (1.8 mg is the maximum dose eating behavior and lifestyle because of a realistic chance of success.
for treating type 2 diabetes) [65], and clinical trials have tested sem- Other patients may instead believe that the GLP-1 RA will ameliorate
aglutide at up to 0.4 mg per day (that is, corresponding to 2.8 vs their obesity problem without them contributing by willingly restricting
1.0 mg per week for type 2 diabetes) [68]. Doses of up to 4.5 mg per caloric intake and engaging in physical activity. This is a hypothesis
week (vs a maximum of 1.5 mg for type 2 diabetes) are being explored worth sparking clinical studies, as would be developing a dedicated
for dulaglutide [85]. In subjects tolerating these higher doses of GLP-1 patient education program aiming at optimizing weight reduction with
RAs, substantially greater reductions in body weight were observed GLP-1 RAs in type 2 diabetes and in particular when using them in
than with “conventional” doses typically employed to treat type 2 obese, prediabetic subjects to prevent progression to type 2 diabetes
diabetes. Impaired glucose tolerance often improves while subjects [68,86,92].
receive this type of treatment, most likely explained by the glucose-
lowering properties of GLP-1 RAs [65,86]. Whether this means a 2.7. Gastrointestinal and other adverse events
true interference with or a delay in the progression to diabetes needs to Side effects most reported with GLP-1 RAs are nausea, vomiting, and
be studied in trials assessing the long-term consequences of with- diarrhea, often summarized as gastrointestinal adverse events. They
drawing GLP-1 RA treatment. GLP-1 RAs need to be continuously are typically most prominent when initiating treatment with (any) GLP-
administered after induction of weight loss. After discontinuation of this 1 RA or after increasing the dose (e.g., during recommended up-
pharmacological treatment, body weight will revert to baseline values titration regimens). Since these symptoms can occur in fasting sub-
or at least close to baseline values within a few months [87]. jects, they are probably not related to the effects of GLP-1 RA treatment
It has often been overlooked that the individual weight reduction on gastrointestinal functions (e.g., deceleration of gastric emptying) but
response of patients with type 2 diabetes treated with GLP-1 RAs is instead are caused by direct interactions with CNS GLP-1 receptors
more variable than the reduction in HbA1c. This is obvious when (Figure 6) most likely located in the brain stem (area postrema).
treatment-related weight and HbA1c changes are plotted individually Nausea is typically reported in up to 25% and vomiting or diarrhea in
[18,88]. It can also be concluded from a higher coefficient of variation up to 10% of subjects treated with GLP-1 RAs [20,49]. For most pa-
(the standard deviation divided by the mean value expressed as a tients, these are short, self-limited episodes that cease spontaneously,
percentage) depicted in Figure 4E. Why some patients do not reduce even with continued treatment. The time point of occurrence is
their body weight at all when treated with GLP-1 RAs while others probably related to the time characterized by maximum drug con-
respond with weight loss very much exceeding the mean values re- centrations typically occurring at Tmax following several hours to days
ported in clinical trials (for example, Figure 4) can only partially be after each injection (Figure 1). The probability of these side effects
answered with current knowledge. Schlogel et al. [89] examined re- varies with sudden incremental exposure to GLP-1 RAs. An often-used
sponders and non-responders (with respect to exenatide’s effect on recommendation to avoid these adverse events is a standardized,
energy intake) and found hypothalamic effects only in responders. This slowly increased exposure through up-titration regimens (Figure 2),
hints at a biological reason most likely related to the mechanisms which have been shown to mitigate gastrointestinal side effects.
summarized in Table 3 and could be the result of genetic poly- Experience with fixed-dose combinations with basal insulin (which
morphisms, for example, regarding GLP-1 receptors or other compo- must be titrated much more slowly) underscore the effectiveness of
nents of the signal transduction pathway. this approach.
However, the weight-lowering effects of GLP-1 RAs can probably be Summarizing adverse event reporting from clinical trials examining
modulated by lifestyle measures aiming at reduced calorie intake [90], GLP-1 RAs discloses subtle differences in the risk of these side effects
although a systematic examination of the combined efficacy of initi- depending on the short- (worse) vs long-acting nature (better) back-
ating treatment with GLP-1 RAs and patient education aiming at ground medication (worse in combination with metformin or insulin)
optimizing the weight-reducing effects of GLP-1 RAs is still lacking (or that are also related to the individual compound/preparation [49].
has failed to provide convincing benefits [91]). Obese patients with In part related to adverse events, patients randomized to GLP-1 RA
type 2 diabetes often tried various dietary approaches to lose weight treatment often discontinue this medication. Table 4 shows reported
and failed. One possible explanation for the wide spectrum of weight figures from cardiovascular (CV) outcome trials with GLP-1 RAs, the
loss observed with initiating treatment with GLP-1 RAs could be that largest trials available reporting the longest durations of exposure to
Table 4 e Proportions of patients randomized to GLP-1 RA treatment in CV outcome trials discontinuing study drug treatment, proportion of the follow-up period
during which patients were exposed to the study drug, and proportions discontinuing due to adverse events.
GLP-1 RA Proportion of patients permanently Proportion of follow-up period Proportion of patients discontinuing the Trial/reference
discontinuing the during which the study drug study drug because of
study drug [%]a was taken [%] adverse events [%]
Lixisenatide 27.5 90.5 11.4 ELIXA [95]
Liraglutide n.p. 84 9.5 LEADER [96]
Once-weekly exenatide 43.0 76 4.5c EXSCEL [97]
Dulaglutide 26.8 82.2 9.1 REWIND [98]
Albiglutide 24.5 87 8.6 HARMONY Outcomes [99]
Semaglutide s.c. 21.3 86.5 13.2 SUSTAIN-6 [100]
Oral semaglutide 15.3 n.p.b 11.6 PIONEER-6 [101]
n.p.: Not presented.
a
Not counting transient “drug holidays.”
b
75% received the study medication for more than 1 year (total follow-up of 15.3 months).
c
Counting only gastrointestinal adverse events. No CV outcome trial has been reported for exenatide b.i.d. (approved before these studies became mandatory).
