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Review

Is there a place for incretin therapies


in obesity and prediabetes?
Jens Juul Holst and Carolyn F. Deacon
The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, The Panum Institute, University of
Copenhagen, DK-2200 Copenhagen N, Denmark

Incretin-based therapies exploit the insulinotropic


actions of the gut hormones gastric inhibitory peptide
(GIP) and glucagon-like peptide-1 (GLP-1) for the treatment of diabetes and include GLP-1 receptor agonists
and inhibitors of dipeptidyl peptidase-4 (DPP-4), the
enzyme that inactivates the incretin hormones in the
body. Both drug classes improve metabolic control in
type 2 diabetes (T2DM), with GLP-1 receptor agonists
also lowering body weight. Pharmacotherapy using
DPP-4 inhibitors has few side effects and is weight
neutral. Animal studies support their use in prediabetes;
however, human data are scarce. GLP-1 receptor agonist
effects are also apparent in non-diabetic obese individuals. Therefore, incretin-based therapies, if safe, may be
effective in preventing progression of prediabetes; and
GLP-1 receptor agonists may have potential for use in
the treatment of obesity.
Incretin biology
Incretins are gastrointestinal hormones that increase insulin secretion from pancreatic b cells following food ingestion. They do so with increasing efficacy as plasma
glucose rises [1]. Two main incretin hormones exist in
humans: gastric inhibitory peptide (GIP; also known as
glucose-dependent insulinotropic peptide) and glucagonlike peptide-1 (GLP-1) [2]. Both are secreted by endocrine
cells in the small intestinal mucosa, and are rapidly inactivated by the ubiquitous enzyme dipeptidyl peptidase-4
(DPP-4) [3]. Incretin hormone release is stimulated by food
ingestion and the underlying molecular mechanisms are
currently being investigated [4], with glucose being best
studied. Once released, incretins are carried to the b cells
where they augment glucose-stimulated insulin secretion
[5] although their action is limited because of degradation
by DPP-4 (Figure 1).
Incretin-based therapies
The term encompasses therapies that seek to exploit
the actions of the incretin hormones GLP-1 and GIP.
The incretin-mediated amplification of insulin secretion
(the so-called incretin effect) is related to the amount
of glucose ingested [6], and may account for up to
7080% of the total insulin response to oral glucose administration; thus, the incretin hormones are clearly
Corresponding authors: Holst, J.J. (jjholst@sund.ku.dk); Deacon, C.F.
(deacon@sund.ku.dk).
Keywords: DPP-4 inhibitors; GLP-1 receptor agonists; glucose-dependent
insulinotropic polypeptide; GIP; type 2 diabetes; appetite regulation; glucagon.

