Diabetes, Obesity and Metabolism 14: 675688, 2012.

2012 Blackwell Publishing Ltd

GLP-1 based therapies: differential effects on fasting

and postprandial glucose
M. S. Fineman1 , B. B. Cirincione2 , D. Maggs2 & M. Diamant3
1 Elcelyx Therapeutics, Inc., San Diego, CA, USA
2 Amylin Pharmaceuticals, Inc., San Diego, CA, USA
3 Diabetes Center, VU University Medical Center, Amsterdam, the Netherlands

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions
including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction
in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies.
However, GLP-1 has signicant limitations as a therapeutic due to its rapid degradation (plasma half-life of 12 min) by dipeptidyl peptidase-4
(DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have
differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering
potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R
agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the
choice of which one to use should depend on the specic needs of the patient. This is analogous to the current use of modern insulins, as
short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose prole as needed. Given that GLP-1-mediated
therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a
signicant paradigm shift for the treatment of type 2 diabetes.
Keywords: antidiabetic drug, DPP-IV inhibitor, exenatide, GLP-1, GLP-1 analogue, incretin therapy
Date submitted 27 June 2011; date of first decision 19 August 2011; date of final acceptance 3 January 2012

Introduction

The Biology of GLP-1

The goal of diabetes therapy is to reduce 24-h blood glucose

to near normal values. While haemoglobin A1c (HbA1c) is the
universally accepted marker of average blood glucose used to
determine if additional therapy is necessary, measurements
of fasting and postprandial glucose provide guidance for
which added therapies are likely to have the most benefit
for that patient. Monnier et al. demonstrated that fasting
hyperglycaemia is the major contributor to HbA1c in poorly
controlled subjects, while postprandial hyperglycaemia is the
major contributor to HbA1c in subjects nearing target goals [1].
Thus, it is important to understand both the fasting and
postprandial potential of diabetes therapies. While glucagonlike peptide-1 (GLP-1)-mediated therapy was originally
considered to be mainly a postprandial treatment, newer
generations of these therapies have different attributes. This
review focuses on the differences in fasting and postprandial
glucose-lowering effectiveness of the various classes and
subclasses of GLP-1-mediated therapies.

GLP-1 is an incretin hormone secreted from gastrointestinal L

cells predominantly found in the ileum, colon and rectum
in response to nutrients [24]. Following food ingestion,
GLP-1 appears in the plasma within minutes and due to
its rapid degradation by dipeptidyl peptidase-4 (DPP-4), is
undetectable by 3 h [57]. Given that enteroendocrine L cells
are predominantly located in the distal gut, it is proposed that
rapid appearance of GLP-1 in the plasma following a meal is
likely a result of indirect hormonal and/or neural signalling as
opposed to direct nutrient contact with GLP-1 secreting cells
in the proximal gut lumen [8].
The human GLP-1 receptor (GLP-1R) is a 463 amino acid
G-protein coupled receptor expressed on pancreatic islet and
cells and many other tissues including the gastrointestinal
tract, heart, kidney, lung and the peripheral and central
nervous systems [9, 10]. Receptor activation is linked to the
cyclic AMP second messenger pathway [11]. Although receptor
desensitization has been demonstrated in vitro, 1 week of twice
daily administration of the GLP-1R agonist exenatide to wildtype mice, did not result in downregulation of the glucose
lowering effect following an oral glucose load [12].

Correspondence to: M.S. Fineman, Elcelyx Therapeutics, Inc., San Diego, CA, USA.
E-mail: marksneman@gmail.com

review
article

review article

review article
GLP-1 is thought to play an important physiological role to
regulate plasma glucose in the postprandial period through
several mechanisms of action: enhancement of glucosestimulated insulin secretion, suppression of glucagon secretion
and slowing of gastric emptying [1319]. GLP-1 enhances
insulin secretion in a glucose-dependent manner [20],
augmenting both the first and second phase of secretion [21].
While GLP-1 clearly has direct effects on pancreatic cells,
a portion of the insulin response may be mediated through
an indirect afferent nervous system pathway [22]. The effect
of GLP-1 on glucagon secretion is also glucose dependent,
occurring during euglycaemia but does not affect the
glucagon response to hypoglycaemia (3.7 mmol/l) [20]. The
mechanisms by which GLP-1 suppresses glucagon secretion
could include a direct effect on the pancreatic -cell but it
is conceivable that additional indirect effects include local
stimulation of insulin, amylin and somatostatin secretion [8].
GLP-1 is a potent inhibitor of gastric acid secretion and
gastric emptying. Although the exact mechanisms by which
GLP-1 regulates gastric function are unknown, it is clear that
vagal afferents are important [23, 24]. Effects on gastric acid
secretion may also be mediated through direct interaction with
parietal cells [25]. On balance, the gastric emptying effect may
be more important than insulin in controlling postprandial
plasma glucose (PPG) as it limits the rate and extent of mealderived glucose presented to the -cell [26]. In fact, infusion
of GLP-1 to subjects with type 2 diabetes results in significant
and dose-dependent reductions in PPG and gastric emptying
without an increase in plasma insulin [27]. There are also
data from experiments in the conscious dog suggesting that
GLP-1 may augment non-hepatic glucose clearance through a
noninsulin-mediated mechanism involving neural signalling
in the portal vein [28, 29]. In addition, both animal and human
studies suggest that GLP-1 may play a role in reducing insulin
resistance. The effect has been observed in a variety of insulinresistant diabetic animal models [30] and in human subjects
with type 2 diabetes [31]. In humans, the magnitude of the effect
appears to be less than that seen with the thiazolidinedione
(TZD) class and it is unclear if the effect is independent
of the concomitant weight loss often observed. Pair-feeding
experiments in non-diabetic, insulin-resistant obese fa/fa
Zucker rats treated with exenatide for 6 weeks suggest that
a portion of the insulin-sensitizing effect (25%) could not
be explained by weight loss [32]. Lastly, GLP-1 appears to
play a role in mealtime satiety signalling, which could impact
plasma glucose through a reduction in caloric load ingestion,
leading to reductions in bodyweight [13, 19, 33, 34]. In the
case of food intake, GLP-1 likely acts centrally by crossing the
bloodbrain barrier and acts indirectly through vagal-mediated
pathways [10, 35]. Collectively, these mechanisms work in
concert to regulate energy intake and glucose flux during the
prandial period, allowing for appropriate consumption and
delivery of nutrients from the gut to the circulation in order
to optimized fuel storage without large glucose fluctuations in
plasma.
In addition, GLP-1R knockout mice have fasting hyperglycaemia, suggesting that GLP-1 could play a tonic role in
regulating fasting plasma glucose (FPG) [36]. The mechanisms

676 Fineman et al.

DIABETES, OBESITY AND METABOLISM

for such an effect are less clearly discerned. However, the pharmacological potential of this molecule was fully manifested
with acute GLP-1 infusion studies in subjects with type 2 diabetes that demonstrated a near-normalization of both FPG
and PPG [31]. The wider biologic role of GLP-1 to positively
regulate body weight adds to the pharmacological potential of
the hormone.

GLP-1-Mediated Therapies for Type 2

Diabetes
The GLP-1R system has become an attractive target for
type 2 diabetes therapies due to the multiple glucose and
bodyweight regulating properties attributed to endogenous
GLP-1. Native GLP-1, however, has significant limitations as
a therapeutic due to its rapid degradation by DPP-4 (plasma
half-life of 12 min). DPP-4 is a ubiquitous plasma membrane
glycopeptidase present on epithelial cells in a host of tissues
including the gastrointestinal tract, kidneys, brain, pancreas,
lymph nodes, thymus and vascular bed [37]. A soluble form
of DPP-4 can also be found in the plasma and in other
body fluids. DPP-4 selectively removes N-terminal dipeptides
when alanine or proline is in the second position. Thus, both
endogenous and exogenous GLP-1 are rapidly metabolized
from GLP-1-(7-36) to GLP-1-(9-36) by DPP-4, rendering it
without glucose-lowering properties [38].
To circumvent the half-life constraint of GLP-1, two
novel classes of glucose-lowering therapeutics have emerged:
DPP-4 inhibitors (also referred to as gliptins) and GLP-1R
agonists. DPP-4 inhibitors enhance the effects of endogenous
GLP-1 by inhibiting the enzyme that inactivates it. GLP-1R
agonists mimic the actions of GLP-1 but have DPP-4resistant properties by virtue of their amino acid sequence
and/or through chemical modification. Both classes have
demonstrated effective utility for the treatment of type 2
diabetes [8, 35, 3943]. Differences in their pharmacology,
however, result in differential mechanisms of action and
ultimately in differences in fasting and postprandial glucoselowering potential as described below.