GLP-1 RAs. The proportions of patients reporting adverse events were Another differentiator is the proportion of patients with pre-existing
not generally different from shorter clinical trials [49]. This indicates cardiovascular damage, albeit defined by previous events or sup-
that while the frequency and severity of side effects can be suc- ported by functional testing and/or imaging, which ranged from 31%
cessfully modulated through optimized up-titration regimens, a certain (REWIND [98]) to 100% (ELIXA [95] and HARMONY Outcomes [99]) and
percentage of patients does not tolerate this treatment with the current obviously had an important impact on the CV event rate observed
regimens of initiating GLP-1 RA. Interestingly, in a recent study during the trials.
allowing individual titration of oral semaglutide, most patients dis-
continuing this treatment did so after exposure to the lowest (initial) 3.1. Heterogeneity regarding principal results from CV outcome
dose of 3 mg per day [93]. This may indicate that the sensitivity of trials comparing GLP-1 RAs with placebo
patients toward developing gastrointestinal adverse events is consid- Figure 7A displays hazard ratios (active treatment vs placebo) for MACE
erably heterogeneous, such that some patients fail to tolerate low and their 95% confidence intervals for all published CV outcome trials
doses, while for others, higher doses than currently used may offer with GLP-1 RAs. With the exception of lixisenatide, all other GLP-1 RAs
better effectivity without increasing side effects. Along these lines, at least show a trend of a reduced incidence of MACE events, which
higher doses of some GLP-1 RAs are being explored, especially to was significant in four studies and not significant in 2 additional
further reduce body weight [65,67,68,71,86]. The reported nausea, studies. Hence, the results are, from a clinical perspective, quite
vomiting, and diarrhea rates are generally lower in Japanese than heterogeneous and suggest that some GLP-1 RAs are more suitable to
Caucasian populations, suggesting that the cultural background and prevent CV events than others. Assessing heterogeneity mathemati-
eating behaviors may also have an impact on the induction of nausea cally as part of the meta-analysis, however, resulted in I2 values
with GLP-1 RAs [94]. suggesting at most moderate heterogeneity. Our interpretation is that
When GLP-1 RAs were introduced as novel agents to treat type 2 comparing the various trials indicates a common mechanism of action,
diabetes, there was uncertainty about several potential adverse but important differences related to pharmacokinetic properties (one
effects such as acute pancreatitis, pancreatic cancer, and thyroid injection per day of lixisenatide does not fully cover a 24 h period),
cancer [102,103]. The availability of large databases from ran- optimized dosages as a result of phase 2 dose-finding studies
domized CV outcome studies that defined pancreatitis, pancreatic (probably applies to 2 mg per week of once-weekly exenatide), and
cancer, and thyroid cancer as “adverse events of special interest” drug discontinuation rates impact the degree of CV benefit that can be
with protocols carefully adjudicating suspected cases has reduced achieved with individual compounds/preparations as suggested by
these concerns since they uniformly reported hazard ratios of these Caruso et al. [109]. Remarkably, the reduction in MACE events with
adverse events not significantly different from 1.0 [104]. In retro- albiglutide is very much comparable if not more pronounced than with
spect, an elevation in amylase and/or lipase activity commonly other effective GLP-1 RAs (Figure 7A) despite its reduced ability to
observed with GLP-1 RAs [105,106] together with abdominal lower HbA1c, fasting plasma glucose, and body weight in clinical trials
symptoms typically triggered by GLP-1 RAs may have led to the (Figure 4) [40]. When choosing a GLP-1 RA to prevent CV events, one of
suspicion of pancreatitis. Since 2 diagnostic criteria are sufficient the compounds significantly reducing MACE should be selected. Lir-
for this diagnosis, pancreatitis may have been diagnosed even in the aglutide (LEADER trial) was unique in not only significantly reducing
absence of imaging results supporting this diagnosis [105]. MACE events, but also CV and all-cause mortality [96]. Semaglutide
Nevertheless, thyroid C cells express GLP-1 receptors [107], and (subcutaneous, SUSTAIN-6 [100], and oral, PIONEER-6 [101]) trials
subjects at risk of (rare) medullary thyroid cancer (e.g., based on showed impressive results, especially considering their small sample
personal or family history or genetic testing) should not be treated sizes and short durations. This was due to their primary ambition to
with GLP-1 RAs. These subjects were consequently excluded from demonstrate safety, the minimum requirement for approval, which
clinical trials with GLP-1 RAs. requires smaller patient numbers, a shorter trial duration, and fewer
events. This preliminary nature makes additional larger trials neces-
3. CARDIOVASCULAR OUTCOME STUDIES sary to fully characterize the potential to prevent CV complications of
type 2 diabetes (oral semaglutide: SOUL, ClinicalTrials.gov NCT
All GLP-1 RAs were approved for treating type 2 diabetes patients after 03914326) or obesity (once-weekly semaglutide s.c.: SELECT Clin-
2008 (except for exenatide b.i.d., which was approved in 2005). icalTrials.gov NCT03574597).
