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MED 270108

REVIEW

CURRENT
OPINION Incretin therapy for diabetes mellitus type 2
Jens Juul Holst

Purpose of review
Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and
glucagon-like peptide-1 have attracted interest because of their importance for the development and
therapy of type 2 diabetes and obesity. New agonists and formulations of particularly the GLP-1 receptor
have been developed recently showing great therapeutic efficacy for both diseases.
Recent findings
The status of the currently available GLP-1 receptor agonists (GLP-1RAs) is described, and their strengths
and weaknesses analyzed. Their ability to also reduce cardiovascular and renal risk is described and
analysed. The most recent development of orally available agonists and of very potent monomolecular
co-agonists for both the GLP-1 and GIP receptor is also discussed.
Summary
The GLP-1RAs are currently the most efficacious agents for weight loss, and show potential for further
efficacy in combination with other food-intake-regulating peptides. Because of their glycemic efficacy and
cardiorenal protection, the GLP-1 RAs will be prominent elements in future diabetes therapy.
Keywords
dulaglutide, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, semaglutide,
weight-losing therapy

INTRODUCTION THE PHYSIOLOGICAL BACKGROUND FOR

According to the newest guidelines and recommen-
dations, GLP-1 receptor agonists and DPP-4 inhib-
itors (which act by increasing levels of active
incretin hormones) are now recommended as at
least second-line treatment for type 2 diabetes [1].
The GLP-1 receptor agonists are particularly recom-
mended for patients with evidence of cardiovascular
disease complicating their diabetes. These recom-
mendations are mainly based on the results of very
large outcome trials, in which the GLP-1 receptor
agonists on top of their well established antidiabetic
activity have proven superior to placebo in reducing
&
the risk of cardiovascular events [2 ] (whereas the
DPP-4 inhibitors have proven neutral in this respect
[3]). Another important finding is the risk of devel-
oping renal adverse events, but in this case, both the
GLP-1 receptor agonists (GLP-1RAs) and DPP-4
inhibitors have shown reduced risk compared with
placebo. The purpose of this brief overview is to
discuss the background for this remarkable develop-
ment, and to discuss briefly the role of the incretin-
based therapies in the modern/future therapy of
type 2 diabetes. The focus will be on GLP-1 receptor
agonists, but the possible role of glucose-dependent
insulinotropic polypeptide (GIP) will also be briefly
discussed.
THE USE OF GLP-1 RECEPTOR AGONISTS
Action on insulin secretion and food intake
The GLP-1 RAs act via activation of the GLP-1 recep-
tor [4] – there are reports of actions that are thought
to be independent of the receptor, but the existence
of such effects needs better experimental support.
The GLP-1 receptor is expressed in numerous tissues,
but even today – about 18 years after the cloning of
the receptor – its precise localization is not known
in detail [5]. A site of very dense expression of the
receptor is the pancreatic beta cells, where activa-
tion by the ligands leads to cAMP formation
and eventually insulin secretion via PKA and
Epac activation [6]. The insulinotropic action is
best described as potentiation of glucose-induced
NNF Center for Basic Metabolic Research and Department of Biomedi-
cal Sciences, The Panum Institute, Faculty of Health Sciences, University
of Copenhagen, Blegdamsvej 3, Copenhagen N, Denmark
Correspondence to Jens Juul Holst, NNF Center for Basic Metabolic
Research and Department of Biomedical Sciences, The Panum Institute,
Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3,
DK-2200 Copenhagen N, Denmark. E-mail: jjholst@sund.ku.dk
Curr Opin Endocrinol Diabetes Obes 2019, 26:000–000
DOI:10.1097/MED.0000000000000516

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Gastrointestinal hormones
KEY POINTS
 Agonists of the receptor for the incretin hormone, GLP-1
(GLP-1RAs) have proven successful for the therapy of
both obesity and diabetes and currently range among
the most efficacious therapies for these diseases.
 Newer GLP-1 RAs suitable for once weekly
administration have been developed and an orally
active GLP-1 RA has recently been approved.
