Bhavsar et al Curr Diabetes Rev 2013

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Current Diabetes Reviews, 2013, 9, 161-193

161

Evolution of Exenatide as a Diabetes Therapeutic
Sunil Bhavsar,1,* Sunder Mudaliar2,* and Alan Cherrington3,*
1

Amylin Pharmaceuticals, Inc., San Diego CA; 2VA San Diego Healthcare System and University of California at San
Diego, San Diego CA; 3Vanderbilt University, Nashville TN, USA
Abstract: Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess
mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to
diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes
cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an
overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice
daily (ExBID) reduced mean HbA1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials
ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA1c by -1.3%
to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side
effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of
hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.

Keywords: Diabetes mellitus, Exenatide, Exendin-4, GLP-1 receptor agonist.
INTRODUCTION
Diabetes is a disease of epidemic proportion [1,2], but
glycemic control is rarely optimized and some therapeutic
interventions cause hypoglycemia, weight gain and possibly
exacerbate cardiovascular (CVD) risk [3]. Data from large
studies indicate that restoration of glycemic control when
coupled with weight loss can improve hypertension, dyslipidemia, and other CVD risk markers [4-6].
Exenatide (synthetic exendin-4) is a glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed as a
first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a treatment for type 2
diabetes (T2DM) from seminal preclinical discoveries, clinical pharmacology investigations, and phase 3 clinical trials
(Fig. 1). By building upon early observations of antihyperglycemic actions by GLP-1 and Gila monster exendin4, exenatide was successfully developed into a diabetes
therapeutic agent with a broad range of beneficial cardiometabolic effects and an acceptable tolerability profile. A twice
daily (BID) exenatide formulation is currently approved for
use in patients with T2DM in the U.S., E.U., Japan, and
other countries. A once weekly (QW) exenatide formulation

*Address correspondence to these authors at the Amylin Pharmaceuticals,
Inc., San Diego CA; VA San Diego Healthcare System and University of
California at San Diego, San Diego CA; Vanderbilt University, Nashville
TN, USA; Fax: 615-343-0490, 858-642-6242;
E-mails: Bhavsar.sunil@live.com, alan.cherrington@vanderbilt.edu, sunder.mudaliar@gmail.com, smudaliar@vapop.ucsd.edu
1875-6557/13 $58.00+.00

is also currently approved for use in the U.S., E.U., and Japan, while a once-monthly formulation is undergoing clinical
testing.
INCRETINS
The 'incretin effect' (Fig. 2A) was originally described as
the observation that oral glucose stimulates insulin secretion
to a greater extent than an intravenous infusion of glucose
[7-11]. Later, ingestion of various solid foods was also found
to stimulate this physiological response to nutrient ingestion.
GLP-1 and glucose-dependent insulinotrophic polypeptide
(ie, gastric inhibitory polypeptide [GIP]) are the gut hormones primarily responsible for the incretin effect. In
healthy, normoglycemic adults the contributions of GLP-1
and GIP to the insulin secretory response to elevated circulating glucose concentrations (nutrient ingestion) are estimated to be 73% of the total response. Because of its pleiotropic metabolic effects and for the reasons explained below, GLP-1 quickly became the primary focus of drug development efforts for treating diabetes (Fig. 2B).
The GLP-1 Receptor and GLP-1
The GLP-1 receptor (GLP-1R) is a seven-transmembrane
domain, G-protein coupled receptor expressed in pancreatic
periductal- and -cells, kidney, heart and blood vessels,
stomach, small and large intestine, lung, and brain [12-16]
The physiology of the GLP-1R and its ligand have been extensively explored within the context of glucose homeostasis
© 2013 Bentham Science Publishers

162 Current Diabetes Reviews, 2013, Vol. 9, No. 2

Bhavsar et al.

Fig. (1). Timeline for the evolution of exenatide (synthetic exendin-4) as a diabetes therapeutic. (Created from references [7,12,13,16-24,3234,39,40-57,60-66,69-121,126,127,130-132,135,137,145]).

using GLP-1R(-/-) knockout (KO) mice [17-24]. GLP-1R
KO mice have elevated blood glucose concentrations following an oral glucose challenge, coupled with lower than normal plasma insulin concentrations [17,19,20]. GLP-1 fails to
stimulate insulin release from isolated pancreatic islets from
GLP-1R KO mice, in sharp contrast to the 2-fold insulin
stimulation in islets from normal mice and despite equivalent
insulin content in islets from both mouse strains [18]. Similar
results were observed using perfused pancreata [19]. In addition, De León et al. [24] examined -cell mass regeneration
after GLP-1R KO mice were 70% pancreatectomized. Five
weeks post-surgery, -cell mass was not significantly different between wild-type pancreatectomized or sham-operated
mice. However, in GLP-1R KO mice, -cell mass remained
significantly lower in pancreatectomized versus shamoperated animals, confirming a role for GLP-1 in pancreatic
islet regeneration in the mouse.
GLP-1, the only endogenous ligand for the GLP-1R, is
rapidly secreted by the L-cells of the intestinal mucosa in
response to nutrient ingestion [25]. This peptide hormone
enhances glucose-dependent insulin secretion, suppresses
inappropriately elevated glucagon secretion, slows gastric
emptying, and reduces food intake [25-31]. In rodent models, GLP-1 treatment is associated with pancreatic islet
neogenesis, -cell proliferation, and increased -cell mass
[32-34].
Initially, a role for GLP-1 in ameliorating diabetes pathophysiology was explored using continuous infusion techniques to increase circulating GLP-1 concentrations [35]. In
patients with T2DM, 6 weeks of continuous GLP-1 infusion
significantly reduced HbA1c, fasting glucose, and postprandial glucose excursions compared with placebo (PBO)
infusion (Fig. 3). GLP-1 infusion also improved -cell sensitivity to ambient glucose by 77% compared with baseline,
and re-established a more normal pattern of both first- and
second-phase insulin secretion. Gastric emptying was slowed
and patients lost weight. GLP-1 reduced sensations of hunger, i.e., enhanced satiety and fullness, and reduced prospective food intake; these effects were absent with PBO infusion. In another study, intravenous infusion of GLP-1 prior

to, and during, a glucose challenge in patients with T2DM
was associated with an insulinotropic effect on both firstand second-phase insulin secretion, augmentation of glucose
disappearance rates, and suppression of circulating glucagon
levels [36]. Despite these positive effects, GLP-1 augmentation as a strategy to treat diabetes was deemed impractical,
because GLP-1 is rapidly degraded in the circulatory system,
by the enzyme dipeptidyl peptidase-IV (DPP-4), with a halflife of less than 2 minutes [37, 38].
EXENDIN-4
Exendin-4, the naturally occurring form of exenatide,
was investigated as a potential ligand for the GLP-1R and a
possible diabetes therapy after a number of nonclinical discoveries. Exendin-4 was originally isolated from the salivary
secretions of the lizard Heloderma suspectum (Gila monster)
[39,40]. Exendin-4 has a 53% amino acid sequence homology with mammalian GLP-1 Fig. (4) [39,40]. However,
mammalian GLP-1 is processed from the proglucagon gene
in L-cells in the small intestine, whereas lizard exendin-4 is
transcribed from a different gene, not the Gila monster
homologue of the mammalian proglucagon [41]. The second
seminal discovery was that exendin-4 is resistant to degradation by DPP-4, the enzyme responsible for rapidly degrading
endogenous GLP-1 [37,38]. Third, although exendin-4 is not
an analogue of GLP-1, exendin-4 and GLP-1 share many
glucoregulatory actions mediated by the GLP-1 receptor
[42]. The pancreatic GLP-1 receptor binds exendin-4 and
GLP-1 with equal affinity in vitro, and both peptides stimulate the receptor equipotently [42-45]. Hence, exendin-4 is a
GLP-1R agonist.
Actions shared by exendin-4 and GLP-1 in non-human
studies include reduction of hyperglycemia, glucosedependent enhancement of insulin secretion, glucosedependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food
intake, often with body weight reduction or blunting of
weight gain [39,44,46-49]. In both in vitro and in vivo preclinical models, exendin-4 promoted -cell proliferation and
islet neogenesis from precursor cells [33,50-56]. Further, as

Exenatide for Diabetes

Current Diabetes Reviews, 2013, Vol. 9, No. 2

163

Fig. (2). (A) Representative diagram of the incretin effect in healthy volunteers after administration of a 50 g oral glucose bolus or an equivalent isoglycemic intravenous glucose infusion. The increasing plasma glucose concentrations (left panel) results in an increase of plasma
insulin concentrations (right panel). However, the route of glucose administration (oral or intravenous) determines the extent of the resulting
-cell response. This difference (incretin effect) prompted investigations into the role of incretins, factors secreted from the intestinal tract
upon food ingestion that enhance the insulin secretion. (Adapted from sub in reference [8]). (B) Illustration depicting the normal physiological actions of GLP-1. GLP-1 stimulates replenishment of insulin stores via stimulation of proinsulin gene expression in -cells; promotes the
differentiation of progenitors derived from pancreatic islets into functioning -cells; reduces apoptosis in pancreatic islets; and reduces ambient glucose concentrations via inhibition of glucagon secretion from pancreatic -cells. GLP-1 also decelerates the rate of gastric emptying;
reduces food intake and body weight; and promotes satiety. In addition, GLP-1 acts on the heart by improving myocardial function and cardiac output. (Adpated from references [154] and [155]).

a result of its enhanced pharmacokinetics compared to GLP1, exendin-4 demonstrated very high in vivo potency relative
to native GLP-1 [44,46,56].
Exendin-4 and Insulin-Secreting
Models of Diabetes