Therefore, all of the compounds/preparations had to provide results of Individual CV outcome trials were not powered to assess single CV
dedicated cardiovascular outcome studies supporting at least the endpoints, but a composite endpoint such as MACE. However, a
cardiovascular safety of these medications in the target population and meta-analysis pooling results from all individual trials provided some
compared to placebo both on a background of standard of care insight that CV events can generally be prevented by GLP-1 RA
(allowing any additional glucose-lowering medication necessary to treatment [108]. As shown in Figure 7B, across all of the trials,
meet targets recommended by current guidelines). The typical primary significant reductions by 9e16% in the incidence of acute myocardial
endpoint was major adverse cardiovascular events (MACE: time to first infarction, stroke, cardiovascular, and even all-cause death could be
event of either CV death or non-fatal myocardial infarction or stroke). achieved for the GLP-1 RA class as a whole, while in the individual
According to guidelines by the US Food and Drug Administration, trials, these effects on individual cardiovascular outcomes were only
definite proof of CV safety would be a hazard ratio for MACE near or occasionally significant. However, the number of such events
below 1.0 with a confidence interval not exceeding 1.3 (equivalent to a (myocardial infarction, stroke, CV death, etc.) in individual trials was
30% elevation in risk). If a study provides preliminary proof of safety too low to provide the power to detect significant differences. This
(upper limit of the confidence interval below 1.8), another CV outcome also applied to a reduction in the hospitalization for heart failure,
study aiming at definite proof is required. Depending on the ambitions, which was not significant in any of the individual trials, but in the
studies with different patient numbers and durations are needed. This meta-analysis (hazard ratio, 0.91; 95% confidence interval, 0.83e
explains the heterogeneity in study designs, sample sizes, and follow- 0.99). This figure contrasts with the consistent z35% risk reduction
up periods between the trials summarized in Figure 7 [20,108]. for hospitalization for heart failure in all studies employing SGLT-2
Review
Figure 7: Results of cardiovascular outcome studies comparing GLP-1 RAs with placebo on a background of standard of care. (A) Reduction in major adverse cardiovascular
events (MACE: time to first event) in published individual clinical trials. (B) Results of a published meta-analysis [108] analyzing various cardiovascular endpoints across all of the
clinical trials shown in panel A. MACE (a combination of either cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) was the primary endpoint in all studies.
Meta-analysis results are supplemented with I2 and related p values indicating the heterogeneity of the analysis of individual endpoints (column of panels to the far right) as
reported in [108].
inhibitors [110,111]. Of note, patients with NYHA IV heart failure were quantitatively similar regardless of the patients’ history of CV events
excluded from the CVOTs with GLP-1 RAs, such that no firm con- (p for interaction was 0.97). Those with or without CV co-morbidities
clusions could be drawn regarding these patients. In light of the at baseline had identical risk reductions (that for both subgroups just
dedicated studies of liraglutide in patients with advanced heart fail- missed statistical significance) [98]. These data suggest a potential
ure, which not only failed to prove benefits, but suggested some to prevent CV complications even in lower-risk type 2 diabetes pa-
potential for harm caused by GLP-1 RAs [112,113], GLP-1 RAs are tients, yet fall short of definite proof.
usually not recommended as first choice if the objective is to prevent Along the same lines, a subgroup analysis within the meta-analysis by
heart failure complications. Indeed, the small increase in heart rate Kristensen et al. [108] identified no statistically significant heteroge-
observed with GLP-1 RA treatment may represent an unfavorable neity for the effect of GLP-1 RAs on MACE between primary vs sec-
mechanism in patients with advanced (NYHA III/IV) heart failure [34]. ondary prevention (p ¼ 0.24) The more recent meta-analysis by
Instead, the pattern of effects observed in CV outcome trials suggests Marsico et al. [114] strengthened this conclusion. However, since the
a primary mode of action preventing complications of atherosclerosis absolute risk reduction was smaller in the primary prevention popu-
such as ischemic events (myocardial infarction and stroke) and lation, it remains to be ascertained whether this intervention would be
associated mortality (vide infra). cost-effective in lower-risk patients.
Most CV outcome trials with GLP-1 RAs recruited patients with type
2 diabetes characterized by established CV disease (e.g., previous 3.2. Mediation analyses aiming to define the mechanism(s) leading
CV events) or indicators of a high risk of CV events. These studies to beneficial cardiovascular effects of GLP-1 RAs
were originally primarily designed as safety trials, and accruing a As previously demonstrated in detail [115], GLP-1 RAs modify a
large number of CV events in high-risk patients was one strategy to number of risk factors for cardiovascular complications, including body
limit the sample size and duration of these trials. Therefore, the weight reduction, lower systolic blood pressure, reduced plasma LDL
results of these trials cannot be extrapolated to the general popu- cholesterol and triglyceride concentrations, and improved glycemic
lation of type 2 diabetes patients including those with short disease control (reductions in fasting and post-meal plasma glucose resulting
duration and lack of CV comorbidities. The REWIND study (employing in lower HbA1c; see Figure 4). Thus, a reduction in the incidence of
dulaglutide as the GLP-1 RA) was exceptional in having recruited a ischemic events could be the consequence of a more beneficial risk
mixed population with 31.5% with and 68.5% without pre-existing profile under treatment with GLP-1 RAs. Mediation analysis is an
atherosclerotic vascular damage [98]. Subgroup analyses of the approach to identify potential mediators that might explain the findings
REWIND trial (dulaglutide vs placebo, both on a background of observed in terms of endpoints. While several mathematical ap-
standard of care) highlighted that dulaglutide was able to induce a proaches have been developed, their common aim is to show that
significant MACE reduction in the overall study population and taking into account the changes in a potential mediator reduces the
effect size with respect to the endpoint of interest. Potential mediators especially since it has been difficult to establish a relationship of HbA1c
are variables measured in the trial that are differentially affected by reduction with cardiovascular benefits in other glucose-lowering
active drugs and placebo. For example, GLP-1 RAs reduce systolic medications [118].