potent and powerful stimulators of postprandial insulin


secretion. Given that the incretin effect is severely impaired in T2DM [6,7], mechanisms that boost the incretin
axis might help to improve the inappropriately low insulin
secretion, which characterizes T2DM. Indeed, patients
respond well to GLP-1 administration, whereas the effect
of GIP is almost completely lost [8,9]. Incretin-based therapies are, therefore, mainly focused on GLP-1.
The main hurdle for pharmaceutical development of
GLP-1 therapies was the extreme sensitivity of the molecule to digestion by DPP-4, which cleaves and inactivates
GLP-1 (7-36) amide to GLP-1 (9-36) [10] within 12 min.
GIP is cleaved more slowly, but still has a DPP-4-related
half-life of only 7 min [11,12]. In addition, because there is
no memory effect of previous exposure to the incretins
[13], GLP-1 receptor activation should be maintained for as
long as possible (>24 h) to have full effect. However, the
rapid renal elimination of incretin hormones does not
permit this. Therapeutic strategies, therefore, relied upon
the development of injectable DPP-4-resistant analogs of
GLP-1 or activators of the GLP-1 receptor, together designated GLP-1 receptor agonists (GLP-1 RAs) [14]. Another
option was to block the activity of DPP-4 using orally
available inhibitors, thereby protecting the endogenous
incretin hormones [15]. Both approaches were followed
and proved fruitful: the first marketed drug was the
GLP-1 RA exenatide isolated from the saliva of the Gila
monster [16], which has a half-life of 23 h after subcutaneous administration, and thus requires two daily injections. Recently, a slow release formulation of exenatide,
suitable for once weekly administration, was approved
[17,18]. The next GLP-1 RA to be marketed was liraglutide, an acylated form of human GLP-1, which owes its
DPP-4 resistance and long half-life (12 h) to albumin
binding [19]. The first of the DPP-4 inhibitors, which
are now designated gliptins, sitagliptin, was launched
in 2006; it is suitable for once daily administration
and causes a 23-fold elevation of GLP-1 and GIP concentrations [20,21]. Subsequent years brought a number of
additional inhibitors (with broadly similar pharmacodynamic properties) to the market such as saxagliptin,
vildagliptin, and linagliptin [3]. Together, these make
up the incretin-based therapies.
Should incretin therapy be considered for obesity and/
or prediabetes intervention?
Current concepts about the pathogenesis of T2DM center
around two pathogenetic traits: (i) insulin resistance, in

1043-2760/$ see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2013.01.004 Trends in Endocrinology and Metabolism, March 2013, Vol. 24, No. 3

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Trends in Endocrinology and Metabolism March 2013, Vol. 24, No. 3

Gut nutrients
DPP-4 inhibitor

Increns: GLP-1, GIP

DPP-4 enzyme
Capillary wall
Liver
Blood
Smulates
insulin release

Inacve GLP-1 and


GIP metabolites

Lower blood
glucose
TRENDS in Endocrinology & Metabolism

Figure 1. The incretin system and its regulation by DPP-4. A schematic of the
incretin system is shown. Glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) stimulate insulin release and help to lower blood
glucose. Dipeptidyl peptidase-4 (DPP-4) degrades GLP-1 and GIP to inactive
metabolites. Blue arrows: without DPP-4 inhibitors. Red arrows: with DPP-4
inhibitors.

general secondary to obesity [22]; and (ii) failure of the b


cells to respond appropriately to insulin resistance by
increasing insulin secretion, probably an inheritable trait,
aggravated by dysmetabolic factors including gluco- and
lipo-toxicity [23]. The etiology/pathogenesis of obesity is
likely to be found in a combination of genetic and environmental factors including sedentary lifestyle and easy availability of high energy density food stuffs. This then raises
the question regarding what incretin physiology looks like
in obesity.
GLP-1 and GIP physiology/pathophysiology
The two incretin hormones are secreted from epithelial
endocrine cells in the gut mucosa in response to meal
ingestion. Classically, the cells producing GIP are described as K cells and are located in the upper small
intestine, whereas L cells, mainly located in the distal
small intestine and colon, produce GLP-1. Interestingly,
some upper intestinal cells have been found to produce
both hormones [24]. Furthermore, the gut endocrine cells
show considerable plasticity and may express a variety of
gut hormones, perhaps dependent on factors like maturation as a function of time and/or location along the villous
axis [25,26]. The main documented activity for GIP is
stimulation of insulin secretion, but GIP receptors are
located in numerous additional tissues including brain,
adrenal glands, and adipose tissue. Mice with global deletions of the GIP receptor do not become obese upon high fat
feeding, suggesting that GIP may have a role in fat deposition [27]. The role of its adipogenic action in humans is,
however, uncertain [28]. GIP appears to have pronounced
effects on bone resorption in rodents [29] and may be one of
the gastrointestinal factors responsible for the marked
postprandial inhibition of bone resorption, although
antiosteoporotic effects of GIP in humans have not yet
been demonstrated. GIP secretion, which is stimulated
146