 In large cardiovascular outcome trials, the GLP-1RAs
are not only well tolerated, but reduce risk of
cardiovascular and renal adverse events, extending
their applicability for metabolic therapy.
 The other incretin hormone, glucose-dependent
insulinotropic polypeptide (GIP), has little acute effect
on insulin secretion in patients with type 2 diabetes,
and no effect on food intake, but may show additional
effects when combined with GLP-1 in monomolecular
co-agonists.
secretion [7], and this is important, because it
explains that GLP1RAs in general do not produce
hypoglycemia (unless they are combined with sul-
fonylurea compounds, which uncouple this glucose
dependency [8]) and also explains that insulin secre-
tion usually is not increased during therapy, but
now occurs at a lower ambient glucose concentra-
tion [9]. Being peptide-based, all GLP-1 RAs require
subcutaneous injection [note, however, that the
first oral GLP1RA has just been approved by the
Food and Drug Administration (FDA) [10]], and this
means that their plasma concentration will increase
after the injection, and that increased concentra-
tions may reach the beta cell and activate the recep-
tors. Most likely, this scenario differs from the
actions of the endogenous hormone, GLP-1, which
is degraded extensively and rapidly by the dipep-
tidyl peptidase-4 in the intestinal capillaries of the
gut and the liver after its release from the gut,
leaving only a very small fraction to reach the
pancreas in the intact form [11]. Instead, the endog-
enous peptide is thought to activate enteric neurons
and sensory afferent fibers of the vagus (there is a
dense expression of the receptors in the enteric
plexuses), with impulses reaching the brain stem
and hypothalamic nuclei involved in regulation of
appetite and gastrointestinal secretions and motility
[7]. To what extent exogenous GLP-1 receptor ago-
nists are able to activate this neural system is not
known. For them, an important site of GLP-1 recep-
tor activation may be the circumventricular organs
of the brain [12], and it appears that the agonists
may access the area postrema, the median eminence
and the arcuate nucleus and that their effects on
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food intake is dependent on this uptake [13]. The
GLP-1 receptor is barely expressed on the pancreatic
alpha cells (if at all) [14], but abundantly on the
somatostatin-producing delta cells, and it is gener-
ally thought that the inhibition of glucagon secre-
tion caused by the GLP-1 RAs is exerted via
stimulation of islet somatostatin, inhibiting gluca-
gon secretion in a paracrine manner [15]. The GLP-1
induced inhibition of glucagon secretion may be of
considerable importance for the antidiabetic effects
of the GLP-1 RAs [16], and from pancreatic clamping
experiments in humans, it has been calculated that
around 50% of the glucose-lowering effect of GLP-1
in type 2 diabetes is because of inhibition of gluca-
gon secretion whereas the remaining 50% is because
of stimulation of insulin secretion [17]. Although
there are clearly GLP-1 receptors in the mentioned
circumventricular organs [18], there are many more
GLP-1 receptors in the brain, which do not seem to
be accessible for peripheral GLP-1 or GP-1RAs [19].
These receptors are probably targets for GLP-1
released from nerve fibers projecting from a small
group of proglucagon-producing neurons in the
nucleus of the solitary tract [20]. These neurons
may be activated by a number of peripheral mainly
vagally transmitted stimuli, and in this way signal to
parts of the brain that are involved in regulation of
appetite, food intake, and reward [21]. The relation-
ship between peripheral GLP-1 and the GLP-1 neu-
rons in the brain stem is not clear, but gastric
emptying, for instance, has been reported to activate
the GLP-1 neurons [22]. It cannot be excluded that,
physiologically, the GLP-1 system mainly functions
as a part of the so-called ileal brake, endocrine
mechanisms evoked by the presence of nutrients
in the distal small intestine (where GLP-1 expression
is greatest), which cause inhibition of appetite and
food intake as well as inhibition of upper gastroin-
testinal secretion and motility [23]. Only with large
meals would the GLP-1 system be sufficiently acti-
vated (the secretory responses are related to meal
size [24]) to allow endocrine interactions with the
pancreatic islets.