blood pressure by 2e4 mmHg compared to placebo treatment [115]. For CV outcome studies of GLP-1 RAs, a relationship that links the
Considering this reduction in systolic blood pressure, if the difference magnitude of the HbA1c reduction achieved (versus placebo) to the
in MACE outcomes is reduced, it can be concluded that a reduction in hazard ratio for major adverse CV events was suggested by Caruso
systolic blood pressure mediates the prevention of MACE. If the effect et al. [119]. In particular, they identified a relationship between the
is nullified, this mechanism is responsible for 100% of the effect, but mean reduction in HbA1c in individual trials and the corresponding
partial mediation is also possible. hazard ratio for stroke [119]. Figure 8 presents a similar analysis,
Using slightly different approaches, mediation analyses have been however, including CV outcome studies with DPP-4 and SGLT-2 in-
published on the effects of liraglutide in the LEADER trial [116] and the hibitors. Remarkably, these additional data points were positioned
effects of dulaglutide in the REWIND study [117]. Interestingly, both along the same regression lines, and the relationship between the
analyses concluded that HbA1c reduction was a potential mediator, reduction in HbA1c and MACE (Figure 8A) or stroke (Figure 8C)
responsible for up to 82% of the total effect. A reduction in urinary remained significant. Similar trends of non-fatal acute myocardial
albumin excretion was found to be another potential mediator in the infarction and CV death were non-significant. A significant reduction in
LEADER trial (responsible for up to 33% of the total effect). Of note, any hospitalizations for heart failure was restricted to SGLT-2 inhibitors and
potential mechanism that does not leave a measurable trace or has not independent from reductions in HbA1c (Figure 8F). Such an analysis
been assessed in a given trial will never be identified as a potential may not only confirm the relationship initially observed by Caruso et al.
mediator using this approach. This applies to intravascular changes [119], but may also explain why DPP-4 inhibitors and SGLT-2 inhibitors
associated with the progression of atherosclerosis unless they are did not consistently reduce MACE [110,111,115]. Given that all of the
accompanied by, for example, inflammatory responses, which can be CV outcome trials aimed at glycemic equipoise (similar if not identical
identified by measuring C-reactive protein or inflammatory cytokines glycemic control for active drug and placebo treatment), only trials with
(which was not done in any of the CV outcome trials of GLP-1 RAs). potent glucose-lowering medications such as GLP-1 RAs, which failed
Hence, identifying HbA1c reduction as a potential mediator of CV to achieve glycemic equipoise, underscored the potential for a CV
benefits induced by GLP-1 RAs leaves a number of open questions, benefit.
Figure 8: Regression analysis of differences achieved in HbA1c concentrations between patients treated with placebo and active drug vs hazard ratios for major adverse car-
diovascular outcomes (MACE; A), cardiovascular death (B), non-fatal stroke (C), non-fatal myocardial infarction (D), and hospitalization for heart failure (E) reported from car-
diovascular outcome studies with GLP-1 receptor agonists (red), SGLT-2 inhibitors (blue), and DPP-4 inhibitors (green). Significant associations are shown for MACE (A) and non-
fatal stroke (C) with similar slopes of the regression lines, while for cardiovascular death (B) and non-fatal myocardial infarction (D), a less prominent, non-significant correlation
resulted from the analysis. Regarding hospitalization for heart failure (E), hazard ratios did not vary with HbA1c reduction. Analyzing GLP-1 receptor agonists only resulted in
significant correlations for MACE and stroke as well as previously reported by Caruso et al. [119] but not for the other endpoints. Numbers in symbols identify the clinical trials: 1:
SUSTAIN-6 (subcutaneous semaglutide) [100], 2: PIONEER-6 (oral semaglutide) [101], 3: REWIND (dulaglutide) [98], 4: LEADER (liraglutide) [96], 5: EXCSEL (once-weekly exe-
natide) [97], 6: ELIXA (lixisenatide) [95], 7: EMPA-REG Outcomes (empagliflozin) [120], 8: DECLARE-TIMI-58 (dapagliflozin) [121], 9: CANVAS program (canagliflozin) [122]; 10:
VERTIS-CV (ertugliflozin, presented at the 80th scientific session of the American Diabetes Association); 11: EXAMINE (alogliptin) [123], 12 CARMELINA (linagliptin) [124], 13:
SAVOR-TIMI-53 (saxagliptin) [125], and 14: TECOS (sitagliptin) [126].
Review
3.3. Mechanisms explaining cardiovascular benefits GLP-1 receptor stimulation. Various steps and mechanisms involved in
Understanding the robust interference of GLP-1 RAs with the pro- atherogenesis [127] are displayed in Figure 9A, while the effects of
gression and complications of atherosclerosis requires detailed GLP-1 receptor stimulation in arterial vessel walls are shown in
knowledge of the pathomechanisms involved and consequences of complementary Figure 9B.
Figure 9: Mechanisms driving the development of atherosclerotic lesions in patients with type 2 diabetes (A) and effects of GLP-1 RAs on the progression of atherogenesis and the
development of its complications (B). See the text for further details on the mechanisms involved and references to the supporting literature. EC: endothelial cell, eNOS: endothelial
nitrous oxide synthase, ICAM-1: intercellular adhesion molecule-1, IL: interleukin, KLF-2: Krüppel-like factor-2, LDL: low-density lipoprotein, MCP-1: monocyte chemoattractant
protein-1, NO: nitrous oxide, oxLDL: oxidized low-density lipoprotein, ROS: reactive oxygen species, TNF-a: tumor necrosis factor, VCAM-1: vascular cell adhesion protein 1, VSMC:
vascular smooth muscle cell.