by dietary fat and other macronutrients, is often increased


in obesity [2]. By contrast, GIP secretion is not particularly
affected by the progression of obesity-induced glucose intolerance, and is generally similar in patients with T2DM
and in weight-, gender-, and age-matched controls [30].
The physiologic actions of GLP-1 appear much more diverse. Important tools for physiologic studies include animals with deletions of the incretin receptors, either alone
or in combination. Such studies clearly support the notion
that both hormones are involved in the incretin effect [31],
but GLP-1 receptor knockout animals do not become obese
[32]. The availability of the GLP-1 receptor antagonist,
exendin 9-39, made it possible to analyze the physiologic
actions of GLP-1 in more detail. Again, the effect on insulin
secretion can be nicely demonstrated, but it is also clear
that inhibition of glucagon secretion, a known action of
GLP-1, has an important role in the glucose-lowering effect
of the hormone [33]. However, under normal physiologic
conditions, it may not be the pancreatic effects of GLP-1
that are most important. Rather, its function as an appetite suppressor and enterogastrone hormone(i.e., one of the
ileal hormones that inhibit upper gastrointestinal motility
and secretion postprandially) may be the major role [5].
Thus, gastric emptying rates, and gastrointestinal (GI)
tract motility in general, are strongly inhibited by GLP1 agonists, and GLP-1 receptor antagonism accelerates
gastric emptying [34]. GLP-1 also powerfully suppresses
food intake, presumably via its action on appetite-regulating centers in the brain [35], and conversely GLP-1 receptor antagonists increase food intake in experimental
animals [36]. Thus, GLP-1 may be a physiologically important regulator of appetite and food intake. It should be
noted that GLP-1 is also produced in certain neurons of the
brain stem, projecting to the hypothalamus where it may
function as a transmitter mediating the inhibition of food
intake, but its relevance of this regarding the effects of
peripheral GLP-1 is unclear [35]. GLP-1 (and DPP-4 inhibitors) may also delay post-absorptive lipid absorption [37],
but the physiologic relevance of this is unclear and malabsorption of lipids during chronic GLP-1 agonist therapy has
not been reported. In contrast to GIP, secretion of GLP-1 is
generally impaired in obesity [5]. GLP-1 secretion is stimulated by absorption of digested nutrients [5] with the
magnitude of the response depending on the amount of
nutrient consumed [5,3841]. Nevertheless, it has been
clearly shown that circulating GLP-1 levels are reduced
in obese patients [4248]. GLP-1 responses to oral stimulation have been negatively correlated to BMI [5,47], and
weight loss was associated with increasing GLP-1
responses to meal ingestion [42]. It has been suggested
that the decrease may be related to the insulin resistance
that accompanies weight gain, and/or reduced L -cell responsiveness to carbohydrates, secondary to increased
levels of circulating fatty acids [5,49]. Interestingly, moderate and intense exercise are associated with increased GLP1 levels and decreased hunger; and elevations in GLP-1 were
inversely correlated with energy intake post-exercise [50].
Overall, individuals who have lost weight following changes
in diet or exercise have increased GLP-1 [5]. These
increases, and their resulting effect on satiation signaling,
may contribute to the weight reductions/maintenance