-cells in Animal

The actions of exendin-4 on insulin secretion from pancreatic -cell has been studied in a number of animal models
of T2DM. T2DM is characterized by progressive loss of cell function [3,4,5,58,59]. The emergence of overt T2DM is
precipitated by the failure of pancreatic -cells to secrete
adequate amounts of insulin to compensate for insulin resistance in peripheral tissues, primarily liver and muscle. Further, T2DM is characterized by the emergence of postprandial- and subsequently, fasting- hyperglycemia. In the
liver, insulin resistance is manifested by glucose overproduc-

tion during the basal state despite fasting hyperinsulinemia,
combined with impaired hepatic response to the normal elevation in postprandial insulin. In muscle, insulin resistance
manifests as impaired postprandial glucose uptake.
A number of preclinical reports demonstrated exendin-4mediated restoration of function and mass of insulinsecreting islets in the rodent pancreas [32,50,52-56]. These
models of T2DM and obesity include the obese (ob/ob)
mouse that is deficient in the hormone leptin and expresses
insulin resistance and impaired insulin tolerance, the db/db
mouse that has a defect in leptin signaling and expresses
insulin resistance, hypertriglyceridemia and has impaired
glucose tolerance, the partial-pancreatectomized rodent
model (rats or mice), the Goto-Kakizaki rat that is genetically predisposed to a neonatal -cell mass deficiency, the
insulin-resistant obese fa/fa diabetic Zucker rat, the nondia-


Bhavsar et al.

Fig. (3). Treatment effects of continuous subcutaneous GLP1 infusion for 6 weeks in patients with T2DM. (A, B) Plasma glucose concentrations. GLP-1 significantly reduced fasting plasma glucose compared with saline or baseline. (C, D) Plasma C-peptide concentrations during a
hyperglycemic clamp. The insert shows the first-phase secretory response (incremental 0-10 min) for patients receiving GLP-1. GLP-1 significantly stimulated the -cell secretory response compared with saline or baseline. Mean±SEM. (Reprinted with permission from reference
[35].)

betic insulin-resistant obese fa/fa Zucker rat, and spontaneously-diabetic Rhesus monkeys. For example, in mice genetically predisposed to develop diabetes (db/db), exendin-4
increased -cell proliferation and islet mass, ameliorated the
normal development of hyperglycemia, improved insulin
secretion, and reduced HbA1c. Exendin-4 also blocked -cell
apoptosis, increased pancreatic expression of transcription
factors, and enhanced islet neogenesis. Due to the difficulty
of reproducing this type of experiment in humans, it is not
known whether the same mechanism is active in patients
with T2DM.
Glucose-dependent insulinotropism, the ability of agents
to stimulate insulin secretion during euglycemia or hyperglycemia, but not during hypoglycemia, was elucidated in
some of the preclinical models of diabetes described above
[39,44,49]. For example, in diabetic db/db mice, chronic
exendin-4 administration resulted in fasting serum insulin
concentrations notably higher than with vehicle treatment
under conditions of hyperglycemia [44]. HbA1c and fasting
glucose concentrations were significantly reduced, but did
not quite reach normoglycemic levels, with no evidence of
hypoglycemia. Another preclinical study investigated
whether the previously-described effects of exendin-4 on
insulin sensitivity, appetite, and body weight were distinct
from its antihyperglycemic effects [53]. In this study, exendin-4 increased -cell mass to a greater extent in nondiabetic insulin-resistant obese fa/fa Zucker rats than would be
expected in animals of comparable insulin-resistance, suggesting a direct trophic effect of exendin-4 on pancreatic islet
neogenesis, independent of improvements in metabolic parameters. This study was the first to show that exendin-4
could improve insulin sensitivity in an environment of insulin resistance, partly due to reductions in food intake and
partly independent of changes in body weight and ambient
glycemia.

Exendin-4 and Body Weight in Animal Models of Diabetes
and/or Obesity
In nonclinical diabetes models, weight loss or blunted
weight gain are consistently associated with exendin-4
treatments [39,46,47,48]. Studies have extended these findings to include obese, normoglycemic animal models. For
example, exendin-4 treatment for 56 days reduced food intake and slowed weight gain in obese fa/fa Zucker rats [47].
Corresponding reductions in HbA1c, fasting glucose, and
fasting insulin also occurred. In a later study, acute exendin4 administration dose-dependently suppressed food intake in
normoglycemic mice and rats fed a high fat diet, while
chronic, continuous exendin-4 infusion significantly slowed
body weight gain, decreased fat mass, and spared lean tissue
[48]. Food intake, total cholesterol, triglycerides and insulin
levels were all significantly reduced. These data suggest that
exendin-4 has an effect on metabolic pathways regulating
food ingestion.
EXENATIDE (SYNTHETIC EXENDIN-4) CLINICAL
PHARMACOLOGY AND EXPLORATORY INVESTIGATIONS
Overview
Clinical pharmacology studies have been conducted using synthetic exendin-4 (exenatide) administered as subcutaneous injections or intravenous infusions. These studies have
identified the appropriate dosing approach for clinical use,
and explored the mechanisms of action in humans. Initial
dosing strategies explored single bolus, continuous infusion,
and twice (BID) and thrice (TID) daily subcutaneous administration before meals. In these studies, subcutaneous
injections of 10-mcg exenatide twice daily (ExBID) demonstrated a consistent pattern of pharmacokinetics and pharmacodynamic responses, with transient, mild-to-moderate nausea as the primary side effect [60-65]. There was a minimal



165

Fig. (4). Amino acid sequence comparison for exendin-4 and GLP-1. (Adapted from references [13,40,41]).

dependence of exenatide pharmacokinetic profiles on body
weight, supporting development of a fixed dosage regimen
for ExBID [59,62]. These studies also found utility in starting patients on a 5-mcg exenatide BID dose, generally for 4
weeks, before increasing to the maintenance dose of 10-mcg
BID [66]. This graduated approach mitigated much of the
nausea and vomiting observed when initiating directly with
the 10-mcg BID dose.
The mechanisms of action elucidated in nonclinical experiments with exendin-4 were largely confirmed in early
human studies in both healthy individuals and in patients
with type 2 diabetes. In patients with T2DM, exenatide
slowed gastric emptying; reduced fasting hyperglycemia and
hyperglucagonemia; stimulated glucose-dependent insulin
secretion (pancreatic -cell function); attenuated postprandial excursions of glucose, insulin, and glucagon; inhibited food intake; and reduced body weight. The integrated
effects of these mechanisms are likely important for the
clinical efficacy of ExBID.
Studies on Gastric Emptying and Satiety
The effects of exenatide on gastric emptying in patients
with T2DM are best understood within the context of the
important role the rate of nutrient delivery from the stomach
to the small intestine plays in the extent of postprandial glucose excursions [67,68]. One of the main confounders in
understanding the pathophysiology of gastric emptying in
diabetes is hyperglycemia itself, as elevated glucose concentrations in healthy individuals slow the rate of gastric emptying in order to moderate postprandial glucose excursions
[67]. Thus the gastric emptying rate in the face of diabetic
hyperglycemia may be considered pathophysiological, as
gastric emptying is relatively accelerated in patients with
diabetes, compared with the usually expected slowing of
gastric emptying that occurs in healthy individuals under
similar hyperglycemic conditions. In patients with T2DM
(without severe autonomic neuropathy), gastric emptying
rates are often accelerated compared with healthy individuals. Conversely, patients with T2DM and severe autonomic
neuropathy often have reduced gastric emptying (gastroparesis).
For exenatide, slowing of gastric emptying and reduced
food intake were first established as important mechanismsof-action in nonclinical experiments [44,47]. Later, clinical
pharmacology studies confirmed slowed gastric emptying in
patients with T2DM given various exenatide doses including
clinically-relevant doses [59-62,69,70]. Using scintigraphy,
5-days of ExBID was shown to slow gastric emptying of
both the solid and the liquid components of a meal [70]. The
T50 (time to achieve 50% stomach emptying) for solid meal
components was 169 minutes, significantly slower than the
T50 of 60 minutes for PBO. The T50 for liquid meal compo-

nents was 114 minutes, also significantly slower than the T50
of 34 minutes for PBO. Thus, ExBID increased the T50 3-fold
for both solids and liquids compared with PBO.
Clinical studies have also documented a significant reduction of food intake and patient reports of increased satiety
after exenatide administration in both normo- and hyperglycemic individuals [69,71,72]. In lean (mean BMI 25 kg/m2),
healthy young adults, bolus injections of 10 mcg exenatide
reduced caloric intake, overall food intake, and ingestion of
proteins, carbohydrates, and total fat, compared with placebo
[71]. When exenatide was injected 60 minutes prior to a
standardized meal, mean caloric intake was significantly
lower (463 kcal compared with 672 kcal for placebo). Postprandial glucose concentrations at 60 and 120 minutes after
meals were also reduced. In another study enrolling healthy
volunteers, exenatide acutely reduced food intake and
slowed gastric emptying [72]. Subjects consumed 19% fewer
calories at a free-choice buffet lunch with exenatide than
with placebo (867±79 kcal versus 1,075±93 kcal, respectively; p=0.012). Further, T2DM patients administered exenatide had significantly reductions in caloric intake, postprandial triglycerides, and body weight, compared to treatment with the DPP-4 inhibitor sitagliptin [69]. Exenatide
reduced total caloric intake by -134±97 kcal compared with
an increase of +130±97 kcal with sitagliptin.
Integrated Effects of Exenatide on Glycemia
In patients with T2DM, exenatide rapidly lowers both
fasting and postprandial plasma glucose by multiple mechanisms [60-61,69,72,74]. In the postprandial state, exenatide
slows gastric emptying to modulate the rate of nutrient absorption and moderate the extent of postprandial glucose
excursions. Representative dose-response profiles found during these early exenatide clinical studies for the simultaneous
changes in glucose, insulin, and glucagon occurring after an
exenatide injection demonstrated these actions at clinicallyrelevant doses (Fig. 5). In two separate early-stage, 28-day
clinical trials, exenatide also dose-dependently reduced
HbA1c [60,63].
Two other clinical pharmacology studies investigated the
relative contributions of slowed gastric emptying, enhanced
insulin secretion, glucagon suppression, and splanchnic and
peripheral glucose metabolism on postprandial glucose excursions in patients with T2DM after intravenous exenatide
administration [75,76]. Glucose retained within the splanchnic bed consists of glucose taken-up and stored by the liver,
glucose metabolized by gastrointestinal tissues, and glucose
remaining in the gastrointestinal tract. Infusion of exenatide
with an oral glucose bolus or a mixed meal attenuated the
rate of glucose appearance in the circulatory system. Exenatide decreased endogenous glucose release from the liver
by approximately 45% and increased glucose retention in the


Bhavsar et al.