Other actions
Other sites of GLP-1 receptor expression include the
Brunner’s glands of the duodenum [25], where GLP-
1 may induce mucus secretion and secretion of
antibacterial agents, and smooth muscles of the
afferent arterioles in the kidney [26], suggesting
involvement in the regulation of renal hemody-
namics and perhaps consistent with the proposal
of an intestinorenal axis regulating sodium excre-
tion [27]. Finally, a dense receptor expression
of receptors has been found on intestinal
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MED 270108
intraepithelial lymphocytes, which may represent
an entry for GLP-1 to the immune systems, perhaps
consistent with the many reports of anti-inflamma-
tory actions of GLP-1 and the GLP-1RAs [28]. Local-
ization of GLP-1 receptors that can explain the
antiatherosclerotic and cardiovascular effects [29]
of the GLP-1RAs is currently lacking, possibly
because of insufficient sensitivity of the applied
methods.
The antidiabetic effect of the incretin
hormones
So being normally secreted, why is it that the incre-
tins do not prevent type 2 diabetes from occurring?
It turns out that the incretin effect, the amplifica-
tion of insulin secretion exerted by hormones from
the gut, is severely impaired in patients with T2DM
[30]. The main reason is that the two hormones, in
physiological concentrations, have lost most of
their insulinotropic effects in these patients [31].
But whereas GIP is ineffective regardless of dose [32],
higher doses of exogenous GLP-1 are able to restore
beta cell responses to glucose to completely normal
values [33] (although the response is lower than that
observed in healthy individuals after combined glu-
cose and incretins). This explains the clinical effec-
tiveness of the GLP-1 RAs and also explains that
GLP-1s have little effect on beta cells with poor
residual secretory capacity [34]. There are also
abnormalities of glucagon secretion in T2DM with
delayed and reduced suppression by glucose, and it
appears that the higher doses of GLP-1 can also
restore alpha cell sensitivity to glucose [32],
although in general, the inhibitory effect of glucose
itself is retained in the diabetic alpha cell [35], as
opposed to the beta cells.
The therapeutic potential of glucagon-like
peptide-1
All together the therapeutic potential of GLP-1 in
T2DM is surprising. It acts on the diabetic beta cells
to stimulate insulin secretion, and it inhibits gluca-
gon secretion, which is generally increased in T2DM
(presumably because of hepatic glucagon resistance
and stimulation of glucagon secretion by elevated
aminoacid levels [36]) and is known to contribute
importantly to the diabetic hyperglycemia in the
fasting state (as demonstrated by the actions of
glucagon receptor antagonists [37]). GLP-1 has also
been proposed to protect beta cells against progres-
sion of disease. Thus GLP-1 appears to protect beta
cells, also human, from apoptosis induced by cyto-
kines [38], but whether protection may actually
occur clinically in humans is uncertain. The best
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Incretin therapy for diabetes mellitus type 2 Holst
evidence for this probably derives from the pro-
longed effect on glycated hemoglobin (hemoglobin
A1c, a measure of average glucose concentrations
over 3 months) upon continued therapy with a
GLP1 RA (for instance up to 5 years with liraglutide
in the LEADER trial [39]). Signs of beta cell regener-
ation or proliferation, originally proposed to occur
[40], have not been observed, however. In addition
to the effects on the islets, GLP-1RAs inhibit appetite
and food intake [41] leading to weight losses.
Weight loss per se has incredibly important conse-
quences for metabolic disease and diabetes with
improvement of insulin resistance being one of
the most important elements [42]. On top of that
comes the cardiovascular and renal benefit.
WHERE ARE WE TODAY WITH RESPECT
TO INCRETIN-BASED THERAPIES?