Review
observed with these interventions. Nevertheless, it is probably too early to assign an important pathogenetic role for
impaired GLP-1 secretion in obesity.
Another interesting set of recent observations support
the notion that GLP-1 has potential in prevention of obesity and diabetes. Bariatric surgery, particularly gastric
bypass surgery, is associated with the greatest weight loss
that can be obtained therapeutically and, notably, this is
often associated with resolution of T2DM, present in about
one-third of those admitted for bariatric surgery [51].
Gastric bypass surgery is associated with dramatically
increased postprandial levels of GLP-1, whereas GIP levels
show only minor and inconsistent changes [52]. The GLP-1
increase seems to be secondary to increased exposure of the
distal small intestine, which contains a larger number of
GLP-1-producing cells, to digested nutrients. This was
clearly illustrated in studies of patients with a bypass in
whom it was possible to switch, on 2 consecutive days,
between normal passage of nutrients via the stomach
(using a gastrostomy catheter) and passage through the
bypass. The exaggerated response was only observed
after bypass feeding [53,54]. The post-operative GLP-1
responses, which can be increased by 30-fold, are associated with: (i) increased insulin secretion, which in turn
explains much of the diabetes resolution this conclusion
is supported by studies in which the actions of GLP-1 were
blocked using the GLP-1 receptor antagonist exendin 9-39
[55,56]; and (ii) inhibition of appetite and food intake [57].
Further evidence for the latter includes observations that
post-operative weight loss was significantly correlated to
the magnitude of the GLP-1 response [57]. These results
support the concept that GLP-1 has a major role in postprandial regulation of glucose metabolism and appetite/
food intake, and support speculations regarding possible
preventive use of GLP-1 in obesity and prediabetes.
Clinical effects of GLP-1 RA
As mentioned, GIP has little effect on insulin secretion and
glucose turnover/tolerance in patients with overt T2DM
[9]. It also appears that GIP has no effect on appetite/food
intake in humans, although it might still influence glucose
tolerance in prediabetes and well-controlled diabetes [58].
The interest in the field, therefore, has focused on GLP-1.
Exenatide and liraglutide have well-documented effects
in overt T2DM, as demonstrated in the registration studies
and supported by postmarketing studies [3]. In many
studies, it has been possible to reach a recommended
treatment target [e.g., a fraction of glycated hemoglobin
(HbA1c) below 7%] in 5060% of those treated, which is
equal to or even better than results obtained with insulin
therapy [59]. Importantly, and in contrast to insulin, GLP1 RA therapy is generally associated with significant
weight loss, as well as absence of hypoglycemia, a consequence of the GLP-1 mechanism of action on pancreatic b
cells, which is to augment glucose-induced insulin secretion. Together, these findings are consistent with the
proposed antidiabetic actions of GLP-1 after gastric bypass
surgery [60]. The weight loss is also consistent with the
actions of GLP-1 on appetite and food intake outlined
above. As mentioned, GLP-1 must be considered a physiologic regulator of appetite and food intake; therefore,