3.4. Atherogenesis in patients with type 2 diabetes (Figure 9A) vulnerability of atherosclerotic lesions in animal models characterized
LDL cholesterol is transported across the intima layer of arterial blood by rapidly progressive atherosclerosis was substantially reduced by
vessels and in part oxidized to oxidized LDL particles (oxLDL) through GLP-1 RA [160]. Studies in humans have partially confirmed anti-
reactive oxygen species (ROS). Contact of monocytes and macro- inflammatory [162] and anti-atherosclerotic actions of GLP-1 RAs
phages with oxLDL and ROS promotes further infiltration of monocytes [163].
by secreting adhesion molecules such as vascular cell adhesion pro-
tein 1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), 4. RENAL EFFECTS OF GLP-1 RAS
intercellular adhesion molecule 1 (ICAM-1), and E-selectin. Stimulated
by oxLDL, monocytes transform into macrophages. M1 macrophages The discovery of beneficial renal effects using GLP-1 RAs is a recent
produce pro-inflammatory cytokines such as tumor necrosis factor a achievement mainly based on the observations that GLP-1 RAs
(TNF-a), interleukin (IL)-6, and IL-1b. M2 macrophages take up lipid prevented new-onset macroalbuminuria [99,164,165], reduced
particles through phagocytosis and suppress the formation of Krüppel- urinary albumin excretion [164,165], or slowed the decline in the
like factor 2 (KLF-2), which in turn suppresses endothelial NO synthase estimated glomerular filtration rate (eGFR) over time [164e166].
(eNOS), leading to lower NO production and preventing vasodilation The mechanisms leading to these renal benefits are largely un-
through NO-mediated vascular smooth muscle relaxation. In an envi- known. While significant reductions in achieving renal composite
ronment dominated by ROS and oxLDL, M2 macrophages transform outcomes were reported [99,164,165], they heavily relied on
into foam cells that can undergo apoptosis and release their lipid dominating effects preventing new-onset persistent macro-
content into the lipid core of nascent atherosclerotic plaques. Stable albuminuria. Clinical events indicating progression to end-stage
plaques are characterized by a dense fibrous cap mainly composed of renal disease (doubling in serum creatinine, major reduction by
collagen that helps prevent rupture. However, as atherogenesis pro- 30e50% in eGFR, achieving eGFR below 15 ml/min per 1.73 m2,
gresses, larger necrotic areas form, endothelial cells (EC) undergo necessary to initiate renal replacement therapy or perform renal
apoptosis, and matrix metalloproteinases (MMP) proteolytically destroy transplantation, or death due to renal causes) have rarely been
the fibrous cap. This results in plaque rupture, thrombus formation, reported in numbers allowing a meaningful analysis. This is due in
and bleeding into necrotic plaque areas. part to the fact that the populations studied had fairly good renal
function at baseline. Studies of selected patients with prominent or
3.5. Interference of GLP-1 RAs with the atherogenesis process advanced renal disease are lacking. A dedicated trial studying the
(Figure 9B) effects of semaglutide on renal outcomes in type 2 diabetic patients
As demonstrated in animal studies and experiments using human with chronic kidney disease is underway to clarify these issues:
cells, GLP-1 receptors expressed in endothelial cells, monocytes, FLOW (ClinicalTrials.gov NCT03819153). Since most GLP-1 RAs can
macrophages, and vascular smooth muscle cells produce numerous be used in chronic kidney disease, while SGLT-2 inhibitors lose
effects potentially interfering with the process of atherosclerotic plaque some of their glucose-lowering efficiency with reduced glomerular
formation or rupture. First, ROS production is reduced by GLP-1 [128e filtration rates, further studies appear to be needed, especially since
130], exenatide [131], liraglutide [130,132e136], and semaglutide patients with reduced eGFR at baseline seem to benefit most in
[137]. The oxLDL-mediated activation of monocytes and macrophages terms of preventing rapid declines in eGFR [164]. For the time
and the consecutive activation of adhesion molecules such as VCAM-1, being, more robust effects have been reported for SGLT-2 inhibitors,
MCP-1, E-selectin, and ICAM-1 is successfully reduced by GLP-1 re- which are preferred glucose-lowering medications interfering with
ceptor stimulation (e.g., GLP-1 [138], exenatide [138e140], dulaglu- the progression of diabetic renal disease even in patients with
tide [141], and liraglutide [142]). This results in a reduction of moderately reduced eGFR [110,111,167].