Fig. (5). Exenatide treatment for 5 days restored a more normal glycemic profile in patients with T2DM. Fasting plasma glucose (A), serum
insulin (B), and (C) glucagon concentrations during the 8 hours following a single dose of placebo (n=11) or 0.1 g/kg exenatide administered at t = 0 (n=12). Mean±SEM. (D, E, F) Postprandial plasma glucose (D), insulin (E), and glucagon (F) concentrations following a single
dose of placebo or 0.1 g/kg exenatide at t=0 followed by a standardized meal. Postprandial glucose: Placebo n=20; Exenatide n=20. Postprandial insulin: Placebo n=16; exenatide n=16. Postprandial glucagon: Placebo n=20; Exenatide n=20. (Adapted from reference [61]).

splanchnic area. However, exenatide did not increase tissue
sensitivity to insulin, nor did it alter the rate of total body
glucose disposal.

support the hypothesis that suppression of glucagon secretion is not merely a consequence of the slowing of nutrient
presentation to the small intestine (gastric emptying).

In multiple clinical pharmacology studies in patients with
T2DM, exenatide was shown to modulate fasting serum insulin and glucagon in a manner dependent upon exenatide
dose and ambient glucose concentrations [60-62,64,69,7780]. Both acute and chronic exenatide therapy improved
-cell secretory function (i.e., insulin secretion in response to
hyperglycemia). In patients with T2DM with a blunted first
phase insulin secretory response after acute elevation of
blood glucose levels, intravenous exenatide in the therapeutic range restored the normal first phase insulin secretory
response [79]. Exenatide also augmented the second-phase
insulin secretory response. Of note, the overweight patients
with T2DM enrolled in this study had a mean HbA1c of
6.6%, indicating good glycemic control at baseline.

Degn et al. [81] explored glucose-dependent insulin secretion and the counter-regulatory response to hypoglycemia
in healthy volunteers given an intravenous infusion of exenatide or PBO (Fig. 6). In the presence of euglycemic hyperinsulinemia, insulin secretory rates with exenatide were
significantly (3.5-fold) higher than with PBO. During hypoglycemia, insulin secretory rates declined similarly and rapidly in both groups. Glucagon was markedly more suppressed with exenatide than with PBO (~50% lower) under
conditions of euglycemia. During worsening of hypoglycemia, glucagon increased progressively with both treatments,
but to a significantly greater extent with exenatide. Plasma
glucose recovery time was equivalent for both treatments.
During the recovery interval, glucagon response was equivalent in both treatment arms. Circulating levels of cortisol,
epinephrine, norepinephrine, and growth hormone were
similar between treatment arms, indicating preservation of
the counter-regulatory response to hypoglycemia during exenatide exposure.

The ability of exenatide to dose-dependently suppress inappropriately-elevated glucagon secretion was demonstrated
in patients with T2DM in a number of clinical pharmacology
studies [61,62,63,69,80]. Exenatide-mediated reductions in
plasma glucagon concentrations under fasting conditions



167

Effects of Exenatide on CVD Risk Markers and in Fatty
Liver Disease
Exenatide has been shown to have beneficial effects on
cardiovascular biomarkers. Acute exenatide administration
suppressed postprandial excursions of pro-atherogenic lipid
and lipoprotein in overweight/obese adults with impaired
glucose tolerance or recent onset T2DM [82,83]. Fifty-seven
percent of these patients were being treated with statins for
dyslipidemia. However, one injection of exenatide was still
able to markedly reduce postprandial elevation of triglycerides, apolipoprotein B-48, apolipoprotein-CIII, remnantlike particles-cholesterol and remnant-like particlestriglyceride compared with baseline. In another study, ExBID significantly improved markers of oxidative stress
(prostaglandin F2 ) and cardiovascular inflammation (high
sensitivity C-reactive protein [hsCRP]), independent of baseline HbA1c, body weight, and BMI [84].
ExBID also had beneficial effects on liver fat content in
patients with type 2 diabetes, in whom nonalcoholic fatty
liver disease is prevalent [85]. ExBID significantly increased
plasma adiponectin, reduced hepatic fat content (from mean
12.1% to 4.7%), and plasma triglyceride concentrations
(-38%), despite no significant change in body weight. In
addition, the hepatic injury biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly decreased by ExBID, suggesting beneficial effects
on fatty liver disease.
EXENATIDE BID EFFICACY IN LATE STAGE
CLINICAL TRIALS
Overview
In controlled trials ranging in treatment duration from 12
to 52 weeks where HbA1c reduction was a primary endpoint,
ExBID as monotherapy and in various combinations with
MET, SFU, TZD, and insulins reduced mean HbA1c by
-0.8% to -1.7% in T2DM patients with mean baseline HbA1c
values ranging from 7.5% to 10.2% (Tables 1 and 2) [86120].1,2 The percentage of patients with T2DM achieving
HbA1c values 7% with ExBID ranged from 20% to 79%,
depending upon the baseline characteristics of the patient
populations, their concomitant medications, and the active
treatment regimen. In a study where weight reduction was
the primary endpoint, patients with T2DM with a mean baseline HbA1c of 7.7% still had mean HbA1c reductions of -0.6%
more than PBO when ExBID was added to intensive lifestyle
modification [121].

Fig. (6). Insulin secretory response and glucagon counterregulatory
hormone response. Basal period: ~30 to 0 min. Infusion of exenatide or placebo commenced at 0 min. Glycemic steps: 0-120
min, euglycemia with plasma glucose at ~5.0 mmol/L; 120–180
min, hypoglycemia with plasma glucose at ~4.0 mmol/L; 180-240
min, hypoglycemia with plasma glucose at ~3.2 mmol/L ending in
nadir of ~2.8 mmol/L; 270-360 min, recovery phase. Open circles,
placebo treatment arm; Filled circles, exenatide treatment arm. Data
are mean±SEM. N=11 per treatment arm. *P<0.05, exenatide versus placebo during the steady-state of the indicated glycemic interval. (Reprinted with permission from reference [82]).

Meta-analyses of large clinical trials have demonstrated a
positive correlation between baseline HbA1c and the magnitude of HbA1c response to therapy, independent of drug class
or mechanism of action [122,123]. Consistent with these
reports, ExBID-treated patients with a high mean baseline
HbA1c of 10.2% had a mean HbA1c change of -1.74% after
24 weeks of treatment [86]. This cohort was insulin-naive,
Buse JB, Nauck MA, Forst T, et al. Efficacy and safety of exenatide once
weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6):
a randomised, open-label study. Diabetologia 2011; 54(Suppl 1): S38.
MacConell L, Walsh B, Li Y, Pencek R, Maggs D. Exenatide once
weekly: sustained improvement in glycemic control and weight loss through
3 years. Diabetes 2011; 60: 969-P.


Bhavsar et al.

Fig. (7). ExBID treatment reduced HbA1c and body weight in patients with T2DM in the three pivotal phase 3 clinical trials on differing oral
antidiabetes drug backgrounds. At Week 30, significant HbA1c and weight reductions were observed in all ExBID groups compared with
placebo (p<0.05). LS mean±SEM. (Adapted from references [92,95,105]).

had a mean diabetes duration of 9 years, and had failed to
maintain glycemic control during treatment with MET plus
SFU. In a study that allowed up-titration of insulin glargine
to help achieve glycemic goals in all treatment arms, patients
with a more moderate mean baseline HbA1c of 8.3% had a
mean HbA1c reduction of -1.74% after 30 weeks of ExBID
treatment [90]. Notably, these patients had a longer mean
diabetes duration (12 years) than in the Bergenstal et al. [86]
study and had failed to achieve glycemic control on more
aggressive therapy (insulin glargine with or without
MET±TZD). A post hoc analysis of pooled data from 17
ExBID clinical trials encompassing 2,096 patients found
reductions in glycemic parameters and body weight across a
wide range of background antidiabetes therapies [124].
Body weight reductions have consistently been associated with ExBID therapy, despite wide variability in T2DM
duration and patient characteristics at baseline, concomitant

medications, and study designs (Tables 1 and 2) [86-120].1,2
Mean weight change with ExBID ranged from -1.2 kg to -8.0
kg in exposure periods ranging from 12 to 52 weeks. The
proportion of ExBID-treated patients who had reductions in
both HbA1c and body weight was reported in two controlled
trials: 66% versus 36% with PBO [99] and 71% versus 54%
with PBO [107]. A small percentage of patients may gain
weight while receiving exenatide therapy.
Pivotal Clinical Trials, Pivotal Trial Extensions, and
Monotherapy
The three primary, 30-week, PBO-controlled exenatide
pivotal trials were conducted in patients with T2DM not
achieving glycemic control with MET and/or SFU
[92,95,105]. Treatment with ExBID resulted in mean HbA1c
reductions ranging from -0.8 to -0.9% (Fig. 7). For patients
treated with ExBID+SFU, when baseline HbA1c was <9%