Trends in Endocrinology and Metabolism March 2013, Vol. 24, No. 3

amplifying this signal by exogenous administration


might also lower appetite and food intake in non-diabetic
subjects.
Recent clinical trials in obese patients without diabetes
have indicated that GLP-1 RA treatment does decrease
body weight in this group. In one study, obese subjects [n =
152; mean BMI = 39.6 kg/m2; 25% with impaired glucose
tolerance (IGT) or impaired fasting glucose (IFG)] were
randomized to receive exenatide or placebo along with
lifestyle intervention for 24 weeks. Exenatide-treated subjects lost 5.1 kg from baseline versus 1.6 kg with placebo
[61]. Another recent double-blind, placebo-controlled, 20week trial enrolled 564 individuals (1865 years of age,
BMI = 3040 kg/m2) who were randomized to liraglutide
(1.2, 1.8, 2.4, or 3.0 mg/day, n = 9095 per group), placebo (n
= 98), or the lipase inhibitor orlistat (120 mg, n = 95). All
subjects had a 2093 kJ (500 kcal) per day, energy-deficit
diet, and increased their physical activity as measured by a
pedometer throughout the trial. Mean weight losses with
liraglutide (1.2, 1.8, 2.4, and 3.0 mg) were 4.8, 5.5, 6.3, and
7.2 kg, respectively, compared with 2.8 kg with placebo
and 4.1 kg with orlistat [62]. Recently reported results
indicate that the efficacy of liraglutide on weight loss is
sustained for at least 2 years [63,64]. It should be noted
that these studies employed doses considerably higher
than those recommended for diabetes therapy, although
the latter (1.2 mg) was chosen on the basis of acceptably
low rates of mainly gastrointestinal side effects (nausea
and vomiting). However, in the obesity studies, the high
doses were administered to heavy individuals and, when
expressed per kg body weight, they were not too dissimilar.
It is also possible, but still unexplored, that overweight
individuals might tolerate higher doses (per kg) than
normal weight individuals. Side effects may also be minimized by gradual dose escalation, and therefore it is currently being investigated whether T2DM patients may also
tolerate larger doses, perhaps with additional antidiabetic
benefit. Moreover, in obese individuals with IGT (about
one-third of the subjects investigated by Astrup et al.)
glucose tolerance was normalized in the majority during
therapy [63]. This important observation suggests that
GLP-1 RA therapy may actually protect against T2DM
in this high-risk population. A number of clinical trials are
currently investigating this possibility.
Can protection of endogenous incretins delay
progression to T2DM or reduce body weight?
Although the effects of exogenously administered GLP-1
have been extensively studied, few studies have investigated the actions of DPP-4 inhibitors in prediabetes and
obesity. However, there are some data in animal models
suggesting that protection of endogenous GLP-1 might
influence the progression of prediabetes to overt T2DM.
In one of the earliest studies, a long-acting prototype DPP4 inhibitor (FE 999-011) not only normalized the glucose
excursion after oral glucose administration but, intriguingly, also delayed the development of hyperglycemia in
insulin-resistant Zucker obese rats [65]. Similarly, in prediabetic db/db mice increased intact GLP-1 levels were
associated with b cell preservation and delayed progression to diabetes following treatment with alogliptin, and
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the effect was more pronounced after combination treatment with alogliptin and pioglitazone, an agonist for the
insulin sensitizer peroxisome proliferator-activated receptor gamma (PPARg) [66]. Recent studies also reported that
the experimental DPP-4 inhibitor DA-1229 improved b cell
function, and slowed the onset of diabetes in young db/db
mice [67]. In a more mechanistic study, the insulinotropic
and glucagonostatic effects of sitagliptin were preserved in
the spontaneously hypertensive obese (SHROB) rat, a
model displaying many of the characteristics of human
metabolic syndrome [68].
Regarding clinical studies, it appears that the mechanism of action of DPP-4 inhibitors (i.e., increased intact
incretin levels and actions) is operative in subjects without
overt diabetes [6972]. In a study in patients with IFG
there were improvements in b cell function and postprandial glycemia after 6 weeks of vildagliptin treatment,
although fasting glucose levels themselves were unaltered
[69]. In another study, sitagliptin treatment for 8 weeks
was associated with modest improvements in b cell function (according to the Disposition Index) in IFG subjects,
although this was not sufficient to alter endogenous glucose production or glucose uptake, and neither fasting nor
postprandial glucose levels were altered [70]. These findings were corroborated in yet another study, which showed
that 4 weeks of sitagliptin administration enhanced incretin concentrations and decreased fasting glucose concentration in IFG and normal glucose tolerance (NGT)
subjects, without changing whole body or hepatic insulin
sensitivity or indices of b cell function [71]. Thus far, only a
single study has investigated the effects of DPP-4 inhibition in subjects with IGT, showing that vildagliptin administration for 12 weeks reduced postprandial glucose
excursions and improved islet function. This was associated with a small but significant reduction in HbA1c levels
( 0.15%, from a baseline of 5.9%) [72].
Taken together, these studies provide some evidence
that the enhancement of endogenous incretin hormone
levels by DPP-4 inhibition is possible in subjects at elevated risk of progressing to overt T2DM, and that DPP-4
inhibitor administration in prediabetic individuals may
have some modest benefit on glucose homeostasis. However, although animal studies suggest that elevating endogenous incretin hormone concentrations in prediabetes may
delay the transition to diabetes, it remains unproven in
humans (several clinical trials investigating this possibility are listed on clinicaltrials.gov). Numerous clinical trials
have indicated that islet cell dysfunction does improve with
DPP-4 inhibitor therapy in T2DM patients, but there is
presently no evidence that this is associated with actual
increases in b cell mass. In an indirect attempt to assess
this a few studies have examined whether the beneficial
effects of DPP-4 inhibition persist after treatment discontinuation, and it was noted that all parameters returned
rapidly to pre-treatment values. Thus, beneficial effects on
b cell function were reversed within 2 weeks of stopping
vildagliptin, after a 6-week treatment period in IGF subjects [69]. However, although 6 weeks may not have been
long enough for any potential b cell preservation effects to
become evident, there was some suggestion that DPP-4
inhibition was associated with an attenuation of the loss of
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Trends in Endocrinology and Metabolism March 2013, Vol. 24, No. 3