The first problem to solve was the apparent instabil-
ity of the GLP-1 molecule which, as mentioned, is
degraded by DPP-4, leaving the peptide with a half-
life in the circulation of less than 2 min [43]. The
discovery of this inactivation [44] lead to the pro-
posal that inhibition of the DPP-4 enzyme might be
useful in diabetes therapy [45], and indeed this
turned out to be the case, as first demonstrated
experimentally [46] and subsequently in clinical
studies [47]. Given the extensive degradation of
endogenous GLP-1 (80–90%), it was expected that
levels of intact GLP-1 might increase by a factor of
more than 5 after inhibition, but clinically the levels
only rise by a factor of 2–3 [48], apparently because
of a negative feed-back cycle involving intestinal
somatostatin restraining on GLP-1 secretion [49].
However, levels of active GLP-1 are apparently ele-
vated sufficiently to influence pancreatic islet secre-
tion. Also the other incretin hormone, GIP, is
protected from degradation by DPP-4 [48], and
although its contribution to the antidiabetic action
of the inhibitors is uncertain, there are reports indi-
cating that the improved glycemic control may
restore some of the lost insulinotropic actions of
GIP [50].
Another way to exploit the GLP-1 system was of
course to develop DPP-4 resistant analogs, and this
turned out to be rather simple, a substitution of the
amino acid residue in position 2 was sufficient [51].
This, however, as it turned out, only prolonged the
half-life to 4–5 min because of extensive renal elim-
ination of the peptide. The discovery of a resistant
GLP-1 RA, exendin-4, a peptide from the saliva of
the Gila Monster, a poisonous lizard from Arizona
[52] was a solution to this problem. This peptide is
stable and exclusively cleared by glomerular filtra-
tion in the kidneys, giving it an intravenous half-life
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Gastrointestinal hormones
of about 30 min (2–3 h after subcutaneous injec-
tion) [53]. A synthetic product, exenatide, came to
the market in 2005 [54] and is still available as the
prototype of the so-called short-acting agonists.
Their duration of action is brief, covering only
one or two meals. This problem has been partly
addressed by giving two daily injections (before
meals) or increasing the dose (as is done with a
modified analogue, lixisenatide). The short-acting
agonists very potently reduce postprandial glucose
excursions because of the pronounced effects on
gastric emptying [54]), but they have, as expected
because of their short duration of action, poor
effects on fasting glycemia, and in a cardiovascular
outcome study (CVOT, see below), lixisenatide (a
slightly modified analogue of exendin-4) did not
show cardiovascular benefits [55], which does not
support the use of short-acting agonists. A formula-
tion of exenatide (Bydureon) making it suitable for
once weekly administration was introduced [56]
from 2008. The subcutaneous administration of this
agonist is not without problems and it has a ten-
dency to generate antibodies and nodules at the
injection site. In addition, its efficacy is weaker in
head-to-head comparisons with other weekly ago-
nists (possibly a dosing problem), and this com-
bined with somewhat discouraging results of a
very large outcome study (EXSCEL [57]) suggests
that in its current dosing scheme, it is less competi-
tive. A modified long-acting (weekly) and poten-
tially more potent exendin-derived agonist,
efpeglenatide, is currently under development [58].
The remaining agonists are derived from the
backbone of the human/mammalian GLP-1 mole-
cule. The first was liraglutide, consisting of the GLP-
1 molecule with a fatty acid chain (palmitate)
attached via a linker, whereby it binds to albumin
in the circulation [59]. This provides it with a half-
life in the circulation (12 h) sufficient to cover the
24 h of the day, ensuring a stable exposure in steady
state. Liraglutide has been extensively evaluated,
particularly in the previously mentioned 3.5 years
(up to 5 years) cardiovascular outcome study,
LEADER [39]. A discussion of its cardiovascular
effect will follow below. As already mentioned, this
agonist provides lasting weight loss and improve-
ments of HbA1c. A fusion molecule between two
GLP-1 sequences and human albumin, designed for
at least weekly use, albiglutide, was introduced in
2012 [60]. This molecule was the first of the large
molecular weight agonists and was suspected to
have lesser effect on body weight [61] (cf. the dis-
cussion on the possible mechanism of action above),
and in comparative studies, it is clearly weaker
in this respect [62]. The company behind this
compound has withdrawn the compound on
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commercial grounds, although in a large recent
cardiovascular outcome trial (the Harmony trial
[63]), it performed surprisingly well.