DPP-4 Inhibitors (Gliptins)

DPP-4 inhibitors sitagliptin, saxagliptin, and recently,
linagliptin have been approved in the United States for the
treatment of type 2 diabetes. In Europe, sitagliptin, saxagliptin
and vildagliptin are approved for use. DPP-4 inhibition leads
to elevated plasma concentrations of GLP-1, which in turn
enhances glucose-dependent insulin secretion and suppresses
inappropriately elevated glucagon secretion [44]. Notably,
DPP-4 inhibitors do not appear to have an effect on gastric
emptying [2, 45].
In a meta-analysis of randomized controlled studies of at
least 12 weeks, DPP-4 inhibitors resulted in a weighted mean
reduction in HbA1c of 0.74% (8.1 mmol/mol) compared to
placebo [46]. Similar results were observed in a second metaanalysis by Fakhoury et al. [43]. While DPP-4 inhibitors have a
small effect on PPG, the majority of the HbA1c lowering effect
results from reductions in FPG [45, 47, 48]. Recently, Hjllund

Volume 14 No. 8 August 2012

review article

DIABETES, OBESITY AND METABOLISM

GLP-1R Agonists with Intermittent Exposure

Exenatide Twice Daily
The first GLP-1R agonist to be approved for clinical use was
exenatide. Exenatide is a synthetic form of exendin-4, a 39
amino acid peptide isolated from the salivary secretions of the
gila monster (Heloderma suspectum). It shares 53% sequence
identity with GLP-1 and is equipotent at the GLP-1R [57].
Exenatide is DPP-4 resistant, resulting in an extended halflife relative to GLP-1 (2.4 h) [58]. Plasma concentrations of
exenatide are detectable for approximately 67 h following a
subcutaneous injection in the abdomen, arm or thigh [59].
Like GLP-1, exenatide slows gastric emptying [60], suppresses
glucagon [61, 62] and enhances first- and second-phase
glucose-stimulated insulin secretion, as well as insulin
secretion in response to a combined glucose and arginine
stimulus [6365]. Importantly, the actions of exenatide on
insulin and glucagon secretion occur during euglycaemia,
but not during hypoglycaemia [64], providing a safeguard
against inducing or prolonging hypoglycaemia with long-term
clinical use. Acute exenatide administration leads to robust
dose-dependent reductions in PPG when bolus subcutaneous
injections are administered prior to a meal [61, 62] and to
reductions in FPG when administered during an extended
fast [61]. When exenatide was subcutaneously infused for 24 h

Volume 14 No. 8 August 2012

in patients with type 2 diabetes, dose-dependent reductions in

both FPG and PPG were observed [66]. The reductions in PPG
observed with acute administration of exenatide were sustained
following 28 days of two times a day (BID) or three times a
day (TID) treatment [67]. Treatment for 1 year with exenatide
BID improved -cell function compared to insulin glargine
with similar overall reductions in HbA1c [68]. At 52 weeks,
C-peptide secretion was increased 2.46-fold with exenatide
compared to 1.34-fold with insulin glargine (p < 0.0001).
The effects of exenatide and sitagliptin on postprandial
glucose metabolism were compared in a randomized 2-week
crossover study in patients with type 2 diabetes [47]. Both treatments resulted in reductions in PPG (figure 1) and glucagon
compared to baseline, although the magnitude of effect was significantly greater (glucose; p < 0.0001, glucagon; p = 0.0011)
for exenatide compared to sitagliptin. It is noteworthy that
with exenatide treatment, the PPG rise is almost completely
blunted following the meal with concentrations falling below
the preprandial concentration within 1 h. This suggests that
the effects on gastric emptying, glucagon secretion and insulin
secretion are all contributing to the overall glucose profile.
Exenatide 10 g significantly slowed gastric emptying while
sitagliptin 100 mg did not change the gastric emptying rate from
baseline. Finally, mean caloric intake during an ad libitum meal
was reduced by 134 kcal from baseline with exenatide compared to an increase of 130 kcal from baseline with sitagliptin
(p = 0.0227).
Treatment with exenatide 10 g BID (breakfast and dinner)
for 30 weeks resulted in mean reductions in HbA1c of 0.91.0%
(9.810.9 mmol/mol) compared to placebo when added to
metformin [69], a sulfonylurea (SFU) [70] or a combination
of metformin and a SFU [71]. Consistent with the fact that
exenatide is cleared from circulation in 67 h, only modest
reductions in FPG (1.0 to 1.4 mmol/l) were observed compared
to placebo. Placebo corrected weight loss ranged from 0.3 to
2.5 kg with the greatest loss observed in metformin-treated
subjects. A subset of the subjects in these studies underwent a
16
Postprandial Glucose (mmoL/L)

et al. reported that DPP-4 inhibitors have a greater impact

on portal vein GLP-1 concentrations (fourfold) than on
concentrations in the peripheral circulation (twofold) [49].
One could speculate that DPP-4 inhibitors may therefore exert
more of an effect on FPG through augmentation of the portal
signal. Glucagon suppression is noted in the prandial state, but
stimulation of insulin secretion is modest compared to other
GLP-1 based therapies and there is little to no effect on gastric
emptying [44, 45, 47, 50].
While both chronic infusions and bolus injections of
GLP-1 are associated with weight loss [31, 33], administration of DPP-4 inhibitors typically results in weight neutrality [8, 5153]. Modest weight loss, however, has been observed
with the DPP-4 inhibitor, vildagliptin, in well-controlled
patients, and it may reduce intestinal fat absorption [53]. It
is not clear if the effects on fat absorption are specific to
vildagliptin or if they can be generalized to other DDP-4
inhibitors or GLP-1R agonists.
The reasons for the reduced effect of DPP-4 inhibitors on
gastric emptying and bodyweight are not clear. DPP-4 inhibition results in an approximate doubling of active GLP-1 in
the peripheral circulation and perhaps these concentrations
are insufficient to induce these mechanisms of action. Given
that both the gastric emptying and satiety effects of GLP-1 are
centrally mediated, higher concentrations of circulating GLP-1
may be required compared to the concentrations necessary to
affect insulin and glucagon secretion [54]. Additionally, DPP-4
activates peptide tyrosine-tyrosine (PYY) [55], a gut peptide
known to slow gastric emptying and reduce food intake [56].
Thus, if DPP-4 inhibitors reduce active PYY (PYY 3-36) concentrations, the effects of GLP-1 to slow gastric emptying and
reduce food intake may be masked by the loss of a PYY effect.

Baseline
Exenatide N=61
Sitagliptin N=61

15
14
13
12
11
10
9
8
7
6
5
-30

30

60

90

120

150

180

210

240

Time (min)

Figure 1. Mean (s.e.) postprandial plasma glucose concentration during a

standard meal at baseline and after treatment with exenatide or sitagliptin.
Exenatide was administered at T = 15 min. Sitagliptin was administered
at T=30 min. Standardized meal was given at T = 0 min. Adapted from
Ref. [47].

doi:10.1111/j.1463-1326.2012.01560.x 677

review article

DIABETES, OBESITY AND METABOLISM

standardized breakfast meal challenge at baseline and after 4

and 30 weeks of treatment. As shown in figure 2, at 4 weeks,
the postprandial rise in plasma glucose was almost completely
blunted with exenatide treatment. The postprandial profiles
at 30 weeks were slightly higher in all three treatment groups
(5 g, 10 g and placebo) compared to the 4-week profiles,
but the differences between exenatide and placebo remain
Baseline
5 mcgs BID N=44
10 mcgs BID N=52
Baseline

Postprandial Glucose (mmol/L)

16
15
14
13
12
11
10
9
8
7
6
-30

30

60

90

120

150

Week 4

Postprandial Glucose (mmol/L)

14
13
12
11
10
9
8
7
0

30

60

90

120

150

180

120

150

180

Time (min)

Week 30
Postprandial Glucose (mmol/L)

16
15
14
13
12
11
10
9
8
7
6
-30

30

60

90

Time (min)

Figure 2. Mean (s.e.) postprandial plasma glucose concentration during a

standardized meal at baseline (day 1) and after 4 and 30 weeks of twice daily
exenatide treatment. Study medication was administered at T = 15 min.
A standardized meal was given at T = 0 min. Results are a combined cohort
of subjects from three published studies, Refs [6971].

678 Fineman et al.

Although the plasma half-life of exenatide is a significant

improvement over native GLP-1, the duration of exposure is
still limited to 67 h following an injection. Thus, exenatide
given twice daily at breakfast and dinner provides intermittent
exposure and exerts its main effects during the prandial period
of those main meals.
Multiple strategies have been employed to extend the
apparent half-life of GLP-1R agonists by slowing the rate
of absorption and/or by reducing plasma clearance. Such
strategies improve patient convenience by reducing the
frequency of administration and enhance the effects on
FPG by providing continuous exposure. One such product,
liraglutide, is currently available in the United States and
Europe. In addition, an extended-release version of exenatide
has been developed which is available in the United States and
Europe.

Exenatide Once Weekly

15

6
-30

GLP-1R Agonists with Continuous Exposure

180

Time (min)
16

constant through 30 weeks. This suggests that there is little

to no tachyphylaxis of the effect of exenatide on PPG with
intermittent administration.