169

Fig. (8). Long-term efficacy of ExBID on HbA1c (A) and body weight (B). (C) Individual patient data showing that the majority of exenatide-treated patients (84%) lost weight after 3-years of ExBID therapy. (D) Individual patient data showing that the majority of exenatidetreated patients (68%) both lost weight and had reduced HbA1c after 3-years of ExBID therapy. N=217 (Reprinted with permission from
reference [106]).

the mean HbA1c change from baseline was -0.65% and when
baseline HbA1c was 9% the mean HbA1c change was -1.2%
[92]. For patients treated with ExBID+MET+SFU, when
baseline HbA1c was <9% the mean HbA1c change from baseline was -0.5% and when baseline HbA1c was 9% the mean
HbA1c change was -1.3% [105]. Thus, ExBID reduced
HbA1c to a greater extent in patients with higher baseline
HbA1c, ie, worse glycemic control. The percentage achieving
an HbA1c 7% after 30 weeks of ExBID treatment in these
pivotal trials ranged from 30% to 46%. These patients also
had progressive body weight reductions ranging from -1.6
to -2.8 kg. These improvements in glycemic control and
body weight are especially notable, because no specific diet
or exercise counseling, nor caloric restriction, were required
by the study protocols.
A series of reports followed patients with T2DM originally enrolled in these first three ExBID pivotal trials during
open-label extensions with up to 3.5 years of exposure
(Tables 1 and 2, Fig. 8) [87,93,106,110,111]. The majority of
ExBID-treated patients with T2DM who continued therapy
maintained HbA1c reductions in combination with progressive weight loss, with 84% of patients reporting weight loss
at Week 104 (2-year evaluable population N=521; 54%
completed) [94]. After 3 years of ExBID, patients with
T2DM on a background of MET, SFU, or MET+SFU had a
mean HbA1c reduction of -1.0%, and 46% achieved an
HbA1c 7% [106]. The sustained nature of the glycemic control associated with ExBID therapy may, in part, reflect effects on pancreatic -cell secretory function, as evidenced by

sustained improvements in HOMA-B out to 3 years. Fifty
percent lost 5% of baseline body weight and 68% had reductions in both HbA1c and weight. This is in contrast to the
weight gain associated with many other antidiabetic agents
as glycemia improves [125]. After 3.5 years of therapy, 10mcg ExBID therapy significantly improved a number of cardiovascular risk factors: mean change from baseline was
-12% for triglycerides, -6% for LDL-C, -5% for total cholesterol, +24% for HDL-C, -2% for systolic BP, and -4% for
diastolic BP [106]. The 25% of ExBID-treated patients who
lost the most weight had the greatest improvements in
triglycerides, HDL-C, and blood pressure. However, for the
entire cohort there were minimal correlations with weight
change. These data suggest that ExBID may improve overall
cardiometabolic risk factors by mechanisms that are partially
dependent on weight loss and partially weight-independent.
Data also suggest a role for exenatide in improving cardiometabolic and hepatic biomarkers in patients with T2DM.
Elevated serum ALT is a biomarker of hepatic injury, often
caused by the nonalcoholic fatty liver disease associated with
obesity and T2DM. After 3 years of ExBID, mean ALT in
patients with elevated baseline ALT declined progressively
(-26%) and 41% had ALT normalization. Although the 25%
of patients who lost the most weight had the greatest reduction in ALT, weight change in the entire cohort was only
mildly correlated with baseline ALT (r= -0.01) or ALT
change r=0.31).
The efficacy of ExBID monotherapy in treatment-naive
patients with T2DM was explored in two PBO-controlled


Bhavsar et al.

109,127]. In addition, weight loss was associated with ExBID therapy, compared with weight maintenance or weight
gain with insulin therapy. In one study, a strategy of aggressive insulin dose titration reduced HbA1c more with insulin
than with ExBID, albeit with greater weight gain in the insulin group [86].
Recently, the data from four ExBID versus insulin comparator studies [94,102,109,127] were pooled (1423 patients)
and analyzed [128]. Treatment ranged from 16 to 52 weeks
in duration. Overall glycemic control with ExBID (mean
HbA1c change -1.2%) was non-inferior to insulin (mean
HbA1c change -1.1%) at 6 months, and patients who continued treatment through 52 weeks showed sustained reductions
in HbA1c from baseline (ExBID, -1%; insulin, -0.9%). When
stratified by HbA1c change from baseline tertiles, ExBID and
insulin were associated with comparable reductions in each
tertile, with the greatest mean reductions of -1.7% (ExBID)
and -1.7% (insulin) observed in the tertile with the highest
baseline HbA1c range (9.0% to 12.7%). ExBID was associated with weight loss (mean -2.0 kg) versus weight gain with
insulin (mean +1.8 kg) at Week 26; the corresponding values
at Week 52 were -3.1 kg vs +1.9 kg. Overall, more ExBIDtreated patients (70%) experienced weight loss than did those
treated with insulin (21%). For patients with an elevated systolic BP at baseline ( 130 mmHg), ExBID reduced systolic
BP to a significantly greater extent than insulin (mean -8.1
vs -3.6 mmHg). The frequency of nocturnal, mild-tomoderate hypoglycemia was lower with ExBID (15%) than
with insulin (29%).
Other CVD Effects

Fig. (9). Pooled analysis of systolic blood pressure data from six
ExBID clinical trials including 2,171 patients with T2DM. (A)
Systolic blood pressure change from baseline in patients treated
with ExBID or placebo for 6 months. Mean+SEM. (B) Systolic
blood pressure change from baseline in patients treated with ExBID
or insulin for 6 months. Mean+SEM. (Reprinted with permission
from reference [129]).

clinical trials, one was preliminary [126] and one was phase
3 [108]. In the preliminary study, ExBID monotherapy significantly reduced hyperglycemia and body weight over 28
days of treatment. In the phase 3 study, 24 weeks of ExBID
monotherapy significantly reduced mean HbA1c by -0.9%,
compared with -0.2% in the PBO group. An HbA1c 7% was
achieved by 46% with ExBID, compared with only 29%
with PBO. Mean daily six-point self-monitored blood glucose concentrations were significantly reduced with ExBID
monotherapy compared with PBO (daily mean change -27
mg/dL versus -5 mg/dL, respectively). In addition, -cell
function measured by HOMA-B improved by 28% in the
ExBID group compared with 6% in the PBO group.
Insulin Comparator Studies
ExBID has generally demonstrated non-inferiority to insulin glargine and biphasic insulin aspart [86,88,94,102,

ExBID effects on BP were analyzed in more depth by
pooling data from patients with T2DM treated in six comparator controlled (PBO or insulin) clinical trials of 24 to 52
weeks duration (Fig. 9) [129]. All patients continued existing
antidiabetes, antihypertensive, and dyslipidemia medications. In the pooled analysis, 6 months of ExBID therapy
was associated with a significantly greater reduction in systolic BP than was PBO or insulin. Patients with elevated
baseline systolic BP ( 130 mmHg) appeared to drive the BP
changes observed in the overall population. This subgroup
had mean systolic BP reductions with ExBID of -8.3 mmHg
versus -4.5 mmHg with PBO; and -8.3 mmHg with ExBID
versus -4.2 mmHg with insulin. Although the majority of
exenatide-treated subjects lost weight, weight loss was only
weakly correlated with systolic BP change (r=0.09), again
suggesting exenatide effects were not solely mediated by
weight loss.
Clinical trial data from patients with T2DM treated with
ExBID or insulin glargine on a background of MET for one
year yielded additional insight into the complex metabolic
changes associated with exenatide therapy [130,131]. Exenatide treatment reduced total body fat mass and improved
the profile of biomarkers for CVD risk compared with insulin glargine. ExBID also significantly reduced post-meal proatherogenic triglycerides, apoB48, VLDL-C, and free fatty
acid excursions, as well as the oxidative stress markers MDA
and oxLDL-to-LDL ratio compared with insulin glargine.
Body weight (-6%), waist circumference (-5%), and total
body fat mass (-11%) were all reduced compared with insu-



171

Fig. (10). ExQW mechanism of drug release from poly-(D,L-lactide-co-glycolide) microspheres. (Reprinted with permission from reference
[133]).