The Lilly company introduced dulaglutide, a
long-acting fusion product of two stabilized GLP-1
moieties with an fc immunoglobulin fragment, in
2015 [64], and immediately this seemed comparable
with liraglutide, but with the benefit of once weekly
administration. Also the cardiovascular outcomes
were positive with dulaglutide (the REWIND trial
&
[65 ], see below). NovoNordisk subsequently intro-
duced another acylated but stabilized and optimized
version of liragutide, semaglutide, suitable for weekly
administration and selected for greater efficacy with
respect to both glycemic control and weight loss [66].
The general features of the GLP-1RAs are thus
their ability to improve glycemic control in patients
with T2DM and to cause weight loss. It is outside the
scope of this short overview to discuss the importance
of improved glycemic control in T2DM, but this
target is still considered key to diabetes therapy.
Losing overweight, on the other hand, is extremely
important: because of the involvement of overweight
in the diabetes pathogenesis, because of the meta-
bolic and cardiovascular improvements following
weight loss, and because of the congruence with most
patients’ desire [42]. When choosing among the vari-
ous GLP-1 receptor agonists, it is, therefore, relevant
to compare their effects on these targets. In addition
to that comes convenience, which, regarding the
injectables, would provide the weekly agonists with
a considerable advantage; and equally importantly,
the side effects, which although the frequency of
severe side effects is low, still remains a problem
for the GLP-1RAs, which almost inevitably cause
nausea, vomiting, diarrhea and stomach pain in
some patients in the initial phase of the therapy.
The importance the patients (and the doctor) may
attribute to each of these features varies a lot (gener-
ally weight loss is the most valued property [67]), so
the choice is not easy. It is important to emphasize
that the magnitude of the effects of the compounds
varies considerably from person to person and from
study to study, which means that direct comparisons
in controlled clinical trials are absolutely essential.
On the basis of such considerations, the currently
most attractive compounds would be the weekly
agonists, semaglutide, and dulaglutide, which are
quite comparable, although with a slightly greater
efficacy for semaglutide, particularly with respect to
weight loss (see also below) [68].
THE CARDIOVASCULAR OUTCOME TRIALS
When it comes to the cardiovascular benefits of the
GLP-1 RAs, the picture is less clear, because the
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Incretin therapy for diabetes mellitus type 2 Holst

outcome trials differ so much. In general, they have
been designed to be event driven, in order to fulfill
requirements regarding cardiovascular safety
demanded by the FDA in 2010. The events typically
constitute MACE: major cardiovascular adverse
events, including nonfatal myocardial infarction,
nonfatal stroke, and cardiovascular death. The sta-
tistical strategy of the studies has been to secure
significance for cardiovascular safety, that is, non-
inferiority compared with placebo, but this design
unfortunately also implies that observed additional
effects rarely reach statistical significance. There-
fore, one should not put too much weight on the
results of the secondary analyses. Figure 1 shows a
comparison of MACE and its individual compo-
nents in the major cardiovascular outcome studies
completed so far. Judging from meta-analyses of
these data, it may be concluded that the GLP-1
receptor agonists are not only well tolerated, but
also that they are in general superior to placebo,
showing an average 13% relative risk reduction of
MACE. Inconsistences between the performances of
the drugs in the various trials regarding the individ-
ual components of MACE as well as all-cause mor-
tality may, therefore, reflect differences between the
trials more than differences between the agonists.
For instance, in the SUSTAIN 6 trial of semaglutide
[69], there was a significant reduction of nonfatal

FIGURE 1. Risk of major cardiovascular adverse events and each of its components in the GLP-1 receptor agonist
cardiovascular outcome trials (CVOTs) published so far. Data from Kristensen et al. [2 ].