glycemic control in drug-naive patients with T2DM and


mild hyperglycemia given vildagliptin therapy for 2 years
[73]. Thus, the rate of increase in HbA1c levels tended to be
slower with vildagliptin compared with placebo, and b cell
function, as reflected by the insulin secretory rate to glucose (ISR:G) ratio appeared to improve with time, showing
a tendency to be greater in the second compared with the
first year of treatment.
Thus, DPP-4 inhibition might have the potential to
improve glucose homeostasis in people with prediabetes.
However, long-term studies are needed to reveal whether
augmenting endogenous incretin hormones can halt or
reverse the loss of functional b cell mass that underlies
the development and progression of T2DM.
With respect to body weight, DPP-4 inhibitors are generally described as being body-weight neutral, although
modest weight reduction has been seen in some clinical
trials, particularly when DPP-4 inhibitors are used in
combination with metformin [74,75]. In direct comparisons, greater weight loss is seen with GLP-1 receptor
agonists than with DPP-4 inhibitors: up to 3.7 kg with
liraglutide versus 1.2 kg with sitagliptin [76]; 2.0 kg
with exenatide once weekly versus 0.8 kg with sitagliptin
[17], and it has been suggested that the greater agonist
concentrations seen with the injectable GLP-1 analogs are
required to obtain the desired effects on body weight [77].
As mentioned, the weight-reducing effects of GLP-1 RAs
involve interaction with central appetite/satiety centers to
reduce food intake, whereas DPP-4 inhibition has not been
shown to affect satiety in obese patients with T2DM, at
least in the short-term (10 days treatment with vildagliptin) [78]. Nevertheless, the mere fact that DPP-4 inhibition
is not associated with the weight gain that typically accompanies improved glycemic control in patients with T2DM
[79] does suggest that DPP-4 inhibitors may not be
completely neutral in this respect. Although they may
not be a candidate for obesity therapy, the fact that they
are weight neutral is clearly advantageous in the context of
treating T2DM. Interestingly, a recent study reported that,
although DPP-4 inhibition with linagliptin did not prevent
weight gain in rats given a high-fat cafeteria diet, it did
reduce weight regain in animals previously treated with
exenatide if they were switched to linagliptin rather than
placebo [80]. Although presently untested in humans, this
raises the intriguing possibility of using injectable GLP-1
RAs to induce weight loss, followed by introduction of an
oral DPP-4 inhibitor for weight maintenance.
Safety
A prerequisite for every intervention given to apparently
healthy individuals for prevention of a development that
may only strike few of the members of the group (diabetes)
or to ameliorate a physical characteristic of the group that
is not associated with an immediate health threat (obesity)
is that it must have an acceptable safety profile. In general,
incretin-based therapies are well tolerated [81]. For the
GLP-1 RAs the most frequent side effects are gastrointestinal, and include nausea and in some cases vomiting [18].
Both are usually mild and occur early during treatment,
maybe only a few times, and then subside. Few patients
dropped out of the clinical studies because of these side