lin glargine. In addition, there were significant changes in
total adiponectin (+12%) and hsCRP (-61%) compared with
insulin glargine. In contrast, insulin glargine only significantly reduced endothelin-1 (-7%) compared with ExBID.
Notably, the adiponectin and hsCRP changes in the ExBID
arm were independent of the changes in total fat mass (adiponectin: r= -0.224; hsCRP: r= -0.023). One year of ExBID
also significantly reduced hsCRP in two other comparatorcontrolled clinical trials [96,97].
Acute exenatide effects on postprandial lipids, remnant
lipoproteins, and apolipoproteins in subjects with impaired
glucose tolerance or recent onset T2DM were also reported
by Schwartz et al. [82]. A single exenatide injection prior to
a high-fat meal significantly reduced postprandial triglyceride, apoB48, apoCIII, non-esterified fatty acid, and remnant lipoprotein excursions, compared with PBO.
Postprandial excursions of total apoB and LDL-C were not
changed. These metabolic effects were not affected by the
degree of ambient hyperglycemia nor by dyslipidemia treatment with statins.
STUDY ON THE FEASIBILITY OF CONTINUOUS
EXENATIDE DOSING
In order to evaluate the feasibility of transitioning from
twice daily to once weekly exenatide administration in humans, 12 patients with T2DM treated with diet/exercise or
MET received continuous infusions of exenatide or PBO
subcutaneously over one-day intervals, delivered via pumps
[131]. Exenatide reached therapeutic plasma concentrations
( 50 pg/ml) and significantly reduced plasma glucose during
both prandial and fasting states, confirming day-long glycemic control with continuous peptide exposure. There were
no serious or severe adverse events, and no cases of hypoglycemia. The most common adverse events with exenatide
treatment were mild nausea and/or vomiting.
EXENATIDE ONCE WEEKLY (QW)
Overview
The formulation of exenatide into a 2-mg once weekly
(ExQW) agent differs from ExBID due to encapsulation of

the exenatide peptide within poly-(D,L-lactide-co-glycolide)
microspheres (Fig. 10) [132]. After mechanical suspension
and subcutaneous injection, ExQW microspheres hydrate in
situ and adhere to each other to form an amalgam. A small
amount of exenatide (1-2% of the total area under the plasma
concentration-time curve) that is loosely bound to the amalgam surface reaches the circulatory system within the first
few hours post-injection. Exenatide located in deeper interstices diffuses out more slowly with a Tmax of approximately
2 weeks. Fully encapsulated exenatide, that is initially inaccessible to diffusion, releases with a Tmax of approximately 7
weeks as the microspheres hydrolyze and are eliminated as
carbon dioxide and water. Plasma exenatide concentrations
reach the therapeutic range by 2 weeks post-injection and
achieve steady state by 6 to 7 weeks post-injection.
In phase 3 clinical trials, 2-mg ExQW significantly reduced mean HbA1c by -1.3% to -1.9% during controlled
treatment periods ranging from 24 to 30 weeks
[113,114,116-118].1 Mean body weight change ranged from
-2.3 to -3.7 kg. Further, the proportion of ExQW-treated patients with reductions in both HbA1c and body weight ranged
from 70% to 79%.
Initial Clinical Testing
The initial phase 2 clinical trial of ExQW evaluated effects in patients with T2DM randomized to ExQW or PBO
for 15 weeks on a background of MET or diet/exercise
[133]. By Week 2, plasma exenatide concentrations exceeded the minimally effective level (approximately 50
pg/ml) shown to reduce fasting plasma glucose concentrations and remained within the target therapeutic range
throughout the remainder of the treatment period. ExQW
patients had an HbA1c reduction of -1.7±0.3% compared
with an HbA1c increase of 0.4±0.3% in the PBO group. In
addition, 86% of patients in the ExQW group achieved an
HbA1c 7%, compared with none in the PBO group. Body
weight was unchanged in the PBO group, but decreased in
the ExQW group by 3.5% (-3.8±1.4 kg). Mild nausea was
the most frequent exenatide-associated adverse event (27%
versus 15% with PBO). Of note, the incidence of injection
site reaction was 7% with ExQW versus 0% with PBO.


Bhavsar et al.

Fig. (11). (A-D) Comparison of treatment effects for ExQW versus ExBID over 24 weeks in the DURATION-5 phase 3 clinical trial in
treatment-naíve patients with T2DM. (A) HbA1c change from baseline. LS mean±SEM. (B) Proportion of subjects achieving HbA1c targets at
study end. *p<0.0001. (C) Fasting plasma glucose change from baseline. LS mean±SEM. (D) Body weight change from baseline. LS
mean±SEM. ITT population: ExQW n=129; ExBID n=123. (A-D adapted from reference [114]). (E) Comparison of postprandial glucose
effects after a normal meal in patients treated with ExQW or ExBID at baseline and at Week 14 in the DURATION-1 phase 3 clinical trial
in patients with T2DM. ExQW n=27; ExBID n=24. (Adapted from reference [117]) (F) HbA1c change from baseline in the 2-year extension
of the DURATION-1 clinical trial. 2-year completer population: ExQW n=216. LS mean±SEM. (Adapted from reference [119]).

Phase 3 Clinical Trials
Phase 3 ExQW clinical development in patients with
T2DM is comprised of the DURATION (Diabetes therapy
Utilization: Researching changes in HbA1c, weight and other
factors Through Intervention with exenatide ONce weekly)
program [134]. In the series of DURATION clinical trials
completed to date, ExQW has been compared with ExBID
(DURATION-1, -5), metformin (DURATION-4), sitagliptin
(DURATION-2, -4), pioglitazone (DURATION-2, -4), liraglutide (DURATION-6), and titrated insulin glargine (DURATION-3) on background antidiabetes therapies of
diet/exercise, MET alone, or combination OAD therapy
(MET, SFU, TZD) (Tables 1 and 2) [86-120].1,2 In controlled
treatment periods of the DURATION trials (ranging from 24
to 30 weeks), ExQW significantly reduced mean HbA1c by

-1.3% to -2.0% from mean baseline HbA1c values ranging
from 8.3% to 8.6%. Mean body weight change ranged from
-2.3 to -3.7 kg with ExQW treatment from mean baseline
weight values ranging from 88 to 103 kg.
DURATION-1 and -5 directly compared ExQW with
ExBID in patients treated with diet/exercise, MET alone, or
combination OAD therapy [114,115]. ExQW significantly
reduced fasting glucose (Fig. 11) and glucagon to a greater
extent than ExBID. In contrast, ExBID reduced postprandial
glucose excursions to a greater extent than did ExQW. During the 30 week controlled portion of DURATION-1, ExQW
reduced mean HbA1c by -1.9%. In the open-label extension,
patients with T2DM treated with ExQW from baseline had
HbA1c reductions of -2.0% at Week 52 [115], -1.7% at Week
104 [119], and -1.6% at Week 1562 on a background of


diet/exercise, MET, SFU, TZD, or any 2 OADs. Treatment
with ExQW was associated with mean weight reductions of
-3.7 kg at Week 30 [117], -4.1 kg at Week 52 [115], -2.6 kg
at Week 104 [119], and -2.3 kg at Week 156.2 In DURATION-5, ExQW reduced mean HbA1c by -1.6% and body
weight by -2.3 kg on a background of diet/exercise, MET,
SFU, TZD, or any combination of the OADs [114].
The second study with long-term data from an open-label
extension (DURATION-2) confirmed that glycemic control
could be sustained for up to one year with ExQW [113,120].
At the end of the controlled treatment period treatment of 26
weeks, ExQW on a background of MET reduced mean
HbA1c by -1.5%, compared with -1.6% at Week 52. The corresponding weight reductions were -2.3 kg and -1.8±0.5 kg,
respectively [114,120].
In the DURATION-6 study, ExQW reduced mean HbA1c
by -1.3% after 26 weeks of treatment, compared with -1.5%
in the liraglutide treatment arm where the liraglutide cohort
underwent a forced titration to the maximum approved dose.1
The HbA1c treatment difference was 0.2%, with a 95% confidence interval of 0.08% to 0.34%. Therefore, under the
predefined study analysis requiring the upper limit of the
HbA1c 95% confidence interval to be <0.25%, ExQW did not
meet the primary endpoint of noninferiority to the maximum
daily dose of liraglutide. Mean weight reduction was significantly greater in patients treated with liraglutide (-3.6 kg)
than with ExQW (-2.7 kg). Both drugs reduced systolic BP,
diastolic BP, and a number of cardiovascular risk factors to a
similar extent.
In the only study to evaluate ExQW in drug-naíve patients (DURATION-4), mean HbA1c and body weight
changes were -1.5% and -2.0 kg, respectively, after 26 weeks
of treatment [118]. However, ExQW is not currently recommended for use as first line therapy in patients failing
diet/exercise [135].
In the controlled DURATION trials, the proportion of
ExQW-treated patients who had reductions in both HbA1c
and body weight ranged from 67% to 79% [113,114,116118].1 In DURATION-2 [112], reductions in both HbA1c and
body weight occurred in 70% with ExQW, 46% with sitagliptin, and 14% with pioglitazone on a background of MET.
In DURATION-3 [116] reductions in both HbA1c and body
weight occurred in 79% with ExQW versus 31% with insulin
glargine, on a background of MET±SFU. In DURATION-5
[114], reductions in both HbA1c and body weight occurred in
71% with ExQW compared with 51% with ExBID on a
background of diet/exercise, MET, SFU, TZD, or a combination of 2 OADs. On the same background therapy, DURATION-1 [117] reported that 73% of ExQW-treated patients
had reductions in both HbA1c and body weight, compared
with 74% of ExBID-treated patients. In DURATION-4
[118], treatment- naíve patients had reductions in both HbA1c
and body weight in 67% with ExQW, 69% with MET, 33%
with pioglitazone, and 59% with sitagliptin.
GLP-1 Receptor Agonism Versus Enhancing Endogenous Incretin Levels
As described in the nonclinical sections of this review,
the GLP-1 receptor agonist exenatide is resistant to degrada-