monocyte accumulation in the vascular wall, as shown for example
with exenatide [143]. Endothelial cells express more eNOS, produce 5. ADHERENCE AND PERSISTENCE (OBSERVATIONAL
more NO, and suppress endothelin formation that overall lead to STUDIES)
vascular smooth muscle relaxation and endothelium-derived vasodi-
lation (e.g., GLP-1 [130,144], exenatide [144], and liraglutide While initiating GLP-1 RA treatment in clinical practice is already
[130,133,145]). M2 macrophages instead of M1 macrophages pref- discrepant from current guidelines, suboptimal treatment persistence
erentially form from monocytes (e.g., lixisenatide [146] and liraglutide and adherence are additional important issues [168]. A recent study
[147]) and the otherwise suppressed KLF-2 formation instead in- suggested that HbA1c reductions with GLP-1 RAs observed in real-
creases (e.g., by lixisenatide [146], liraglutide [147], and dulaglutide world studies were w0.5% below those observed in controlled clin-
[141]). The reduced exposure to ROS after GLP-1 receptor stimulation ical trials [169]. The authors attributed approximately three-fourths of
slows the process of foam cell formation (e.g., GLP-1 [148,149] and this gap to poor medication adherence in clinical practice. In a retro-
liraglutide [150]) and reduces caspase-mediated apoptosis of foam spective analysis comparing different GLP-1 RAs, once-weekly
cells (e.g., GLP-1 [151] and semaglutide [152]) and the formation of injectable dulaglutide demonstrated greater adherence rates than
necrosis in the core of atherosclerotic plaques (e.g., GLP-1 [153] and once-weekly exenatide or once-daily injectable liraglutide [170]. Of
lixisenatide [154]). Furthermore, GLP-1 receptor stimulation reduces note, over a six-month treatment period, 26.2% of dulaglutide and
vascular smooth muscle proliferation (e.g., exenatide [155] and lir- 48.4% of once-weekly exenatide patients discontinued treatment, and
aglutide [156]) and possible migration into plaques (liraglutide [157]). in a direct comparison of dulaglutide and liraglutide, the respective
The integrity of endothelial cells was shown to be stabilized by exe- discontinuation rates were 28.0% and 35.6% [170]. When the pro-
natide [158,159]. Plaque hemorrhage was reduced by semaglutide portion of days covered (PDC) was compared between once-weekly
[160]. The reduced expression of MMP preserves intact fibrous caps exenatide and liraglutide, the proportions of patients with good
and prevents plaque rupture (e.g., GLP-1 [153], exenatide [161] and adherence (PDC > 0.80) after 6 months were 53.4% and 48.1%,
semaglutide) [160]. The overall result is a slowing of plaque pro- respectively [171]. Likewise, an analysis of Medicare recipients in the
gression and plaque stabilization. The formation, extent, and US reported a PDC >80% of 43.2% in patients receiving exenatide
Review
QW, 39.0% in patients receiving exenatide b.i.d., and 35% in patients (that is, three or more major risk factors or diabetes duration 10
receiving liraglutide [172]. Hence, no consistent data on differences in years without target organ damage, plus any other additional risk
adherence between short- and long-acting GLP-1 RAs could be found. factors) [181]. According to these international recommendations,
A recent real-world retrospective observational study showed that w30e60% of patients with type 2 diabetes would qualify for a
dulaglutide users were less likely to interrupt treatment than sem- GLP-1 RA. However, in clinical reality, the percentage of patients
aglutide and exenatide BCise users [173]. In a pairwise meta-analysis receiving GLP-1 RA treatment remains low, ranging between 1%
comparing treatment adherence and persistence between GLP-1 RAs and 10% in different countries [182].
and long-acting insulin analogues, the odds ratio for non-adherence The reasons for this apparent gap between guideline recommen-
was 1.95, suggesting better adherence with the insulin analogs dations and clinical reality are heterogeneous: first, the cost of
[174]. As a general trend from these comparisons, adherence to GLP-1 treatment with GLP-1 RAs is considerably higher than most oral
RAs seems to be better with lower injection frequencies. glucose-lowering drugs, but instead comparable to the cost of an
However, these studies must be interpreted with caution because of intensified insulin treatment regimen (including glucose-monitoring
the retrospective study designs and partially incomplete data costs). Although various cost-effectiveness analyses suggested that
assessment. Furthermore, observation periods of 6e12 months are the overall benefits associated with GLP-1 RA treatment outweigh
still too short to judge the long-term adherence to GLP-1 RAs. the direct treatment costs [183], the price of the currently available
GLP-1 RAs remains a major barrier in most countries. Second, the
6. DISCONTINUATION RATES IN RANDOMIZED CV OUTCOME need for daily or weekly injections discourages some patients from
TRIALS initiating GLP-1 RAs [184]. Third, contraindications (i.e., history of
pancreatitis, diabetic retinopathy, or medullary thyroid cancer) may
As presented in Table 4, some patients randomized to GLP-1 RA prevent the use of GLP-1 RAs in affected patients [185]. Finally,
treatment discontinued the assigned medication. The proportion gastrointestinal adverse events remain an important limitation of
withdrawing from GLP-1 RA treatment in CV outcome trials ranged GLP-1 RA treatment [49].
from 15% (oral semaglutide) to approximately 25%; an exceptionally
high withdrawal rate was observed with once-weekly exenatide 8. OPPORTUNITIES FOR FUTURE DEVELOPMENT OF GLP-1 RAS
(43%), possibly related to the less comfortable pen injection device
requiring resuspension of the active ingredient in buffer (Figure 3) or Since 2005, when exenatide was first approved, rapid development
the occurrence of subcutaneous nodules at injection sites [175]. began that has yielded progress with respect to GLP-1 RAs phar-
Approximately one-half of the discontinuations were reported to be macokinetics, with the obvious consequence that instead of 2 (or
associated with adverse events (Table 4). In the trials reporting more) injections per day, now once-weekly injections are available.
discontinuation because of any adverse events and those specifically While advances making GLP-1 RA treatment more comfortable are
due to gastrointestinal side effects, the latter were responsible for welcome, it should not be overlooked that the effectiveness of GLP-1
approximately one-half of the withdrawals. Another potential reason RAs has increased in large steps (e.g., going from exenatide to lir-
contributing to withdrawals was a perception of ineffective glycemic aglutide, the first long-acting GLP-1 RA, but also advancing to
and body weight control achieved (including a suspicion to have semaglutide, which clearly has superior efficacy than other GLP-1
been randomized to placebo), perhaps as a consequence of the RAs, especially with respect to body weight reduction as depicted
progression of the type 2 diabetes mellitus disease process [176]. in Figure 4). These significant advances, occurring in substantial
Whether or not GLP-1 RA treatment counters this progression (e.g., leaps, suggest that this development has not yet come to an end.