The extended-release formulation of exenatide was developed to provide continuous exenatide exposure with once
weekly administration (exenatide once weekly). The formulation utilizes biodegradable polymeric microspheres, composed
of exenatide in a poly lactide-co-glycolide (PLG) polymeric
matrix. This extended-release formulation is injected subcutaneously and slowly releases native exenatide into the
subcutaneous space through a complex process of polymer
hydration and degradation [72]. Thus, this absorption ratelimited formulation allows for continuous systemic exposure
of exenatide without modification of the native peptide. Once
absorbed, the general pharmacokinetic properties of exenatide
are unchanged compared to exenatide BID.
In 26- and 30-week controlled trials, the extended-release
formulation of exenatide once weekly resulted in HbA1c
reductions from baseline ranging from 1.5 to 1.9% (16.4
to 20.8 mmol/mol) [7376] with more substantial improvements in FPG than had been observed in the exenatide
BID studies. The short and long-acting exenatide formulations were directly compared in two studies of 26-week [74]
and 30-week [76] duration. In the 26-week study, exenatide once weekly resulted in significant improvements in
HbA1c compared to exenatide BID [1.6 vs. 0.9% (17.5 vs.
9.8 mmol/mol); p < 0.0001] with improved FPG relative to
exenatide BID (1.94 vs. 0.66 mmol/l; p = 0.0008). Reductions in mean body weight from baseline to week 24 were
not statistically different between groups (2.3 and 1.4 kg).
Similar results were observed in the 30-week study [HbA1c:
1.9 vs. 1.5% (20.8 vs. 16.4 mmol/mol), p = 0.0023; FPG:
2.3 vs. 1.4 mmol/l, p < 0.0001].
The 30-week study also included a standardized meal
challenge at baseline and 14 weeks (after exenatide once
weekly achieved steady-state plasma exenatide concentrations).

Volume 14 No. 8 August 2012

review article

DIABETES, OBESITY AND METABOLISM

Notably, the effects on postprandial glucose excursion and

gastric emptying were greater with exenatide BID than with
exenatide once weekly (figure 3A, B and Table 1). The mean
reduction from baseline in 2-h postprandial plasma glucose
was 6.9 mmol/l with exenatide BID versus 5.3 mmol/l with
exenatide once weekly (p = 0.0124). Gastric emptying was
assessed by comparing the absorption of acetaminophen
following a 1000-mg oral dose administered before the
standardized meal tests. Exenatide BID treatment resulted in a
21% reduction in acetaminophen Cmax and a 20% reduction
in area under the curve (AUC) compared to baseline. In
contrast, exenatide once weekly treatment resulted in only a
5% reduction in Cmax and a 4% reduction in AUC.
The reduced PPG and gastric emptying effects of exenatide
once weekly cannot be explained by lower exenatide plasma
exposure, as the geometric mean plasma concentrations were
higher with exenatide once weekly (280310 pg/ml) than with
exenatide BID (60140 pg/mL) over the 5-h meal test period
(figure 3C, D). The differences also cannot be explained by
differences in chemical structure between the two therapies
because both release unmodified exenatide into circulation.
These data therefore suggest that continuous GLP-1 agonist
exposure downregulates the effects on gastric emptying which
in turn reduces the effect on postprandial glucose excursions.
A

Geometric mean (SE)

Ratio of week 14/baseline

Baseline

Geometric
LS mean

90% CI of
the mean

0.95
0.79

0.81, 1.11
0.66, 0.93

0.96
0.80

0.84, 1.09
0.70, 0.92

Week 14

Cmax 0 5h
(g/ml)
Exenatide QW 11.22 (0.99) 10.61 (0.75)
Exenatide BID 11.67 (0.80) 9.17 (0.94)
AUC0 5h
(g min/ml)
Exenatide QW 1729 (113) 1651 (141)
Exenatide BID 1831 (96) 1462 (158)

AUC 0 5h , area under the 5 h concentration curve; BID, two times a

day; Cmax , maximum concentration; SE, standard error of the mean; LS,
least squares mean; CI, confidence interval; Exenatide QW, exenatide once
weekly.

This hypothesis is consistent with a recent report by Nauck

et al. that demonstrated a reduced gastric emptying and PPG
effect at the lunch meal compared to the breakfast meal
during a continuous intravenous infusion of native GLP-1 [77].
B

Exenatide BID

Exenatide Once Weekly

16

15
14

Baseline
Week 14

13
12
11
10
9
8
7
6
5
-30

30

60

90

Postprandial Glucose (mmol/L)

Postprandial Glucose (mmol/L)

16

Table 1. Acetaminophen pharmacokinetic parameters following a 1000mg oral dose (N = 75).

15
14
12
11
10
9
8
7
6
5
-30

120 150 180 210 240 270 300

Baseline
Week 14

13

30

60

90

400

C
Week 14

350
300
250
200
150
100
50
0
-30

30

60

90

120 150 180 210 240 270 300

Time (min)

120 150 180 210 240 270 300

Time (min)

Geometric mean (SD) Exenatide pg/mL

Geometric mean (SD) Exenatide pg/mL

Time (min)

400

D
Week 14

350
300
250
200
150
100
50
0
-30

30

60

90

120 150 180 210 240 270 300

Time (min)

Figure 3. Mean (s.e.) time profiles of postprandial plasma glucose concentrations at baseline and week 14 during the meal challenge comparing exenatide
two times a day (BID) (A) versus exenatide once weekly (B). Geometric mean (s.d.) time profiles of plasma exenatide concentration at week 14 during the
meal challenge for exenatide BID (C) versus exenatide once weekly (D). Meal challenge subgroup, N = 51. Adapted from Ref. [76].

Volume 14 No. 8 August 2012

doi:10.1111/j.1463-1326.2012.01560.x 679

review article

DIABETES, OBESITY AND METABOLISM

Given the short time course (4 h between meals), the authors

proposed that this finding indicated a tachyphylaxis of the
gastric emptying effect at the level of the vagal nerve rather
than GLP-1R downregulation or desensitization. Interestingly,
there appears to be tachyphylaxis of nausea (the most common
side effect) with chronic exenatide BID treatment without a
loss of effect on gastric emptying or PPG [6971, 78] and
less nausea is observed with exenatide once weekly than with
exenatide BID despite higher plasma concentrations [76].
Several groups have described the observation that glucose
tolerance is improved at the second meal of the day relative
to the first, a phenomenon referred to as the Staub-Traugott
effect [79, 80]. Interestingly, Bonuccelli et al. have shown that
plasma concentrations of GLP-1 are elevated at the second
meal of the day relative to the first, and that the Staub-Traugott
effect is mediated through an enhanced insulin response to
glucose, and a suppression of hepatic glucose production
without changes in the gastric emptying rate [79]. This suggests
that augmentation of GLP-1 concentrations by means other
than DPP-4 inhibition also does not affect gastric emptying but
may improve glucose tolerance through other mechanisms.

Liraglutide
Liraglutide is a DPP-4-resistant GLP-1 analogue that achieves
slowed absorption and increased half-life through the
substitution of arginine for lysine at position 34 and the addition
of a C16 fatty acid chain at position 26 allowing for reversible
binding to albumin [81, 82]. The half-life of liraglutide is
1115 h resulting in continuous exposure with once-daily
(QD) administration [82]. Although the potency of liraglutide
is reduced 100-fold relative to GLP-1 (albumin binding is
9899%), it retains the basic actions of GLP-1 [2]. Longterm treatment with liraglutide 1.8 mg results in reductions in
HbA1c of 1.01.3% (10.914.2 mmol/mol) and reductions in
FPG of up to 2.4 mmol/l [8387].
Clinical trial results with liraglutide support the hypothesis
that continuous GLP-1R agonism may downregulate the gastric
emptying effect. While there are no head-to-head studies
available that directly compare the gastric emptying effects
of exenatide BID and liraglutide, it appears that liraglutide has
a reduced effect on gastric emptying compared to exenatide
BID based on individual observations. In a single dose study
of liraglutide on subjects with diabetes, gastric emptying was
significantly reduced by 9% compared to placebo as assessed by
the 4-h plasma AUC of 3-o-methyl-glucose (3-OMG) following
oral administration [88]. No effect on gastric emptying at
breakfast or dinner was observed in subjects with type 2
diabetes treated with liraglutide for 1 week as assessed using
the acetaminophen technique [89]. In addition, when gastric
emptying was assessed at weekly intervals during a dose titration
of liraglutide 0.6 mg (week 1), 1.2 mg (week 2) and 1.8 mg
(week 3), the effects were more pronounced at week 2 than
week 3 despite a higher dose at week 3 [90]. This is suggestive of
tachyphylaxis although definitive conclusions cannot be made.
Consistent with a reduced effect on gastric emptying, liraglutide lowers PPG mostly through a reduction in preprandial
glucose (figure 4) [8890] although some reduction in the
postprandial increment above fasting is evident [90]. The latter

680 Fineman et al.

Figure 4. Mean postprandial plasma glucose profiles during a meal test

performed at steady-state liraglutide doses of 0.6, 1.2 and 1.8 mg or
placebo (N = 18). Reprinted with kind permission from Springer Science
and Business Media, Ref. [90], figure 3.