173

tion by the DPP-4 enzyme responsible for rapidly metabolizing endogenous GLP-1. An alternative strategy for targeting
the GLP-1 signal transduction pathway has been to inhibit
DPP-4 activity, which increases the time that endogenous
incretins remain active. Exenatide has been directly compared with the DPP-4 inhibitor sitagliptin in patients with
T2DM in several clinical trials. In the DURATION-2 trial,
26 weeks of 2-mg ExQW was compared with 100-mg sitagliptin once daily in patients concomitantly treated with
MET [113]. Mean HbA1c reductions were significantly
greater with ExQW than with sitagliptin (LS mean change
from baseline for ExQW: -1.5%, sitagliptin: -0.9%). In addition, ExQW-treated patients lost a mean of -2.3 kg, compared with mean weight loss of -1.5 kg in sitagliptin-treated
patients. When patients were later switched from sitagliptin
to ExQW for an additional 26 weeks of treatment, mean
HbA1c was further reduced by -0.3% and mean weight by 1.1 kg [120]. In the DURATION-4 clinical trial, 26 weeks of
2-mg ExQW was compared with 100-mg sitagliptin once
daily in treatment-naíve patients [118]. Mean HbA1c reductions were significantly greater with ExQW than with sitagliptin (LS mean change from baseline for ExQW: -1.5%,
sitagliptin: -1.2%). LS mean body weight changes were significantly greater with ExQW (-2.0 kg) than with sitagliptin
(-0.8 kg). As described in the clinical pharmacology section
above, ExBID treatment was also associated with greater
effects on glycemic indicators than was sitagliptin [69,74].
EXENATIDE ADVERSE EVENTS IN CLINICAL
TRIALS AND ROUTINE CLINICAL USE
Overview
ExBID was approved for human use in 2005 by the U.S.
Food and Drug Administration and there is a large clinical
trial database of safety events available for analysis [137].
The most common side effects are gastrointestinal in nature,
mild, and transient. Nausea is the most prevalent adverse
event at drug initiation, and it tends to decrease in frequency
with continued exenatide exposure.
Recently, MacConell et al. [137] published an integrated
analysis of 5594 patients with T2DM from 19 comparatorcontrolled exenatide BID clinical trials. In this report, representing over 1500 patient-years of exposure, the exenatide
BID safety profile was compared with the safety profile of a
pooled comparator (PBO, insulin aspart, or insulin glargine)
cohort treated for 12 to 52 weeks on background therapies of
diet/exercise, MET, SFU, TZD, and OAD combinations.
Both cohorts had comparable baseline characteristics. For
the 3261 exenatide-treated subjects, 44% were female with a
mean age of 56 years and a mean BMI of 32 kg/m2. Mean
baseline HbA1c was 8.3% and mean treatment exposure was
166 days. For the 2333 subjects in the pooled comparator
cohort, 46% were female with a mean age of 56 years and a
BMI of 32 kg/m2. Mean HbA1c was 8.3% and mean treatment exposure time 171 days. No specific safety signals of
concern were identified with exenatide use. Both cohorts had
comparable rates of serious adverse events, discontinuations
due to serious adverse events, and deaths (exenatide: 3.6%,
0.8%, and <0.1%, respectively; pooled comparator: 3.9%,
0.7%, and <0.1%, respectively). Consistent with the results
from individual clinical trials, transient mild-to-moderate


Bhavsar et al.

Fig. (12). Incidence, recurrence, and duration of nausea and vomiting with ExBID (4-week lead-in period with 5 mcg BID followed by a
dose increase to 10 mcg BID for the duration of the trial). ExBID n=2558. Placebo n=1325. Insulin n=1008. (A) Occurrence and recurrence
of nausea over time (grouped into 4-week intervals). (B) Occurrence and recurrence of vomiting over time (N=2558). Each event is attributed to a defined period according to the event onset date, and recurrence of nausea/vomiting is defined as an event with onset during the
defined period and previous period. Percentages are based on number of subjects who remained in the trial during the defined period. (C)
Duration of nausea. (D) Duration of vomiting. The duration of the nausea/vomiting event is calculated as the resolution date (or the last participation date if an event is ongoing at the time of study termination) minus the event onset date plus 1. (Reprinted with permission from
reference [137]).

nausea was the most frequent side effect associated with
exenatide (36.9% versus 8.3% in the pooled comparator)
(Fig. 12). Overall, gastrointestinal adverse events were more
frequently observed with exenatide than with comparator
treatment (51% versus 21%, respectively). Gastrointestinal
adverse events were also the most common reason for discontinuation of clinical trial participation in the exenatide
cohort. Vomiting had a composite frequency of 14% compared with 3% in the pooled comparator group, while diarrhea had a composite frequency of 11% versus 5% in the
pooled comparator group. However, nausea and vomiting
decreased over time in the exenatide group (independent of
dose), with a substantial reduction in incidence rate after 8

weeks of treatment. Of the other most-frequent adverse
events ( 5% frequency), only dizziness occurred significantly more frequently with exenatide than with comparator
exposure (5% versus 3%, respectively).
In another integrated analysis, MacConell et al. published
a preliminary report of adverse events from 4,328 patients
with T2DM treated in 8 randomized phase 3 ExQW trials.3
The most frequent adverse events with ExQW were gastroin
MacConell L, Gurney K, Malloy J, Zhang H, Zhou M, Chen S. Safety and
tolerability of exenatide once weekly in patients with type 2 diabetes: an
integrated analysis of 4328 patients. Diabetes 2012; 61(Suppl 1): A598
(2372-PO).



Table 1. Overview of Exenatide Phase 3 Clinical Trial Designs.
Study
Dur (wk)

Double Blind?

Multi-National?
(#countries)

Analysis Pop

Mean Calc

NCT#a

Bergenstal 2009 [86]

24

No

No (US)

ITT & per protocol

Mean

00097877

Blonde 2006 [87]

82

No

No (US)

ITT & completers

Mean

00111540

Bunck 2009 [88]

52

No

Yes (3)

ITT & evaluable

Mean

00097500

Bunck 2011 [89]

168

No

Yes (3)

ITT & evaluable

Mean

00097500

Buse 2011 [90]

30

Yes

Yes (5)

ITT

LS Mean

00765817

Buse 2009 [91]

26

No

Yes (15)

ITT & per protocol

LS Mean

00518882

Buse 2004 [92]

30

Yes

No (US)

ITT & evaluable

Mean

00039026

Buse 2007 [93]

104

No

No (US)

ITT & completers

Mean

00111540

Davies 2009 [94]

26

No

No (UK)

ITT

LS Mean

00360334

DeFronzo 2005 [95]

30

Yes

No (US)

ITT & evaluable

Mean

00039013

Derosa 2010 [96]

52

No

No (Italy)

ITT

Mean

NA

Derosa 2011 [97]

52

No

No (Italy)

ITT

Mean

NA

Forti 2008 [98]

12

No

Yes (2)

Per protocol

LS Mean

00359879

Gallwitz 2011 [99]

26

No

No (Germany)

ITT

LS Mean

00434954

Gao 2009 [100]

16

Yes

Yes (4)

ITT & per protocol

LS Mean

00324363

Gill 2010 [101]

12

Yes

Yes (2)

ITT & per protocol

LS Mean

00516074

Heine 2005 [102]

26

No

Yes (13)

ITT & per protocol

LS Mean

00082381

Kadowaki 2009
[103]

12

Yes

No (Japan)

ITT

Mean

00382239

Kadowaki 2011
[104]

24

Yes

No (Japan)

ITT

LS Mean

00577824

Kendall 2005 [105]

30

Yes

No (US)

ITT & evaluable

Mean

00035984

Klonoff 2008 [106]

156 / 182

No

No (US)

ITT & completers

Mean

00111540

Liukus 2010 [107]

26

Yes

Yes (5)

ITT

LS Mean

00603239

Moretto 2008 [108]

24

Yes

Yes (4)

ITT

LS Mean

00381342

Nauck 2007 [109]

52

No

Yes (13)

ITT & per protocol

Mean

00082407

Ratner 2006 [110]

82

No

No (US)

ITT & completers

Mean

00111540

Riddle 2006 [111]

82

No

No (US)

ITT & completers

Mean

00111540

Zinman 2007 [112]

16

Yes

Yes (3)

ITT & per protocol

LS Mean

00099320

Bergenstal 2010
[113]

26

Yes

Yes (3)

ITT & evaluable

LS Mean

00637273

Blevins 2011 [114]

24

No

No (US)

ITT & evaluable

LS Mean

00877890

Buse 2010 [115]

52

No

Yes (2)

ITT & evaluable

LS & Geo
Mean

00308139

Study Citation
Exenatide BID

Exenatide QW

175


Bhavsar et al.
Table 1. Contd….

Study
Dur (wk)

Double Blind?

Multi-National?
(#countries)

Analysis Pop

Mean Calc

NCT#a

Buse 20111

26

No

Yes (21)

ITT

LS Mean

01029886

Diamant 2010 [116]

26

No

Yes (15)

ITT

LS Mean

00641056

Drucker 2008 [117]

30

No

Yes (2)

ITT & evaluable

LS & Geo
Mean

00308139

MacConell 20112

156

No

Yes (2)

Completers

LS & Geo
Mean

00308139

Russell-Jones 2012
[118]

26

Yes

Yes (22)

ITT

LS Mean

00676338

Taylor 2011 [119]

104

No

Yes (2)

ITT & Completers

LS Mean

00308139

Wysham 2011 [120]

52

No

Yes (3)

Evaluable

LS Mean

00637273

Study Citation

a

Additional information on these trials is available at clinicaltrials.gov
Abbreviations: BID, twice daily; Dur, duration; Geo, geometric; ITT, intent-to-treat; LS, least squares; NA, not applicable; NCT, national clinical trial database; NI, non-inferiority;
Pop, population; QW, once weekly; Rx, change or different diabetes medication prior to randomization; S, superiority.