Review
effects and, given a promise of weight loss, it seems that a
bit of nausea was acceptable for most. The same applies to
the mode of administration subcutaneous injections do
not seem to represent a major obstacle. More serious are
reports of acute pancreatitis in conjunction with incretinbased therapies [82]. During the registration studies, neither liraglutide nor exenatide therapies were associated
with increased incidences of pancreatitis, but a number of
post-marketing reports [83,84] elicited a black box warning
against this risk for exenatide and subsequently also liraglutide and the DPP-4 inhibitors. In the subsequent
follow-up, it became evident that the risk of pancreatitis
is increased approximately 3-fold in people with T2DM
compared with the non-diabetic background population
[85]. However, it has not been possible to identify a mechanism for a GLP-1-induced pancreatitis and, in preclinical
studies examining GLP-1 therapies in experimentally induced pancreatitis, there was amelioration rather than
aggravation [86,87]. In toxicology studies, where huge
doses of GLP-1 agonists were administered to experimental animals for their lifetime, there were no signs of pancreatitis [88]. Additional, careful experiments in large
groups of animals, including diabetic animals, revealed
no evidence of pancreatitis or ductal abnormalitites
[87,89,90]. Furthermore, analyses of very large (>1 million
individuals) health-claim databases have been negative
[91,92]. A recent review of clinical studies discussed the
11 cases observed with liraglutide to date, but provided no
new evidence supporting increased risk of pancreatitis
[93]. A single report claiming increased risk of pancreatitis
and cancer with GLP-1-based therapies, inspired by studies in transgenic animal models [94,95], stands out [96].
The data in this report were collected from the FDA
Adverse Event Reporting System (FAERS) database,
which is open for reporting to everybody, and where reporting frequency, therefore, is strongly influenced by public
awareness. After the FDA pancreatitis warning, the
reporting frequency to the FAERS also increased. The
FDA therefore specifically warns against using the FAERS
database for risk calculation. In the same study [96], the
authors reported increased risk of certain cancers including
pancreatic cancer. Again, neither toxicology nor registration
and postmarketing studies have supported increases in
pancreatic cancer risk. In toxicology studies for liraglutide
increased occurrence of thyroid C cell cancers was noted in
mice and rats [97]. Subsequent studies revealed much
higher GLP-1 receptor expression in C cells from rodents
than in humans and non-human primates, and a sequence of
events encompassing dose-dependent stimulation of secretion (calcitonin), hyperplasia, adenoma, and, in a few cases,
cancer formation could be demonstrated. In human cells
lines there was no similar development. Similar findings
were made with other GLP-1 receptor agonists, suggesting
that the rodent phenomenon is probably a class effect [97]. In
the clinical studies, calcitonin levels have therefore been
carefully followed. This has in itself provided interesting
data on calcitonin levels and secretion in large numbers of
T2DM patients and controls, but a relationship between
secretion and liraglutide therapy could not be established
[98]. Neither registration studies nor postmarketing surveys have identified any increased risk for C cell carcinoma