can be explained by modest reductions in the rate of gastric emptying and more pronounced effects on glucagon and
insulin secretion as is the case with exenatide once weekly [76].
This is in contrast to the PPG profiles observed with exenatide
BID in which little to no rise above fasting concentrations can
be observed following a meal (figures 1, 2 and 3). The differences between exenatide BID and liraglutide are well illustrated
in a 26-week head-to-head study in subjects with type 2 diabetes [91]. In that study, the reduction in HbA1c was greater
with liraglutide compared to exenatide BID [1.16 vs. 0.87%
(12.7 vs. 9.5 mmol/mol)] as a result of larger reductions in FPG
(treatment difference = 1.0 mmol/l). In contrast, exenatide
BID had greater reductions in PPG compared to liraglutide at
breakfast (difference = 1.3 mmol/l) and at dinner (difference
= 1.0 mmol/l).
The improvements in FPG observed with liraglutide are likely
a result of the higher fasting plasma insulin and lower fasting
plasma glucagon concentrations observed with liraglutide
versus exenatide BID, although the glucagon difference did not
achieve statistical significance (p = 0.144). This difference can
be explained by differences in pharmacokinetics as exenatide
BID should be cleared from circulation by the time the fasting
samples were drawn.
There is currently no data to directly compare the effects of
liraglutide and exenatide on fasting insulin and glucagon when
both compounds are at their individual plasma therapeutic
concentrations. Additionally, there is currently no data to
directly compare the effects of liraglutide and exenatide on
postprandial plasma insulin and glucagon. Interestingly, it
appears that short- and long-acting GLP-1R agonists have
similar effects on bodyweight as described in head-to-head

Volume 14 No. 8 August 2012

review article

DIABETES, OBESITY AND METABOLISM

studies [74, 76, 91]. This is somewhat surprising given that

exenatide BID administration only results in therapeutic plasma
concentrations during the breakfast and dinner meals, and
exenatide once weekly and liraglutide administration result
in therapeutic concentrations throughout the day (breakfast,
lunch, dinner and snack times). This may suggest that the
effect of exenatide BID on satiety may last longer than the
pharmacokinetics would predict. Alternatively, it may suggest
that there is a partial downregulation of the satiety signal
with continuous GLP-1R agonism that is compensated for by
providing coverage across all meals.

GLP-1R agonists in Development

There are several GLP-1R agonists in late-stage development
including the relatively short-acting lixisenatide, once weekly
dulaglutide (LY2189265) and once weekly or once monthly
albiglutide. Although public data on the pharmacokinetics
and effects on PPG are somewhat limited for these compounds, it appears that the shortest acting compound may
have the most robust postprandial effect, while the longacting molecules appear to work predominantly through
improvements in FPG.

Lixisenatide
Lixisenatide is based on the structure of exenatide but it has been
C-terminally modified with six lysine residues. Its terminal halflife is reported to be approximately 3 h which may be slightly
longer than that of native exenatide [92, 93]. In a phase 3 trial of
lixisenatide in patients with type 2 diabetes inadequately treated
with metformin, QD and BID administration of lixisenatide
for 13 weeks resulted in statistically significant reductions
in HbA1c compared to placebo [94]. The highest dose of
20 g achieved an HbA1c reduction from baseline of 0.76%
(8.3 mmol/mol) and 0.87% (9.5 mmol/mol) for the QD and
BID regimens, respectively, compared to a reduction of 0.18%
(2.0 mmol/mol) for placebo. The authors conclude that the
20-g dose administered QD provided the best efficacy-totolerability ratio. The 20-g QD dose was associated with
robust reductions in the 2 h PPG value following a breakfast
meal (3.57 0.62 mmol/l) but had modest reductions in FPG
(0.80 0.25 mmol/l). In a 28-day trial of lixisenatide comparing
20 g QD to 20 g BID, the effects on PPG appeared to wane by
the evening meal in the QD arm [95]. These data are consistent
with lixisenatide providing intermittent exposure which may
be an advantage for targeting PPG either alone or on the
background of basal insulin [96].

Dulaglutide
Dulaglutide is an analogue of GLP-1 covalently linked to the
Fc fragment of an IgG4 [97]. The molecule is DPP-4 resistant
and has reduced renal clearance due to the size of the fusion
protein. The mean plasma half-life is approximately 4 days and
steady-state concentrations are achieved after the second weekly
dose [98]. In a 16-week study, 262 overweight/obese patients
titrated to 1.0 or 2.0 mg once weekly achieved HbA1c reductions of 1.28% (14.0 mmol/mol) to 1.52% (16.6 mmol/mol)

Volume 14 No. 8 August 2012

compared to a reduction of 0.27% (3.0 mmol/mol) on placebo.

These reductions were accompanied by robust effects on FPG
(2.09 to 2.64 mmol/l for dulaglutide vs. 0.49 mmol/l for
placebo) and weight loss (1.58 to 2.51 kg dulaglutide vs.
0.07 kg placebo) [99]. Glucose excursions following a test
meal were statistically significant on dulaglutide compared
to placebo, but the overall effect was small relative to FPG
reductions.

Albiglutide
Albiglutide consists of two copies of a DPP-4-resistant GLP-1
analogue linked to human albumin. The resultant molecule
has a plasma half-life of approximately 58 days making it
very suitable for once-weekly dosing and could possibly be
effective as a monthly therapy [100]. Steady-state concentrations of albiglutide are achieved by 5 weeks with weekly dosing.
Weekly and monthly treatment regimens were compared in a
phase 2 study of 356 patients with type 2 diabetes. After 16
weeks, the HbA1c reduction was 0.87% (9.5 mmol/mol), 0.79%
(8.6 mmol/mol) and 0.87% (9.5 mmol/mol) for albiglutide
30 mg weekly, 50 mg biweekly and 100 mg monthly, respectively, compared with a reduction of 0.17% (1.9 mmol/mol)
for placebo [101]. As with other long-acting GLP-1 agonists,
the predominant effect is a lowering of FPG and preprandial
glucose with very little effect on the postprandial rise above the
fasting value [102].

Potential Risks of GLP-1-Mediated Therapies

Despite the large number of substrates for DPP-4, the adverse
event profile in clinical studies of DPP-4 inhibitors appears
to be relatively benign. Only upper respiratory tract infection,
nasopharyngitis and headache have been identified as adverse
events more commonly observed with DPP-4 inhibitors than
with placebo [2, 103, 104]. For GLP-1R agonists, gastrointestinal adverse events are common, dose-dependent, transient,
and can be reduced through dose-titration strategies in most
cases [96]. Gastrointestinal tolerability appears to be better with
long-acting GLP-1R agonists than with short-acting GLP-1R
agonists at least with regimens that have limited peak-to-trough
fluctuations [76, 101].

Pancreatitis
Acute pancreatitis has been rarely reported as part of postmarketing surveillance activities for both DPP-4 inhibitors and
GLP-1R agonists. Given that type 2 diabetes is associated
with an increased risk of acute pancreatitis, large case
controlled studies are required to determine if there is a
drug-specific association. Three separate controlled healthcare
claims database studies have been completed that evaluate
the association of exenatide and acute pancreatitis [105107].
Two of those studies also evaluated the risk of acute pancreatitis
with sitagliptin [106, 107]. The studies concluded that rates of
acute pancreatitis in patients receiving exenatide or sitagliptin
are not different from rates observed in patients using
other antidiabetic therapies. Longer term studies are needed,
however, to completely rule out any association.

doi:10.1111/j.1463-1326.2012.01560.x 681

review article

DIABETES, OBESITY AND METABOLISM

Cancer
Epidemiological studies indicate that diabetes is associated
with an increased risk of several cancers including liver,
pancreas, endometrium, colon/rectum, breast and bladder
and it may be associated with an increased risk of cancerrelated mortality [108, 109]. Confounding factors such as
diabetes duration, hyperglycaemia, obesity, oxidative stress,
family history and smoking make it difficult to quantify
the true risk of cancer in diabetes or to determine if
certain diabetes therapies may increase or decrease that
risk. While there is currently no evidence that GLP-1-based
therapies alter the incidence of human cancers [108], medullary
thyroid cancer and pancreatic cancer both warrant further
discussion.
Rodent thyroid C-cells express the GLP-1R and continuous
high-dose GLP-1R agonist exposure results in increased
calcitonin secretion, C-cell hyperplasia and C-cell carcinoma in
rats and female mice [110]. In contrast, GLP-1R expression in
human C-cells is very low, and high doses of liraglutide did not
result in C-cell proliferation in non-human primates [110]. In
addition, plasma concentrations of calcitonin were not altered
in over 5000 subjects in liraglutide clinical trials [111]. On
the basis of the species-specific differences in GLP-1R biology
in the thyroid, the FDA considered the risk of developing
medullary thyroid cancer as a result of GLP-1R agonist therapy
to be low in humans [112]. Liraglutide treatment is, however,
contraindicated in patients with a personal or family history
of medullary thyroid carcinoma and in patients with Multiple
Endocrine Neoplasia syndrome type 2 [112].
The association of GLP-1 based therapies and pancreatitis
has led some investigators to speculate that these drugs
may promote pancreatic cancer and Elashoff et al. described
increased reports of pancreatic cancer with exenatide and
sitagliptin usage in the FDA AERS (Adverse Event Reporting
System) database compared to other diabetes therapies [113].
The authors indicate, however, that the AERS database is not an
ideal source to compare adverse event rates between drugs due
to disproportionate reporting across therapies and incomplete
data on confounding factors. Drucker et al. described further
limitations to using the AERS database in this way, pointing
out that the Elashoff AERS analysis showed a sixfold increase in
pancreatitis reports with GLP-1-based therapies while the large

controlled healthcare claims studies did not show an increased

risk of pancreatitis [103].
As GLP-1-based therapies are still relatively new, there are
not sufficient numbers of patients exposed to drug for long
enough periods of time to fully assess their possible effects on
cancer risk. Currently, the available evidence does not suggest
GLP-1-based therapies confer an increased risk of cancer, in
pancreas, thyroid or otherwise, but further assessments are
required either from epidemiological databases or in a large
controlled study setting ideally with long duration to draw
conclusions.