&

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Gastrointestinal hormones
stroke and near-significant effects on nonfatal myo-
cardial infarction, but no effect whatsoever on
cardiovascular death. This should be contrasted
with the LEADER trial [39], where liraglutide had
a marked beneficial effects on precisely cardiovas-
cular death. Does this mean that the two very related
compounds, liraglutide and semaglutide, differ with
respect to protection against cardiovascular death?
This is unlikely; rather, the explanation is that the
SUSTAIN 6 trial was a short, preregistration trial in a
limited number of patients, in which the number of
cardiovascular deaths were too few to reveal a sig-
nificant difference against placebo. Indeed, in this
trial, the risk reduction regarding overall MACE
(26%) was the greatest among all the trials com-
pleted so far, consistent with the considerable effi-
cacy of this agonist.
A major problem regarding the evaluation of the
cardiovascular effects of the agonists in these trials is
that we really do not know the mechanisms that are
responsible for the effects. The only established
cardiovascular effect of the agonists is an increase
in heart rate, which is generally considered harmful
by cardiologists. The CVOTs are in general designed
for glycemic equipoise between placebo and study
compound – thus, the studies are blinded and the
clinicians instructed to do their best to keep hemo-
globin A1C levels below the recommended target of
7% in all patients. As the GLP-1RAs agonists are
efficient glucose-lowering agents, this means that
the placebo groups receive much larger amounts of
additional antidiabetic medications, in particular
more insulin. As a result, hypoglycemia is much
more frequent in the placebo groups [39]. Could
the seemingly beneficial effects of the GLP-1 ago-
nists in reality be because of harmful effects of the
additional therapeutics given to the placebo groups?
This cannot be excluded at present. Regarding heart
failure, it is a general finding that the GLP-1RAs do
not have a beneficial effect (but, importantly, they
also do not cause or aggravate heart failure [70]).
This is in stark contrasts to the SGLT2 inhibitors [71]
showing a marked effect on exactly heart failure,
perhaps consistent with their ability to cause extra-
cellular volume constriction. Although still incom-
pletely founded in experimental research, this has
led many to conclude that the GLP-1RAs act to
slow down atherosclerotic disease progression [70]
(as illustrated by their effects to reduce the risk of
myocardial infarction, incidence of stroke, or revas-
cularization procedures by 35%) as observed in the
SUSTAIN 6 trial [69].
Other beneficial effects include a significant
lowering of blood pressure in most trials, but again
the mechanism behind this is completely unknown
(acute administration of GLP-1 increases blood
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pressure in agreement with the increase in heart
rate and output). Also, in the kidneys, the beneficial
effect on adverse events is mainly restricted to a
reduced risk of albuminuria, whereas a clear effect
on glomerular filtration rate is not seen (again, in
contrast to the SGLT2 inhibitors) [72]. The most
recent research has pointed to a lowering of angio-
tensin 2 levels [27], but this needs further investiga-
tion. Thus, choosing among the different agonists
on the basis of their cardiovascular effects may be
difficult (the ‘weakest’ antidiabetic, albiglutide, had
a very significant effects on MACE in the HARMONY
trial), although of course, a documented effect,
would weigh more than no significant effect.
WHAT ABOUT THE FUTURE?
The GLP-1 receptor agonists are potent antidiabetic
agents, and when it comes to T2DM, they often
perform significantly better than insulin. Thus, after
failure of oral therapy (with metformin and SU) the
GLP-1 agonists may perform better than basal insu-
lin [73], and in more advanced cases, better than
basal-bolus insulin therapy [74], both in terms of
glycemic control and with respect to body weight
control and absence of hypoglycemia. In addition,
the agonists may be associated with reduced athero-
sclerotic progression and improved cardiovascular
risk, as discussed above.