Trends in Endocrinology and Metabolism March 2013, Vol. 24, No. 3

(medullary thyroid carcinoma), and the US and European


health authorities have accepted that this risk is likely to be
small [99] and, therefore, acceptable in light of the benefits of
the therapy. Although it is impossible on the basis of the
existing data to exclude the possibility that GLP-1-based
therapies may increase the risk of pancreatitis and pancreatic cancer, it can be concluded that the risk is so small that it
escapes detection from even very large databases.
Postmarketing reports regarding renal failure in conjunction with exenatide therapy have also appeared, and
led to a warning against this complication. Although the
effect may possibly be less during chronic treatment, GLP1 RAs are known to cause natriuresis [100]. If this is
superimposed on electrolyte disturbances of other genesis,
perhaps in combination with existing renal insufficiency
(and possibly, in some individuals, mild dehydration due to
prolonged vomiting and/or diarrhea), a mechanism relating therapy and renal failure may actually exist. It is,
therefore, relevant to exert particular care in such cases.
The cardiovascular risk associated with GLP-1 receptor
agonists was reviewed recently [101]. Rather than increasing cardiovascular risk, therapy seems to be associated
with decreased risk. In fact, in a recent study of nearly 40
000 patients treated with exenatide the risk of a cardiovascular event was significantly reduced compared with
other glucose-lowering therapies [102].
For the oral DPP-4 inhibitors the side effect profile
resembles that of placebo [103]. Careful analysis of all
the data collected during the clinical development programs and postmarketing period have revealed no increased incidence of adverse effects relative to placebo or
active comparator; the most commonly reported side
effects have been headache and nasopharyngitis [104
106]. Importantly, given that the incretin-based therapies
were developed for T2DM therapy, it is relevant that
hypoglycemia does not pose a risk, even in subjects with
normal glucose homeostasis, because of the glucose dependency of their islet effects. Cardiovascular risk has also
been assessed but, rather than increasing this risk, it
seems from controlled clinical trials that GLP-1-based
therapies may actually decrease cardiovascular risk
[101]. Similar findings were reported from a meta-analysis
of 43 clinical trials involving more than 20 000 patients
treated with DPP-4 inhibitors [104]. Currently, a number
of very large, long-term outcome studies of cardiovascular
risk associated with incretin-based therapies are being
carried out and results are expected from 2014 onward.
Concluding remarks
Obesity and prediabetes are generally looked upon as
being inflicted by an unhealthy lifestyle, and the logical
approach to their prevention and therapy, therefore, is
lifestyle changes. Although this approach can be effective
[107], its application on a larger scale is generally disappointing and, because the problem is enormous and already imposing a heavy burden on societal health
expenses, it may be relevant to look for medical/pharmaceutical solutions. Recent studies have documented that
GLP-1 agonist therapy brings about significant weight
loss, not only in individuals with T2DM but also in nondiabetic obese individuals. Simultaneously, the therapy is
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associated with improved metabolism and glucose tolerance, suggesting that GLP-1 agonists may indeed be useful
for diabetes prevention. The weight loss with higher doses
may amount to 510% of body weight and may therefore
satisfy criteria set up for successful antiobesity therapy.
The effect of the DPP-4 inhibitors on body weight is minimal, but they do have beneficial effects on glucose metabolism and possibly also lipid metabolism, therefore having a
(as yet poorly explored) potential for diabetes prevention in
high risk groups. The GLP-1 agonists require subcutaneous injections, but this seems acceptable for most subjects
who seek to lose weight. This promising potential should,
however, be weighed against the risk of side effects. It must
be recognized that obesity and prediabetes are themselves
associated with a not inconsiderable increased health risk;
if treatment of the condition reduces this risk, even if
associated with new treatment-related risks in a minority
of subjects, this must be considered beneficial. Currently, it
is impossible to obtain precise estimates of the risk of the
more serious adverse effects (i.e., pancreatitis and cancer)
that have been claimed by some to be associated with GLP1-based therapies. This is because they are so rare that
they are difficult to distinguish from the spontaneous
occurrence rates in the (obese) background population.
In the coming few years, the results of very large, longlasting outcome studies, including those evaluating cardiovascular safety or risk benefit, that are currently ongoing will be known and will provide a background for a
decision on whether to engage in preventive therapeutic
studies of lifestyle diseases.
Disclaimer statement
The authors have not received any fees or other forms of support from any
pharmaceutical agency for the preparation of this review.
J.J.H. has consulted for NovoNordisk and is an advisory board member
for NovoNordisk, MSD, and Eli Lilly, and has received lecture fees from
them. C.F.D. has consulted for Eli Lilly and MSD, and has received
lecture fees from BMS, MSD, Boehringer Ingelheim, Eli Lilly, and
NovoNordisk.

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