Cardiovascular Disease
Studies of GLP-1R agonists and DPP-4 inhibitors suggest
that GLP-1-mediated therapies have beneficial effects on
cardiovascular risk factors including bodyweight, blood
pressure, postprandial lipids and markers of oxidative stress.
In addition, systematic reviews of clinical trial cardiovascular
adverse event data from the various GLP-1R agonist and
DDP-4 inhibitor drug development programs do not suggest an
increase in cardiovascular risk [114-119]. Table 2 summarizes
the main details of each analysis and presents the calculated
ratio detailed in each report (incidence ratio, relative risk
or hazard ratio). While these results are promising, longterm cardiovascular outcomes studies are needed to better
understand the cardiovascular risks of these therapies. Large
outcomes trials have been initiated for both classes of
compounds, but results are still several years away in most cases.

Other Treatments for Postprandial Control

Several non-GLP-1-mediated therapies exist for the treatment
of PPG. The -glucosidase inhibitors (acarbose and miglitol)
delay digestion of carbohydrate and thus reduce PPG by
1.54.0 mmol/l [120]. Because carbohydrate absorption is
delayed but not reduced, neither malabsorption or weight
loss occur [121]. -Glucosidase inhibitors have had limited
uptake and adherence due to significant gastrointestinal side
effects.
The amylin analogue pramlintide is indicated as adjunct
therapy to improve glucose control in type 1 and type 2
diabetes patients using mealtime insulin. Pramlintide shares

Table 2. Cardiovascular safety of incretin-based therapies.

Therapy

Active/comparator
(N/N)

Events included

RR, IR or HR

95% CI of the
ratio

Exenatide [114]
Liraglutide [115]
Sitagliptin [116]
Vildagliptin [117]
Saxagiptin [118]
Linagliptin [119]

2279/1629
4257/2381
5429/4817
6116/6061
3356/1251
3319/1920

CVD-extended events
MACE
MACE
CVD event
CVD event
CVD composite

0.69 RR
0.73 IR
0.68 RR
0.84 RR
0.43 RR
0.34 HR

0.46, 1.04
0.38, 1.41
0.41, 1.12
0.62, 1.14
0.22, 0.86
0.16, 0.70

CVD-extended events = myocardial infarction/ischaemia, stroke, cardiac death, arrhythmia, revascularization procedures, heart failure.
CVD event = myocardial infarction, ischaemic stroke or coronary revascularization procedure.
CVD composite = CV death, nonfatal stroke/myocardial infarction and hospitalization for unstable angina pectoris.
CVD, cardiovascular disease; MACE, major adverse cardiovascular events; RR, relative risk; IR, incidence ratio; HR, hazard ratio.

682 Fineman et al.

Volume 14 No. 8 August 2012

review article

DIABETES, OBESITY AND METABOLISM

some of the mechanisms of action of GLP-1-mediated therapies

(glucagon suppression, slowing of gastric emptying, reduction
in food intake), but it is currently only indicated in patients
using mealtime insulin. PPG reductions of approximately
2 mmol/l are observed above that observed with mealtime
insulin alone [120, 121].
Glinides increase insulin secretion by a mechanism similar
to SFUs but they have a much more rapid onset of action and
a much shorter duration of action. As such, they can be very
effective PPG lowering agents (reductions of 2.6 mmol/l) with
less hypoglycaemia than that observed with SFUs [120, 121].
Weight gain with glinide treatment is similar to that observed
with SFUs.

Summary and Clinical Relevance

The first in class GLP-1R agonist, exenatide BID, was approved
by FDA in 2005 and the first DPP-4 inhibitor, sitagliptin, was
approved the following year. These novel therapies should
be considered significant treatment advancements as each
addresses multiple pathophysiologies of type 2 diabetes. A
second generation of GLP-1R agonists have been developed
more recently to provide continuous exposure and reduced
administration frequency. The first of these to be approved for
use is liraglutide, which was approved by the European regulatory authorities in 2009 and by FDA in 2010. Exenatide once
weekly was approved in Europe in 2011 and was approved in the
United States early in 2012. Although all three classes of GLP1-mediated therapies (DDP-4 inhibitors, short-acting GLP-1R
agonists and continuous GLP-1R agonists) share the same basic
mechanisms, differences in pharmacokinetics and the magnitude of effect for each mechanism results in differences in FPG,
PPG and bodyweight. Table 3 summarizes the relative effect of
each drug on the main mechanisms of action and on their glucose lowering ability in both the fasting and postprandial states.
In their 2009 consensus algorithm, the American Diabetes
Association (ADA) and the European Association for the Study
of Diabetes (EASD) recommended the use of GLP-1R agonists
as Tier 2 interventions especially when hypoglycaemia and/or
weight gain should be avoided [121]. DPP-4 inhibitors were
not included in the current algorithm because of limited
data availability at the time the algorithm was created. In
contrast, the American Association of Clinical Endocrinologists
(AACE) and The American College of Endocrinology (ACE)
included both DPP-4 inhibitors and GLP-1R agonists in
their 2009 consensus algorithm [122]. Because of their low
risk of hypoglycaemia, DPP-4 inhibitors were recommended
as monotherapy if pretreatment HbA1c is between 6.5%
(48 mmol/mol) and 7.5% (58 mmol/mol), particularly if
metformin is contraindicated. For dual therapy, GLP-1R
agonists, DPP-4 inhibitors and insulin secretagogues (glinide
or sulphonylurea) were recommended (in the order listed) to
potentiate insulin secretion in combination with an insulin
sensitizer (metformin or a TZD). GLP-1R agonists were the
preferred choice in this portion of the treatment algorithm
due to their PPG and weight lowering potential despite
the greater likelihood of gastrointestinal side effects and the
need for twice daily injections. The National Institute for

Volume 14 No. 8 August 2012

Table 3. Relative effects of GLP-1-mediated therapies.

Mechanism of action in the

fasting state
Enhance insulin secretion
Suppress glucagon
secretion
Mechanism of action in the
postprandial state
Enhance insulin secretion
Suppress glucagon
secretion
Slow gastric emptying
Reduce food intake
Clinical effects
Reduce FPG
Reduce PPG increment
Reduce bodyweight

GLP-1R agonists

DPP-4
inhibitors

Short-acting Continuous

+
+

+/Neutral
+/Neutral

++
++

+
+

+++
+++

++
++

Neutral
Neutral

+++
++

+
++

++
+
Neutral

+
+++
+

+++
++
+

DPP-4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1; FPG,

fasting plasma glucose; PPG, postprandial plasma glucose.
When considering the lower glycaemic load due to gastric emptying
effects.
Postprandial plasma glucose rise above fasting levels.
Fasting plasma glucose.

Health and Clinical Excellence (NICE) also included both

GLP-1-mediated therapies in their updated 2009 clinical
guideline [123]. Defronzo proposed that treatment algorithms
should target the known pathophysiological disturbances in
type 2 diabetes by using combinations of drugs and drugs that
have multiple mechanisms of action early in the disease [124].
In this regard, GLP-1R agonists have a unique advantage as they
can treat disturbances in -cell function, glucagon secretion,
gastric motility and satiety signals.
At the time these algorithms were developed, exenatide
BID was the only GLP-1R agonist clinically available. Thus,
no distinction between short-acting GLP-1R agonists and
continuous GLP-1R agonists were made. As described in this
review, however, DPP-4 inhibitors and the two generations
of GLP-1R agonists have district properties and each can be
used to treat different patient phenotypes and different patient
preferences. DPP-4 inhibitors have the advantage of simple oral
administration, and they produce clinically relevant reductions
in HbA1c. However, the effects on PPG are minimal. Shortacting GLP-1R agonists have more complex administration
(twice daily injections), but robust effects on PPG. Effects on
FPG are less pronounced. The continuous GLP-1R agonists
have the advantage of once daily (liraglutide) and once weekly
(exenatide) administration and substantial effects on FPG.
Effects on the postprandial glucose increment are less robust.
In addition, long-acting GLP-1 agonists may have less nausea
than observed with short-acting GLP-1 agonists [76, 91]. All
three classes of GLP-1-based therapies have a low risk of
hypoglycaemia when not combined with a hypoglycaemic
agent such as insulin or an SFU.
On the basis of the differential pharmacology of GLP-1mediated therapies, selection of the agent to use should depend,