through b cell-preserving effects [177]) remains an open question. In
rodents, these effects are restricted to earlier periods in life [178] 8.1. Oral administration of GLP-1 RAs
when b cells have a propensity to proliferate, which they lose in One development worth noting is that, despite the peptide nature of
adult animals [179]. Overall, randomized controlled clinical trials all of the GLP-1 RAs, semaglutide is now available for oral
showed that high persistence regarding GLP-1 RA treatment could administration. An absorption enhancer molecule (SNAC; see Sec-
be maintained for periods up to 5 years, which contrasts with data tion 2) must be part of the oral preparation to promote absorption
from observational studies (as previously described). Efforts to through the gastric mucosa. Low bioavailability after oral adminis-
encourage persistent use of GLP-1 RA, as successful in clinical tration makes daily administration of a semaglutide tablet necessary
trials, may be necessary to achieve better persistence in clinical to avoid wide fluctuations in drug exposure. It must be taken on an
practice as well. empty stomach, and for 30 min after taking oral semaglutide, no
other food, drink, or medication should be administered to allow
7. GUIDELINE RECOMMENDATIONS AND CLINICAL REALITY undisturbed absorption. With these precautions, in principle,
quantitatively similar effects can be achieved with respect to gly-
The current ADA/EASD consensus algorithm suggests that GLP-1 cemic control and lowering body weight [19]. The phase 3 PIONEER
RAs should be preferentially used after metformin failure in (a) program, however, was conducted with somewhat lower doses
patients with established atherosclerotic cardiovascular disease and (maximum, 14 mg/d) than would be necessary to match the
(b) patients without established cardiovascular disease with high- effectiveness of subcutaneous semaglutide at 0.5 or 1.0 mg/week
risk indicators, such as age 55 years, carotid, lower extremity [43].
or coronary artery stenosis >50%, left ventricular hypertrophy, In addition to developing peptide-based GLP-1 RAs for oral adminis-
eGFR < 60 ml/min, or albuminuria [180]. GLP-1 RAs may also be tration, some reports described small molecules with GLP-1 receptor
used to prevent hypoglycemia or weight gain. The ESC guidelines agonist properties that should be suitable for oral administration
have gone even further in recommending GLP-1 RAs (or SGLT-2 without additives and/or sensitive procedures. To date, the binding
inhibitors) as first-line therapy in patients with established athero- affinities of these compounds has been too low to support further
sclerotic cardiovascular disease or in those at high or very high risk development as clinically effective drugs [186e189].
8.2. Use in patients with type 1 diabetes decreased substantially, while body weight declined by only 1 kg (at a
Effects of GLP-1 or GLP-1 RAs on residual insulin secretion [190], higher dose of 1.5 mg) [206]. Systolic blood pressure was also lowered
glucagon suppression [190,191], gastric emptying delay [190], and substantially by this combination [204e208]. The effects of combining
plasma glucose [192,193] in type 1 diabetic subjects were described GLP-1 RAs with SGLT-2 inhibitors were corroborated in a meta-
starting in the early stages of GLP-1 discovery. Clinical trials employing analysis by Castellana et al. [209], confirming this combination’s
liraglutide or exenatide (un-retarded preparation usually administered potential.
b.i.d.) in addition to intensified insulin regimens, however, did not This leads to the essential question, will combining GLP-1 RAs and
demonstrate convincing benefits (e.g., with respect to optimized gly- SGLT-2 inhibitors result in even better CV outcomes? No data are
cemic control or the frequency of hypoglycemic episodes) or described available to estimate the effects on CV outcomes using this combi-
potential adverse outcomes such as a higher risk of ketoacidosis. Only nation. It is uncertain whether a large enough clinical trial addressing
body weight and insulin doses were consistently reduced [194e197]. this question will ever be conducted. Real-world studies analyzing
However, these results do not rule out benefits for specific subgroups existing databases documenting medication use and clinical outcomes
(e.g., obese patients with type 1 diabetes or subjects at high risk of may help in this respect, but no such analysis seems to be currently
cardiovascular complications) or with dosage recommendations that available.
may differ from those used to treat type 2 diabetes.
8.5. Unimolecular oligo-hormonal agonists address more than just
8.3. Individualized use in well-defined type 2 diabetes subtypes GLP-1 receptors
Cluster analysis was applied to define subgroups within the type 2 One avenue of further increasing the potency of GLP-1 RAs is devel-
diabetes population that differ with respect to insulin secretory ca- oping molecules that address not only GLP-1 receptors, but a second
pacity, insulin sensitivity, age at diagnosis, and the presence of (co-agonist) or even a third (tri-agonist) receptor (choosing from
autoimmune markers [198e200]. These subgroups display significant glucagon, glucose-dependent insulinotropic polypeptide [GIP], or
differences in the development of CV and renal complications [198e peptide YY [PYY] receptors). Preliminary findings suggest that highly
200]. Thus, given the beneficial actions of GLP-1 RAs on preventing effective compounds (e.g., tirzepatide [210]) can be developed this
CV events (and on the progression of nephropathy), they may turn out way, in particular providing weight loss far exceeding that reported
to be particularly effective in those presenting a high a priori risk of with pure GLP-1 RAs. These developments will be the focus of another
these complications. Identifying a central pathophysiological defect manuscript on the present supplement volume (Baggio et al. [211]).