Table 2. Overview of Exenatide Phase 3 Clinical Studies.a
Achieve

T2DM
Study

Ther

BG

DO

ITT

Citation

Studied

Ther

(%)

N

F

White

Dur

(%)

(%)

(y)

BL HbA1c

HbA1c

(%) ±SD

(%) ±SE

±SD

d HbA1c
7% or
<7%
(%)

BL
Wt (kg)

BMI

BL Wt

(kg/m2)

(kg) ±SD

±SE

±SD

Exenatide BID
ExBID
Bergenstal
2009 [86]

Aspart
QD

29.8

Bunck 2009
[88]

Bunck 2011
[89]

9±6

10.2±1.5

-1.75

20

34±7

96.6±24

-1.9

16.1

124

51.6

67.7

8±6

10.1±1.8

-2.34

26

34±7

96.9±25

2.8

124

52.4

59.7

10±6

10.3±1.9

-2.76

37

34±7

93.8±24

4.1

43.0

551

39

74

7±6

8.4±1.0

-1.1±0.1

48

34±6

98±20

-4.4±0.3

16.7

36

36.1

100

6±1

7.6±0.1

-0.8±0.1

NG

31±1

90.6±2.1

-3.6 ±0.6*

9.1

33

33.3

97

4±1

7.4±0.1

-0.7±0.2

NG

30±1

92.4±2.4

1.0±0.8

44.4

36

36.1

100

6±1

7.6±0.1

-1.0

NG

31±1

90.6±2.1

-5.7 ±1.3*

48.5

BID

2006 [87]

63.7

33

33.3

97

4±1

7.4±0.1

-0.5

NG

30±1

92.4±2.4

2.1±1.3

19

137

49

75

12±7

8.32± 0.85

60*

34±6

95.4±20.4

-1.8 ±0.3*

35

33±6

93.4±21.2

1.0±0.3

SFU

Aspart

Blonde

51.6

19.4

MET +

124

MET
ExBID

+/or
SFU

ExBID
MET
Glarg
ExBID
MET
Glarg
ExBID

Buse 2011

Glarg
±MET

[90]

and/or

-1.74
±0.1*
-1.04

PBO

Buse 2009
[91]

TZD

18

122

36

80

12±7

8.50± 0.96

ExBID

MET ±

19.5

231

45

91

8±6

8.1±1.0

-0.8±0.1

43

33±6

93.0±19.5

-2.9±0.3

14.2

233

51

93

9±6

8.2±1.0

-1.1±0.1

54

33±6

93.1±20.1

-3.2±0.3

LIRA

SFU

±0.1



177

Table 2. Contd….

Study
Citation

Ther
Studied

5 mcg
ExBID

ExBID

ExBID
Davies
2009 [94]
Glarg

5 mcg
ExBID

MET
+/or
SFU
+/or
TZD

MET

ExBID

Derosa
2011 [97]

ExBID

Forti 2008
[98]

8.6±1.2

-0.9
±0.1*

34.2*

33±6

95±18

-1.6 ±0.3*

24.0

125

40.8

61.6

6±5

8.5±1.1

-0.5
±0.1*

26.7*

303±6

95±22

-0.9±0.3

123

37.4

66.7

6±5

8.7±1.2

0.1±0.1

7.7

34±5

99±18

-0.6±0.3

45.7

521

41

74

8±6

8.4±1.1

-1.1±0.1

50

34±6

99±20

-4.7±0.3

16.1

118

29.7

NG

9±5

8.7±0.7

-1.25±
0.09

NG

35±6

101.4±19.
8

-2.7 ±0.3*

10.3

117

33.6

NG

8±4

8.5±0.7

-1.26
±0.09

NG

34±5

97.6±16.4

3.0±0.3

113

39.8

79.6

5±5

8.2±1.0

-0.8
±0.1*

46*

34±6

101±20

-2.8 ±0.5*

18.2

110

48.2

77.3

6±6

8.3±1.1

-0.4
±0.1*

32*

34±6

100±22

-1.6 ±0.4*

113

40.7

72.6

7±6

8.2±1.0

0.1±0.1

13

34±6

100±19

-0.3±0.3

BL HbA1c
(%) ±SD

Wt (kg)
±SE

6.3

63

52.4

100

NG

8.8±0.7

-1.5

NG

29±2

82.0±8.3

-8.0

65

49.2

100

NG

8.9±0.8

-1.8

NG

29±1

82.4±9.1

+4.3

8.8

57

50.9

100

NG

8.7±0.7

-1.2

NG

28±1

80.2±7.5

-5.1

9.3

54

51.9

100

NG

8.8±0.8

-1.4

NG

29±1

81.4±8.1

-0.9

11.1

190

58.4

41.0

9±6

8.4±0.9

-1.2±0.1

45.1

31±4

82.7±16.1

-1.3±0.2

16.0

187

51.3

45.0

8±6

8.5±1.0

-1.1±0.1

32.6

31±4

81.8±14.2

-1.1±0.2

25.4

181

NG

NG

5±4

7.9±0.8

-1.00

49.2

33±4

NG

-4.1 ±0.2*

20.8

173

NG

NG

5±5

7.9±0.9

-1.14

56.6

33±4

NG

1.0± 0.2

MET ±
SFU

17.5

234

52

0

8±6

8.3±1.0

-1.2*

48*

26±3

69.6±11.2

-1.2*

10.3

232

59

0

8±5

8.3±1.0

-0.4

17

26±3

67.9±11.0

-0.1

MET
+/or
TZD

21.4

28

32

86

7±4

7.5±0.9

NG

NA

30±3

91.6±15.2

-1.8 ±0.4*

11.5

26

58

96

6±4

7.1±0.7

NG

NA

30±4

85.9±12.2

-0.3±0.4

MET +
SFU

19.1

282

45.0

79.8

10±6

8.2±1.0

-1.1

46

31±4

87.5±16.9

-2.3*

9.4

267

43.4

80.5

9±6

8.3±1.0

-1.1

48

31±5

88.3±17.9

+1.8

16.2

38

37.8

0

10± 6

7.9±0.9

-1.4
±0.1*

79.4*

26±5

70.3±15.9

-1.3±0.3

10.8

37

32.4

0

11± 6

7.9±0.8

-1.2
±0.1*

71.4*

25±3

65.6±9.8

-0.2±0.3

8.1

38

29.7

0

15±11

8.0±0.8

-0.9
±0.1*

50.0*

24±3

64.9±11.6

-0.08±0.2

2.5

40

25.0

0

12±6

8.1±0.7

0.02±
0.1

5.1

26±5

71.1±14.0

-0.7±0.2

MET
Gli
ExBID
at B, D
ExBID
at L, D

Gao 2009
[100]

ExBID

MET ±
SFU ±
TZD

MET
Aspart

PBO
ExBID
PBO
ExBID
Glarg
ExBID

Kadowaki
2009 [103]

7±7

F

12.3

ExBID

Heine 2005
[102]

59.7

ITT
N

MET
Gli

Gallwitz
2011 [99]

Gill 2010
[101]

42.6

21.2

MET
+/or
SFU

PBO
Derosa
2010 [96]

129

17.7

SFU

ExBID
DeFronzo
2005 [95]

BL Wt
(kg) ±SD

(%)

DO
(%)

29.5

PBO
Buse 2007
[93]

BL
BMI
(kg/m2)
±SD

White
(%)

39.8

BG
Ther

ExBID
Buse 2004
[92]

HbA1c
(%) ±SE

Achieve
d HbA1c
7% or
<7%
(%)

T2DM
Dur
(y)
±SD

5.0 mcg
ExBID
2.5 mcg
ExBID
PBO

SFU
±MET
or
±TZD


Bhavsar et al.

Table 2. Contd….

HbA1c
(%) ±SE

Achieve
d HbA1c
7% or
<7%
(%)

BL
BMI
(kg/m2)
±SD

BL Wt
(kg) ±SD

Wt (kg)
±SE

-1.6*
±0.1

71.0*

26±4

69.1±11.2

-1.5 ±0.3*

67.1*

25±4

67.0±11.5

-0.4±0.3

(%)

White
(%)

72

31.9

0

12±7

8.2±1.0

9.7

72

31.9

0

12±6

8.3±0.8

5.7

35

31.4

0

12±7

8.1±0.9

-0.3±0.2

15.2

26±4

70.3±13.3

-0.5±0.4

17.8

241

40.7

66.4

9±6

8.5±1.1

-0.8
±0.1*

30*

34±6

98±21

-1.6 ±0.2*

15.9

245

40.8

69.0

9±6

8.5±1.0

24*

33±6

97±19

-1.6 ±0.2*

23.9

247

44.1

68.4

9±6

8.5±1.0

0.2±0.1

7

34±5

99±19

-0.9±0.2

58.8

527

36

83

8±6

8.2±1.0

-1.0±0.1

46

34±5

99±18

-5.3±0.4

14

111

40

57

6±4

8.2±0.9

-0.8
±0.2*

49

34±6

94.5±17.8

-1.4±0.6

PBO

7

54

43

61

6±5

8.3±0.9

-0.1±0.2

36

33±5

92.6±18.0

-0.8±0.7

ExBID

Study
Citation

T2DM
Dur
(y)
±SD

14

78

38

72

2±3

7.8±1.0

-0.9
±0.1*

46*

31±5

86±16

-3.1 ±0.3*

13

77

48

65

2±3

7.9±1.0

-0.7
±0.1*

48*

32±5

85±15

-2.8 ±0.3*

12

77

45

66

1±2

7.8±1.0

-0.2±0.1

29

32±5

86±16

-1.4±0.3

BG
Ther

DO
(%)

ITT
N

ExBID
Kadowaki
2011 [104]

Ther
Studied

SFU±
MET
or
SFU±

27.4

5 mcg
ExBID
PBO

TZD

ExBID
Kendall
2005 [105]