doi:10.1111/j.1463-1326.2012.01560.x 683

review article
at least in part, on the glycaemic disturbance that is in most
need of correction. Because postprandial hyperglycaemia is the
major contributor to HbA1c in subjects nearing target goals [1],
short-acting GLP-1R agonists should be considered early in
the disease and as part of combination therapy for patients
nearing glycaemic goals, especially if weight loss would be
beneficial. Long-acting GLP-1R agonists should be considered
when larger reductions in HbA1c are needed, when fasting
glucose elevations are the main problem, and when weight
loss would be beneficial. DPP-4 inhibitors could be used
in patients with mild to moderate fasting hyperglycaemia
and in subjects that need to maintain their bodyweight,
especially if subcutaneous injections or gastrointestinal side
effects limit the use of other GLP-1-mediated therapies.
Exenatide BID was recently approved in the United States
as add-on therapy to insulin glargine. Although data are
limited, existing results suggest that this combination could
be a promising therapy to treat both fasting and postprandial
hyperglycaemia with accompanied weight loss and no increase
in hypoglycaemia [125]. An indication for use with basal insulin
is also being pursued for the other short-acting GLP-1R agonist,
lixisenatide, [96].
The availability of three unique GLP-1-mediated therapies
is analogous to the current use of modern insulins as short,
intermediate, and long-acting versions are all used to optimize
fasting and postprandial glucose as needed. Unlike the insulins,
however, short and long-acting GLP 1R agonists are not
currently approved for use in combination with each other, nor
are DPP-4 inhibitors approved for use with GLP-1R agonists.
Such combinations could potentially be useful, but further
exploration is needed to determine their combined safety
and efficacy.

Conclusion
GLP-1-based therapies operate through multiple novel mechanisms of action that address many of the pathophysiological
disturbances in type 2 diabetes. DPP-4 inhibitors, short-acting
GLP-1R agonists and long-acting GLP-1R agonists each have
unique attributes. Short-acting GLP-1R agonists should be
used to target postprandial hyperglycaemia as monotherapy or
as part of a combination regimen with orals or basal insulin
if fasting hyperglycaemia is also present. DPP-4 inhibitors or
long-acting GLP-1R agonists should be used if fasting hyperglycaemia is the main target of therapy. Long-acting GLP-1R
agonists appear to be the most potent HbA1c lowering agent
of the GLP-1 based therapies and thus may be the best choice
for patients that are far from their glycaemic goals. Safety and
tolerability, patient preference for administration frequency,
concomitant therapies and the need for weight loss or avoidance of weight gain should also be considered when selecting
a therapy.

Acknowledgement
We thank Dr James Ruggles and Lily Kinninger for their
manuscript reviews and revisions.

684 Fineman et al.

DIABETES, OBESITY AND METABOLISM

Conict of Interest
M. F. is a consultant and stock holder of Amylin
Pharmaceuticals, Inc. B. B. C. and D. M. are employees and
stock holders of Amylin Pharmaceuticals, Inc. M. D. is a
member of advisory boards for Abbott, Eli Lilly & Co, Merck
Sharp & Dohme, Novo Nordisk, Poxel Pharma, consultant for
Astra Zeneca/BMS, Eli Lilly & Co, Merck Sharp & Dohme,
Novo Nordisk, Sanofi Aventis and speaker for Eli Lilly & Co,
Merck Sharp & Dohme, Novo Nordisk. All payments connected
to these activities are received by the Diabetes Workshop
Foundation, connected to the VU University Medical Center,
Amsterdam, the Netherlands.
Prof. Diamant does not receive payments personally.
Through Prof. Diamant, the VU University Medical Center,
Amsterdam, the Netherlands, received research support from
Eli Lilly & Co, Merck Sharp & Dohme, Novo Nordisk and
Sanofi Aventis.
M. F., B. B. C., D. M. and M. D. designed this study. M. F. and
B. B. C. carried out the analysis. M. F. performed conduct/data
collection. M. F., D. M. and M. D. wrote the manuscript.

References
1. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial
plasma glucose increments to the overall diurnal hyperglycemia of type
2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes
Care 2003; 26: 881885.
2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Lancet 2006; 368: 16961705.
3. Vilsboll T, Holst JJ. Incretins, insulin secretion and Type 2 diabetes mellitus.
Diabetologia 2004; 47: 357366.
4. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR.
Human distribution and release of a putative new gut hormone, peptide
YY. Gastroenterology 1985; 89: 10701077.
5. Holst JJ. Glucagon-like peptide 1 (GLP-1): an intestinal hormone, signalling
nutritional abundance, with an unusual therapeutic potential. Trends
Endocrinol Metab 1999; 10: 229235.
6. Deacon CF. What do we know about the secretion and degradation of
incretin hormones? Regul Pept 2005; 128: 117124.
7. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1
by human plasma in vitro yields an N-terminally truncated peptide that
is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995;
80: 952957.
8. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus:
properties, functions, and clinical implications. Am J Med 2011;
124(1 Suppl.): S3S18.
9. Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3:
153165.
10. Holst JJ, Burcelin R, Nathanson E. Neuroprotective properties of GLP-1:
theoretical and practical applications. Curr Med Res Opin 2011; 27:
547558.
11. Thorens B. Expression cloning of the pancreatic beta cell receptor for the
gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S
A 1992; 89: 86418645.
12. Baggio LL, Kim JG, Drucker DJ. Chronic exposure to GLP-1R agonists
promotes homologous GLP-1 receptor desensitization in vitro but does
not attenuate GLP-1R-dependent glucose homeostasis in vivo. Diabetes
2004; 53(Suppl. 3): S205S214.

Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM

13. Flint A, Raben A, Ersboll AK, Holst JJ, Astrup A. The effect of physiological
levels of glucagon-like peptide-1 on appetite, gastric emptying, energy
and substrate metabolism in obesity. Int J Obes Relat Metab Disord 2001;
25: 781792.
14. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin
secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol
Metab 2004; 287: E199E206.

review article
duration of infusion and involvement of hepatoportal region. Am J Physiol
Endocrinol Metab 2004; 287: E75E81.
30. Young AA, Gedulin BR, Bhavsar S et al. Glucose-lowering and insulinsensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db)
mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca
mulatta). Diabetes 1999; 48: 10261034.

15. Komatsu R, Matsuyama T, Namba M et al. Glucagonostatic and

insulinotropic action of glucagonlike peptide I-(7-36)-amide. Diabetes
1989; 38: 902905.

31. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of
glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and
beta-cell function in type 2 diabetes: a parallel-group study. Lancet
2002; 359: 824830.

16. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide
1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.
Diabetologia 1993; 36: 741744.

32. Gedulin BR, Nikoulina SE, Smith PA et al. Exenatide (exendin-4) improves
insulin sensitivity and -cell mass in insulin-resistant obese fa/fa Zucker
rats independent of glycemia and body weight. Endocrinology 2005;
146: 20692076.

17. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric
emptying, glucose responses, and insulin secretion after a liquid
test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin
Endocrinol Metab 1996; 81: 327332.

33. Naslund E, King N, Mansten S et al. Prandial subcutaneous injections of

glucagon-like peptide-1 cause weight loss in obese human subjects. Br
J Nutr 2004; 91: 439446.

18. Hare KJ, Vilsboll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute
equally to its glucose-lowering action. Diabetes 2010; 59: 17651770.

34. DAlessio D. Intestinal hormones and regulation of satiety: the case for
CCK, GLP-1, PYY, and Apo A-IV. JPEN J Parenter Enteral Nutr 2008; 32:
567568.
35. Cernea S, Raz I. Therapy in the early stage: incretins. Diabetes Care 2011;
34(Suppl. 2): S264S271.

19. Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like

peptide 1 increases the period of postprandial satiety and slows gastric
emptying in obese men. Am J Clin Nutr 1998; 68: 525530.

36. Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from
single and double incretin receptor knockout mice. Regul Pept 2005;
128: 125134.

20. Nauck MA, Heimesaat MM, Behle K et al. Effects of glucagon-like peptide
1 on counterregulatory hormone responses, cognitive functions, and
insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp
experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87:
12391246.

37. Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV

from bench to bedside: an update on structural properties, functions,
and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003; 40:
209294.