(e.g., reduced insulin secretory capacity) may also help select a spe-
cific therapy addressing this point (e.g., GLP-1 RAs augmenting insulin 8.6. Pharmacogenomics
secretion triggered by hyperglycemia). While prospective studies Since GLP-1 RAs exert their biological effects by interacting with the
comparing various therapies in type 2 diabetes patients belonging to GLP-1 receptor, interindividual differences in the expression of these
different subgroups are lacking, this sub-classification promises to be receptors or polymorphisms at the GLP-1 receptor gene may modify
a helpful tool assisting in a more individualized approach toward biological responses [212e215]. Along these lines, certain poly-
selecting glucose-lowering medications for a given patient. morphisms regarding the TCF7L2 gene (probably involved in deter-
mining b cell mass and the expression of GLP-1 receptors) impair
8.4. Combination treatment with GLP-1 RAs plus SGLT-2 inhibitors insulin responses to exogenous GLP-1 [216]. One study described a
In addition to GLP-1 RAs, SGLT-2 inhibitors are another class of modification of the in vitro effects of GLP-1 RAs for the GLP-1 receptor
glucose-lowering medications that have proven beneficial CV effects, variant T149M (methionine instead of threonine in position 149) on b
especially regarding the prevention of heart failure complications cells [217]. However, a preliminary clinical study did not describe
(Figure 6 [110,111]). This raises the question of differential indications differences in pharmacological effects in response to short-term
[201]. Based on the pattern of effects on various CV endpoints, GLP-1 treatment with exenatide [218]. Given the potential of selecting pa-
RAs seem to better prevent ischemic events potentially resulting from tients with a predicted greater clinical effectiveness [219], the issue of
anti-atherogenic effects (as previously described). The mechanisms of pharmacogenomics regarding GLP-1 RA still appears to be an under-
action of SGLT-2 inhibitors differ and aim to prevent heart failure studied research area. Furthermore, patients not responding to GLP-1
complications (using hospitalization as an indicator) and the progres- RAs as expected, either when initially exposed to GLP-1 RAs (primary
sion toward end-stage renal failure [110,111]. Therefore, if a patient non-responders) or after a satisfactory response period (secondary
seems to be at risk of ischemic events (e.g., because of previous non-responders), have often been observed in clinical practice. Sys-
events), GLP-1 RAs appear to be the better option. However, if the risk tematic studies elucidating the mechanisms of a potential non-
of congestive heart failure complications is considered the primary response to GLP-1 RA treatment (such as genetics or lifestyle is-
problem, SGLT-2 inhibitors are the better choice. sues) remain lacking.
Since the severalfold elevated risk of CV events that type 2 diabetes
demonstrates is only partially reduced by both GLP-1 RAs and SGLT-2 8.7. Potential novel indications: neurodegenerative diseases and
inhibitors, it may be necessary to combine medications from both psoriasis
classes to further improve their effectiveness. Combining dapagliflozin Interest in using GLP-1 RAs to treat neurodegenerative diseases
with exenatide once weekly lowers plasma glucose and body weight emerged from preclinical studies showing that GLP-1 receptor
more than any of the single agents alone [202], even for prolonged signaling is involved in cognitive functions [220] and GLP-1 RAs can
periods of time [203]. Similar results were observed after adding induce neuronal growth and synaptic plasticity and reduce apoptosis
empagliflozin to liraglutide in Japanese patients [204] and when and oxidative stress [221].
adding canagliflozin to liraglutide treatment [205]. The weight loss In Alzheimer’s disease, the most prevalent form of dementia, animal
induced by the combination compared to the single agents appeared to studies have shown the positive effects of GLP-1 RAs on cognitive
be additive, but HbA1c reduction was less than additive. When adding impairment [222,223]. In a clinical trial of patients with prediabetes
dulaglutide to pre-existing treatment with SGLT-2 inhibitors, HbA1c and type 2 diabetes, memory function improved after 4 months of
Review
liraglutide administration [224]. However, there was no placebo con- & Dohme, and Novo Nordisk. He has also served on the speakers’ bureau of
trol. In another trial with non-diabetes subjects at increased risk of AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Menarini/Berlin-Chemie,
Alzheimer’s disease, administration of liraglutide for 3 months Merck, Sharp & Dohme, and Novo Nordisk. J.J.M. has received consulting and
improved brain region connectivity (assessed by functional MRI), but speaker honoraria from AstraZeneca, Eli Lilly and Company, Merck, Sharp & Dohme,
cognitive functions did not improve [225]. Another trial in non-diabetes Novo Nordisk, Sanofi, and Sevier. He has received research support from Boehringer
patients with Alzheimer’s disease found that 6 months of liraglutide Ingelheim, Eli Lilly and Company, Merck, Sharp & Dohme, Novo Nordisk, and Sanofi.
treatment prevented a further decline in brain glucose uptake J.W. and D.Q. have nothing to declare.
(assessed by positron emission tomography), but did not change
cognitive function tests [226]. A larger clinical trial is currently ongoing
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GLP-1 Receptor Agonists in The Treatment of Type 2 Diabetes e State-Of-The-Art

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Review

GLP-1 receptor agonists in the treatment of type

Michael A. Nauck*, Daniel R. Quast, Jakob Wefers, Juris J. Meier

Time to reaching maximum plasma concentrations

Liraglutide 0.6 mg 1.2 mg 1.8 mg q.d.

Exenatide once weekly 2.0 mg q.w.

Dulaglutide 1.5 mg q.w.a

Semaglutide s.c. 0.25 mg q.w.c 0.50 mg q.w. 1.00 mg q.w.

Semaglutide oral 3 mg q.d. 7 mg q.d. 14 mg q.d.

2.5. Combination with (basal) insulin therapy

important reason for testing higher doses, for example, dulaglutide

observation that doseeresponse relationships have shown a plateau

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