The SGLT-2 inhibitors represent an extremely
valuable addition to the diabetes therapeutics, but
are in general less effective with respect to glucose
control and weight loss [75], and they are not
thought to be associated with slowing of atheroscle-
rotic progression. Their beneficial effects on cardio-
vascular (in particular, heart failure) and renal
complications are so clear that their use in patients
with nondiabetic cardiovascular and renal disease is
now being implemented [76]. Whether the GLP-
1RAs may also be accepted for nondiabetic patients
is more uncertain. At least the REWIND study with
dulaglutide suggested that beneficial cardiovascular
effects could also be expected in diabetic individuals
without established cardiovascular disease at the
&
start of trial [65 ]. A number of studies are currently
being performed looking at combinations of SGLT2-
inhibitors and GLP-1 receptor agonists, which from
a theoretical point of view, would be very attractive.
Indeed, there seems to be additive effects of com-
bining the two therapies [77].
As mentioned above, the GLP-1 RAs may even-
tually be associated with secondary failure because
of progression of beta cell failure [34]. One obvious
way of solving this problem is to treat the patients
with combinations of basal insulin and a GLP-1 RA,
and such combinations have shown remarkable
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efficacy, and the fixed combinations currently rep-
resent the most efficacious diabetes therapy at all.
Thus, the introduction of the GLP-1RAs to diabetes
therapy must be considered a very significant
improvement
As discussed above, some of the agonists have
shown efficacy as weight-losing agents. By slow and
careful up-titration of the agonists, it may be possi-
ble to reach higher doses than those recommended
for diabetes therapy without creating intolerable
side effects whereby their food-intake inhibiting
effects can be exploited better. Thus, liraglutide at
3 mg (as opposed to 1.8 mg for diabetes therapy) has
been approved for nondiabetic (and diabetic) obe-
sity. It is moderately effective [78], but has the
benefit, compared with other weight-losing agents,
that it also counteracts the metabolic complications
of obesity, above all the development of diabetes,
which may be prevented or delayed to a consider-
able extent [79]. The more effective agonist, sema-
glutide, has also been investigated in higher doses,
for example, using lower but daily injections
amounting to a several fold higher total dose per
week than the currently approved 1 mg dose, and in
these studies up to 15% weight losses have been
&
observed [80 ]. This makes semaglutide the most
efficacious weight-losing agents of all, illustrating
the huge future potential of the GLP-1RAs in
this field.
GLP-1 is not the only appetite-inhibiting and
food intake-inhibiting hormone from the gastroin-
testinal tract, and studies of patients after bariatric
surgery have taught us that the weight loss associ-
ated with these operations is probably because of
exaggerated secretion of gut hormones, perhaps in
particular the hormones GLP-1 and PYY [81]. Long-
acting agonists of PYY are, therefore, being devel-
oped for combinations with GLP-1 RAs for obesity
therapy. Another combination that deserves men-
tioning is the GLP-1-amylin combination. Amylin
has been around as diabetes therapy for decades in
the form of pramlintide, a modified and soluble
form of the human beta cell product. It was observed
that treating T2DM patients with large doses of
pramlintide resulted in weight loss, and therefore,
long-acting amylin receptor agonists are being
developed, again for combination with GLP-1 recep-
tor agonists [82]. A final, unexpected development,
was the generation of monomolecular GLP-1–GIP
dual agonists, among which tirzepatide from Eli
Lilly is the most interesting. In phase two studies,
this compound had antidiabetic and weight-losing
effects that appeared (at least) comparable with
&&
those of semaglutide [83 ]. The contribution of
GIP to the effects of tirzepatide is unclear at present,
given the general understanding that GIP has no
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Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Incretin therapy for diabetes mellitus type 2 Holst
effects of food intake and no effects on insulin
secretion and glycemia in patients with T2DM.
In conclusion, it seems safe to conclude, on the
basis of these recent developments that the GLP-1
RAs have a bright future ahead of them and that
diabetes and obesity therapy is likely to include
some form of GLP-1 receptor agonism for many
years ahead.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
JJH has received lecture fees and participated in advisory
boards for MSD, NovoNordisk, Lilly, GSK, Sanofi,
Hamni, and AstraZeneca.
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