21. Quddusi S, Vahl TP, Hanson K, Prigeon RL, DAlessio DA. Differential
effects of acute and extended infusions of glucagon-like peptide-1
on rst- and second-phase insulin secretion in diabetic and nondiabetic
humans. Diabetes Care 2003; 26: 791798.
22. Ahren B. Sensory nerves contribute to insulin secretion by glucagon-like
peptide-1 in mice. Am J Physiol Regul Integr Comp Physiol 2004; 286:
R269R272.
23. Imeryuz N, Yegen BC, Bozkurt A, Coskun T, Villanueva-Penacarrillo ML,
Ulusoy NB. Glucagon-like peptide-1 inhibits gastric emptying via vagal
afferent-mediated central mechanisms. Am J Physiol 1997; 273:
G920G927.
24. Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory
effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid
secretion in humans depends on an intact vagal innervation. Gut 1997;
40: 597601.
25. Schmidtler J, Dehne K, Allescher HD et al. Rat parietal cell receptors for
GLP-1-(7-36) amide: northern blot, cross-linking, and radioligand binding.
Am J Physiol 1994; 267: G423G432.
26. Nauck MA, Niedereichholz U, Ettler R et al. Glucagon-like peptide 1
inhibition of gastric emptying outweighs its insulinotropic effects in
healthy humans. Am J Physiol 1997; 273: E981E988.
27. Meier JJ, Gallwitz B, Salmen S et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during
intravenous glucagon-like peptide 1 in patients with type 2 diabetes.
J Clin Endocrinol Metab 2003; 88: 27192725.
28. Johnson KM, Edgerton DS, Rodewald T et al. Intraportal GLP-1 infusion
increases nonhepatic glucose utilization without changing pancreatic
hormone levels. Am J Physiol Endocrinol Metab 2007; 293: E1085E1091.
29. Dardevet D, Moore MC, Neal D, DiCostanzo CA, Snead W, Cherrington AD.
Insulin-independent effects of GLP-1 on canine liver glucose metabolism:

Volume 14 No. 8 August 2012

38. Vahl TP, Paty BW, Fuller BD, Prigeon RL, DAlessio DA. Effects of GLP-1(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose
tolerance and glucose-induced insulin secretion in healthy humans. J Clin
Endocrinol Metab 2003; 88: 17721779.
39. Campbell RK, Cobble ME, Reid TS, Shomali ME. Distinguishing among
incretin-based therapies. Glucose-lowering effects of incretin-based
therapies. J Fam Pract 2010; 59(9 Suppl. 1): S10S19.
40. Calabrese D. Differentiating incretin-based therapies for populationbased health care. Am J Manag Care 2011; 17(Suppl. 2): S52S58.
41. Hansen KB, Vilsboll T, Knop FK. Incretin mimetics: a novel therapeutic
option for patients with type 2 diabetesa review. Diabetes Metab
Syndr Obes 2010; 3: 155163.
42. Gentilella R, Bianchi C, Rossi A, Rotella CM. Exenatide: a review from
pharmacology to clinical practice. Diabetes Obes Metab 2009; 11:
544556.
43. Fakhoury WK, Lereun C, Wright D. A meta-analysis of placebo-controlled
clinical trials assessing the efcacy and safety of incretin-based
medications in patients with type 2 diabetes. Pharmacology 2010;
86: 4457.
44. Ahren B, Foley JE. The islet enhancer vildagliptin: mechanisms of
improved glucose metabolism. Int J Clin Pract Suppl 2008; 814.
45. Vella A, Bock G, Giesler PD et al. Effects of dipeptidyl peptidase-4
inhibition on gastrointestinal function, meal appearance, and glucose
metabolism in type 2 diabetes. Diabetes 2007; 56: 14751480.
46. Amori RE, Lau J, Pittas AG. Efcacy and safety of incretin therapy in type
2 diabetes: systematic review and meta-analysis. JAMA 2007; 298:
194206.
47. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose,
insulin and glucagon secretion, gastric emptying, and caloric intake: a
randomized, cross-over study. Curr Med Res Opin 2008; 24: 29432952.

doi:10.1111/j.1463-1326.2012.01560.x 685

review article
48. Vilsboll T, Rosenstock J, Yki-Jarvinen H et al. Efcacy and safety of
sitagliptin when added to insulin therapy in patients with type 2 diabetes.
Diabetes Obes Metab 2010; 12: 167177.
49. Hjollund KR, Deacon CF, Holst JJ. Dipeptidyl peptidase-4 inhibition
increases portal concentrations of intact glucagon-like peptide-1 (GLP-1)
to a greater extent than peripheral concentrations in anaesthetised pigs.
Diabetologia 2011; 54: 22062208.
50. Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for
patients with type 2 diabetes who did not have adequate glycaemic
control with metformin: a 26-week, randomised, parallel-group, openlabel trial. Lancet 2010; 375: 14471456.
51. Davidson JA. Advances in therapy for type 2 diabetes: GLP-1 receptor
agonists and DPP-4 inhibitors. Cleve Clin J Med 2009; 76(Suppl. 5):
S28S38.
52. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular
risk factors. Diabetes Care 2011; 34(Suppl. 2): S276S278.
53. Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin:
mechanistic basis and clinical experience. Vasc Health Risk Manag 2010;
6: 541548.
54. Madsbad S. Treatment of type 2 diabetes with incretin-based therapies.
Lancet 2009; 373: 438439.
55. Unniappan S, McIntosh CH, Demuth HU, Heiser U, Wolf R, Kieffer TJ.
Effects of dipeptidyl peptidase IV on the satiety actions of peptide
YY. Diabetologia 2006; 49: 19151923.
56. Karra E, Batterham RL. The role of gut hormones in the regulation of
body weight and energy homeostasis. Mol Cell Endocrinol 2010; 316:
120128.
57. Nielsen LL, Baron AD. Pharmacology of exenatide (synthetic exendin-4)
for the treatment of type 2 diabetes. Curr Opin Investig Drugs 2003; 4:
401405.

DIABETES, OBESITY AND METABOLISM

sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care

2003; 26: 23702377.
68. Bunck MC, Corner A, Eliasson B et al. One-year treatment with exenatide
vs. insulin glargine: effects on postprandial glycemia, lipid proles, and
oxidative stress. Atherosclerosis 2010; 212: 223229.
69. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects
of exenatide (exendin-4) on glycemic control and weight over 30 weeks
in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;
28: 10921100.
70. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects
of exenatide (exendin-4) on glycemic control over 30 weeks in
sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;
27: 26282635.
71. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin4) on glycemic control over 30 weeks in patients with type 2 diabetes
treated with metformin and a sulfonylurea. Diabetes Care 2005; 28:
10831091.
72. Fineman M, Flanagan S, Taylor K et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple
dosing. Clin Pharmacokinet 2011; 50: 6574.
73. Bergenstal RM, Wysham C, Macconell L et al. Efcacy and safety of
exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to
metformin for treatment of type 2 diabetes (DURATION-2): a randomised
trial. Lancet 2010; 376: 431439.
74. Blevins T, Pullman J, Malloy J et al. DURATION-5: exenatide once weekly
resulted in greater improvements in glycemic control compared with
exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol
Metab 2011; 96: 13011310.

58. BYETTA (exenatide) Package Insert. Amylin Pharmaceuticals, Inc, 2010.

75. Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared
with insulin glargine titrated to target in patients with type 2 diabetes
(DURATION-3): an open-label randomised trial. Lancet 2010; 375:
22342243.

59. Calara F, Taylor K, Han J et al. A randomized, open-label, crossover study

examining the effect of injection site on bioavailability of exenatide
(synthetic exendin-4). Clin Ther 2005; 27: 210215.

76. Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice
daily for the treatment of type 2 diabetes: a randomised, open-label,
non-inferiority study. Lancet 2008; 372: 12401250.

60. Linnebjerg H, Park S, Kothare PA et al. Effect of exenatide on gastric

emptying and relationship to postprandial glycemia in type 2 diabetes.
Regul Pept 2008; 151: 123129.

77. Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the
glucagon-like Peptide 1-induced deceleration of gastric emptying in
humans. Diabetes 2011; 60: 15611565.

61. Kolterman OG, Buse JB, Fineman MS et al. Synthetic exendin-4 (exenatide) signicantly reduces postprandial and fasting plasma glucose
in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88:
30823089.

78. Fineman MS, Shen LZ, Taylor K, Kim DD, Baron AD. Effectiveness of
progressive dose-escalation of exenatide (exendin-4) in reducing doselimiting side effects in subjects with type 2 diabetes. Diabetes Metab
Res Rev 2004; 20: 411417.

62. Kolterman OG, Kim DD, Shen L et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus.
Am J Health Syst Pharm 2005; 62: 173181.

79. Bonuccelli S, Muscelli E, Gastaldelli A et al. Improved tolerance to

sequential glucose loading (Staub-Traugott effect): size and mechanisms.
Am J Physiol Endocrinol Metab 2009; 297: E532E537.

63. Fehse F, Trautmann M, Holst JJ et al. Exenatide augments rst- and

second-phase insulin secretion in response to intravenous glucose
in subjects with type 2 diabetes. J Clin Endocrinol Metab 2005; 90:
59915997.

80. DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J. Regulation of

splanchnic and peripheral glucose uptake by insulin and hyperglycemia
in man. Diabetes 1983; 32: 3545.

64. Degn KB, Brock B, Juhl CB et al. Effect of intravenous infusion of exenatide
(synthetic exendin-4) on glucose-dependent insulin secretion and
counterregulation during hypoglycemia. Diabetes 2004; 53: 23972403.
65. Bunck MC, Diamant M, Corner A et al. One-year treatment with
exenatide improves beta-cell function, compared with insulin glargine,
in metformin-treated type 2 diabetic patients: a randomized, controlled
trial. Diabetes Care 2009; 32: 762768.

81. Knudsen LB, Nielsen PF, Huusfeldt PO et al. Potent derivatives of

glucagon-like peptide-1 with pharmacokinetic properties suitable for
once daily administration. J Med Chem 2000; 43: 16641669.
82. Meece J. Pharmacokinetics and pharmacodynamics of liraglutide, a longacting, potent glucagon-like peptide-1 analog. Pharmacotherapy 2009;
29(12 Pt 2): 33S42S.

66. Taylor K, Kim D, Nielsen LL, Aisporna M, Baron AD, Fineman MS. Daylong subcutaneous infusion of exenatide lowers glycemia in patients
with type 2 diabetes. Horm Metab Res 2005; 37: 627632.

83. Marre M, Shaw J, Brandle M et al. Liraglutide, a once-daily human GLP-1

analogue, added to a sulphonylurea over 26 weeks produces greater
improvements in glycaemic and weight control compared with adding
rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU).
Diabet Med 2009; 26: 268278.

67. Fineman MS, Bicsak TA, Shen LZ et al. Effect on glycemic control of
exenatide (synthetic exendin-4) additive to existing metformin and/or

84. Nauck M, Frid A, Hermansen K et al. Efcacy and safety comparison of

liraglutide, glimepiride, and placebo, all in combination with metformin,

686 Fineman et al.

Volume 14 No. 8 August 2012

DIABETES, OBESITY AND METABOLISM

in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2

study. Diabetes Care 2009; 32: 8490.
85. Russell-Jones D, Vaag A, Schmitz O et al. Liraglutide vs insulin glargine
and placebo in combination with metformin and sulfonylurea therapy in
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial.
Diabetologia 2009; 52: 20462055.
86. Zinman B, Gerich J, Buse JB et al. Efcacy and safety of the human
glucagon-like peptide-1 analog liraglutide in combination with metformin
and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD).
Diabetes Care 2009; 32: 12241230.
87. Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride
monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised,
52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;
373: 473481.
88. Juhl CB, Hollingdal M, Sturis J et al. Bedtime administration of NN2211,
a long-acting GLP-1 derivative, substantially reduces fasting and
postprandial glycemia in type 2 diabetes. Diabetes 2002; 51: 424429.
89. Degn KB, Juhl CB, Sturis J et al. One weeks treatment with the longacting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly
improves 24-h glycemia and alpha- and beta-cell function and reduces
endogenous glucose release in patients with type 2 diabetes. Diabetes
2004; 53: 11871194.
90. Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The once-daily human
glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial
glucose levels in type 2 diabetes patients. Adv Ther 2011; 28: 213226.
91. Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus
exenatide twice a day for type 2 diabetes: a 26-week randomised,
parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;
374: 3947.
92. Christensen M, Knop FK, Holst JJ, Vilsboll T. Lixisenatide, a novel GLP-1
receptor agonist for the treatment of type 2 diabetes mellitus. IDrugs
2009; 12: 503513.
93. Christensen M, Knop FK, Vilsboll T, Holst JJ. Lixisenatide for type 2 diabetes
mellitus. Expert Opin Investig Drugs 2011; 20: 549557.
94. Ratner RE, Rosenstock J, Boka G. Dose-dependent effects of the oncedaily GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes
inadequately controlled with metformin: a randomized, double-blind,
placebo-controlled trial. Diabet Med 2010; 27: 10241032.
95. Distiller LRP. Pharmacokinetics and pharmacodynamics of GLP-1 agonist
AVE0010 in type 2 diabetes patients (Abstract 520-P). 68th Annual
Meeting of the American Diabetes Association, San Francisco, California,
2008.
96. Garber AJ. Novel GLP-1 receptor agonists for diabetes. Expert Opin
Investig Drugs 2012; 21: 4557.
97. Glaesner W, Vick AM, Millican R et al. Engineering and characterization
of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc
fusion protein. Diabetes Metab Res Rev 2010; 26: 287296.
98. Barrington P, Chien JY, Showalter HD et al. A 5-week study of the
pharmacokinetics and pharmacodynamics of LY2189265, a novel, longacting glucagon-like peptide-1 analog, in patients with type 2 diabetes.
Diabetes Obes Metab 2011; 13: 426433.
99. Umpierrez GE, Blevins T, Rosenstock J, Cheng C, Anderson JH, Bastyr EJ
3rd. The effects of LY2189265, a long-acting glucagon-like peptide1 analogue, in a randomized, placebo-controlled, double-blind study
of overweight/obese patients with type 2 diabetes: the EGO study.
Diabetes Obes Metab 2011; 13: 418425.
100. Bush MA, Matthews JE, De Boever EH et al. Safety, tolerability,
pharmacodynamics and pharmacokinetics of albiglutide, a long-acting
glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes
Metab 2009; 11: 498505.

Volume 14 No. 8 August 2012

review article
101. Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. Potential of
albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes:
a randomized controlled trial exploring weekly, biweekly, and monthly
dosing. Diabetes Care 2009; 32: 18801886.
102. Matthews JE, Stewart MW, De Boever EH et al. Pharmacodynamics,
pharmacokinetics, safety, and tolerability of albiglutide, a long-acting
glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin
Endocrinol Metab 2008; 93: 48104817.
103. Drucker DJ, Sherman SI, Bergenstal RM, Buse JB. The safety of incretinbased therapiesreview of the scientic evidence. J Clin Endocrinol
Metab 2011; 96: 20272031.
104. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB.
Incretin-based therapies for the treatment of type 2 diabetes: evaluation
of the risks and benets. Diabetes Care 2010; 33: 428433.
105. Dore DD, Bloomgren GL, Wenten M et al. A cohort study of acute
pancreatitis in relation to exenatide use. Diabetes Obes Metab 2011; 13:
559566.
106. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug
safety surveillance system to assess the risk of acute pancreatitis with
exenatide or sitagliptin compared to metformin or glyburide. Curr Med
Res Opin 2009; 25: 10191027.
107. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes
treated with exenatide or sitagliptin: a retrospective observational
pharmacy claims analysis. Diabetes Care 2010; 33: 23492354.
108. Giovannucci E, Harlan DM, Archer MC et al. Diabetes and cancer: a
consensus report. Diabetes Care 2010; 33: 16741685.
109. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer.
Endocr Relat Cancer 2009; 16: 11031123.
110. Bjerre Knudsen L, Madsen LW, Andersen S et al. Glucagon-like Peptide1 receptor agonists activate rodent thyroid C-cells causing calcitonin
release and C-cell proliferation. Endocrinology 2010; 151: 14731486.
111. Hegedus L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and
calcitonin concentration in humans: lack of evidence of calcitonin release
from sequential screening in over 5000 subjects with type 2 diabetes
or nondiabetic obese subjects treated with the human GLP-1 analog,
liraglutide. J Clin Endocrinol Metab 2011; 96: 853860.
112. Parks M, Rosebraugh C. Weighing risks and benets of liraglutidethe
FDAs review of a new antidiabetic therapy. N Engl J Med 2010; 362:
774777.
113. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis,
pancreatic, and thyroid cancer with glucagon-like peptide-1-based
therapies. Gastroenterology 2011; 141: 150156.
114. Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L.
Cardiovascular safety of exenatide BID: an integrated analysis from
controlled clinical trials in participants with type 2 diabetes. Cardiovasc
Diabetol 2011; 10: 22.
115. Marso SP, Lindsey JB, Stolker JM et al. Cardiovascular safety of liraglutide
assessed in a patient-level pooled analysis of phase 2: 3 liraglutide
clinical development studies. Diab Vasc Dis Res 2011; 8: 237240.
116. Williams-Herman D, Engel SS, Round E et al. Safety and tolerability of
sitagliptin in clinical studies: a pooled analysis of data from 10,246
patients with type 2 diabetes. BMC Endocr Disord 2010; 10: 7.
117. Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M,
Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin:
meta-analysis of adjudicated events from a large Phase III type 2
diabetes population. Diabetes Obes Metab 2010; 12: 485494.
118. Frederich R, Alexander JH, Fiedorek FT et al. A systematic assessment of
cardiovascular outcomes in the saxagliptin drug development program
for type 2 diabetes. Postgrad Med 2010; 122: 1627.
119. Johansen OEND, von Eynatten M. Cardiovascular risk with linagliptin
in paients with type 2 diabetes: a pre-specied, prospective, and

doi:10.1111/j.1463-1326.2012.01560.x 687

review article
adjudicated meta-analysis from a large phase III program (Abstract
30-LB). June Abstract presented at the American Diabetes Association
71st Scientic Sessions, San Diego, CA, June 2428, 2011.
120. Blevins T. Control of postprandial glucose levels with insulin in type 2
diabetes. Postgrad Med 2011; 123: 135147.
121. Nathan DM, Buse JB, Davidson MB et al. Medical management of
hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation
and adjustment of therapy: a consensus statement of the American
Diabetes Association and the European Association for the Study of
Diabetes. Diabetes Care 2009; 32: 193203.

DIABETES, OBESITY AND METABOLISM

Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm

for glycemic control. Endocr Pract 2009; 15: 540559.
123. (NICE) NIfHaCE. Type 2 diabetes: newer agents for blood glucose control
in type 2 diabetes. Issue Date May 2009, 2009
124. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet:
a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes
2009; 58: 773795.
125. Buse JB, Bergenstal RM, Glass LC et al. Use of twice-daily exenatide
in Basal insulin-treated patients with type 2 diabetes: a randomized,
controlled trial. Ann Intern Med 2011; 154: 103112.

122. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of

688 Fineman et al.

Volume 14 No. 8 August 2012