5 mcg
ExBID

MET +
SFU

PBO
Klonoff
2008 [106]
Liukus
2010 [107]

Moretto
2008 [108]

ExBID

ExBID

5 mcg
ExBID

MET,
+ SFU
TZD ±
MET

D/E

PBO

F

BL HbA1c
(%) ±SD

-1.3
±0.1*

-0.6
±0.1*

ExBID

MET +

21.3

253

47

NG

10±6

8.6±1.0

-1.0±0.1

32*

31±4

85.5±15.7

-2.5 ±0.2*

[109]

Aspart

SFU

10.1

248

51

NG

10± 6

8.6±1.1

-0.9±0.1

24

30±4

83.4±15.6

2.9±0.2

Ratner
2006 [110]

ExBID

MET

39

150

31

86

5±5

8.1±1.0

-1.3±0.1

59

34±6

102±21

-5.3±0.8

Riddle
2006 [111]

ExBID

SFU ±
MET

45

401

39

75

8±6

8.4±1.0

-1.0±0.1

44

34±6

99±21

-4.0±0.3

Zinman

ExBID

28.9

121

46.3

85.1

7±5

7.9±0.9

62*

34±5

97.5±18.8

-1.8 ±0.3*

PBO

14.3

112

42.9

82.1

8±6

7.9±0.8

0.1±0.1

16

34±5

96.9±19.0

-0.2±0.3

ExQW

20.6

160

44

33

6±5

8.6±1.2

-1.5*

~58*

32±5

89±20

-2.3*

13.3

166

48

30

5±4

8.5±1.2

-0.9

~30

32±5

87±20

-0.8

20.6

165

52

39

6±5

8.5±1.1

-1.2

~42

32±6

88±20

2.8

15.5

129

40

63

7±5

8.5±1.1

-1.6
±0.1*

58.1*

34±6

97.0±20.7

-2.3±0.4

22.8

123

45

55

7±5

8.4±1.2

-0.9±0.1

30.1

33±5

94.3±18.9

-1.4±0.4

Nauck 2007

TZD ±
MET

-0.9
±0.1*

2007 [112]
Exenatide QW

Bergenstal
2010 [113]
DURATION-2

Blevins
2011 [114]
DURATION-5

100 mg
SITA

MET

45 mg
PIO
ExQW

ExBID

D/E,
MET,
SFU,
TZD
or any
comb



179

Table 2. Contd….

(%) ±SD

HbA1c
(%) ±SE

Achieve
d HbA1c
7% or
<7%
(%)

BL
BMI
(kg/m2)
±SD

BL Wt
(kg) ±SD

(%)

White
(%)

148

43

83

7±6

8.3±1.0

-2.0

71

35±5

103±19

-4.1

18

147

47

74

6±5

8.2±0.9

-2.0

71

35±5

102±20

-4.5

13.2

461

44.9

83.3

8±6

8.4±1.0

-1.3

52.3

32±6

90.9±19.5

-2.7

13.1

450

45.6

81.8

9±7

8.4±1.0

-1.5

60.2

32±5

91.1±19.1

-3.6

10.3

233

48

82

8±6

8.3±1.1

-1.5
±0.1*

60*

32±5

91.2±18.6

-2.6 ±0.2*

6.3

223

45

85

8±6

8.3±1.0

-1.3±0.1

48

32±5

90.6±16.4

1.4±0.2

13.5

148

45.0

83

7±6

8.3±1.0

-1.9
±0.1*

77*

35±5

102±19

-3.7±0.5

11.6

147

49.0

73

6±5

8.3±1.0

-1.5±0.1

61

35±5

102±21

-3.6±0.5

34

295

NG

NG

7±5

8.2±1.0

-1.6

57

NG

101±18

-2.3

15.3

248

44

68.1

3±3

8.5±1.2

-1.5±0.1

63

31±5

88±19

-2.0±0.2

13.4

246

37

65.0

3±4

8.6±1.2

-1.5±0.1

55

31±6

86±20

-2.0±0.2

PIO

18.4

163

41

67.5

3±4

8.5±1.2

-1.6±0.1

61

31±5

86±18

1.5±0.3

SITA

Study
Citation

T2DM
Dur
(y)
±SD

DURATION-1

14.1

163

42

69.3

3±4

8.5±1.3

-1.2±0.1

43

32±5

89±19

-0.8±0.3

27

295

47

79

7±5

8.2±1.0

-1.7±0.1

60

35±5

101±19

-2.6±0.5

35.6

160

43

32

6±5

8.6±1.2

-1.6±0.1

58

32±5

90±19

-1.8±0.5

21.7

166

42

35

6±5

8.5±1.1

-1.8±0.5

53

32±5

88±21

-1.1±0.3

39.4

165

49

39

6±5

8.4±1.0

-1.6±0.1

59

32±5

86±21

-3.0±0.3

BG
Ther

DO
(%)

ITT
N

ExQW
Buse 2010
[115]

Ther
Studied

D/E,
MET,
SFU,
TZD
or 2
OAD

19

ExBID
then
ExQW
ExQW

Buse 20111
LIRA

Diamant
2010 [116]

ExQW

MET,
SFU,
TZD,
or any
comb

MET ±
SFU

Glarg
ExQW
Drucker
2008 [117]
ExBID

MacConell
20112

ExQW

D/E,
MET,
SFU,
TZD
or 2
OAD
D/E,
MET,
SFU,
TZD
or 2
OAD

ExQW
RussellJones 2012
[118]

Taylor
2011 [119]

MET

BL HbA1c

Wt (kg)
±SE

D/E

ExQW

D/E,
MET,
SFU,
TZD
or 2
OAD

ExQW

Wysham
2011 [120]

F

SITA
then
ExQW
PIO
then
EQW

MET

Note: when 'ExBID' is listed without dose, dose was 10 mcg BID. When ExQW listed without dose, dose was 2 mg.
*p<0.05 improvement in HbA1c or weight versus control group.
a
Portions of table adapted from: Aroda V, Henry R, Han J, et al. A meta-analysis and systematic review of the efficacy of GLP-1 receptor agonists and DPP-4 inhibitors. Clin Ther.
2012;34:1247-58.e22


testinal and injection site-related. These adverse events were
generally mild and incidences decreased over time. Gastrointestinal adverse events were lower with ExQW than with
ExBID (35% vs 46%, respectively) or another GLP-1 receptor agonist, liraglutide (26% vs 42%, respectively). Hypoglycemia occurred infrequently unless there was concomitant
SFU use. The adverse events of pancreatitis, pancreas cancer, thyroid cancer, and renal-related problems were generally similar for ExQW, ExBID, and a pooled comparator
group of patients treated in these trials with non-GLP-1 receptor agonists.
An overview of selected adverse effects observed in individual phase 3 exenatide clinical trials are summarized in
Table 3 [86-120].1,2 Nausea was the most frequent exenatide
side effect, ranging from 12% to 57% upon initiation of 10mcg exenatide BID (preceded by 4 weeks of 5-mcg ExBID)
and 7% to 26% upon first initiation of 2-mg ExQW. Nausea
tended to be mild-to-moderate and decreased in frequency
with longer duration of exenatide exposure, independent of
formulation (BID or QW) [136]. Vomiting had a lower incidence than nausea, ranging from 4% to 22% upon initiation
of 10-mcg ExBID and 4% to 11% upon first initiation of 2mg ExQW. Due to differences in the pharmacokinetic profiles of ExBID and ExQW upon initiation of dosing (rapid
achievement of therapeutic concentration of exenatide with
ExBID versus 6-7 weeks to achieve final therapeutic concentration of exenatide with ExQW), the lessened incidence and
intensity of gastrointestinal side effects with ExQW is not
unexpected.
Accidental Overdosing
Several reports have described the adverse events associated with exenatide overdosing [138,139]. During one clinical trial, three patients were accidently injected with approximately 100-mcg of exenatide [138]. All three presented
with severe nausea and vomiting, and one of them experienced severe hypoglycemia that resolved with intravenous
administration of 5% dextrose. All three patients recovered
without further sequelae. In another report, Cohen et al.
[139] discussed the emergency room presentation of a 40year-old morbidly obese woman with T2DM who selfinjected 90-mcg of exenatide in addition to her usual morning medications. The patient presented with dizziness, weakness, nausea, one episode of vomiting, normal vital signs,
normal laboratory values, and fasting blood glucose ranging
from 84 to 109 mg/dL upon hourly monitoring. Treatment
consisted of metoclopramide intravenously. The patient did
not become hypoglycemic and fully recovered. In summary,
accidental exenatide overdosing was associated with shortterm gastrointestinal sequelae and the possibility of an increased hypoglycemia risk. Adverse events due to overdosing have so far been managed successfully with prompt and
appropriate medical care.
Hypoglycemia
In the MacConell et al. integrated analysis, the overall
incidence of hypoglycemia was comparable between groups
without SFU use, but between-group differences became
apparent when hypoglycemic events were evaluated based
on concomitant use of insulin-secretogogue SFU therapy

Bhavsar et al.

[136]. The incidence rate of mild-to-moderate or major hypoglycemia without concomitant SFU therapy was 3.1%
with exenatide and 2.7% with comparators. In contrast, hypoglycemia was more prevalent when exenatide was administered with a SFU (26.5%) than in the pooled comparator
cohort (20.7%).
In individual phase 3 exenatide clinical trials major/severe hypoglycemia was rare with 10-mcg ExBID or 2mg ExQW exposure (Table 3) [86-120]1,2, ranging from <1%
to 4%. The incidence of all cases of reported hypoglycemia
ranged from 0% to 58% upon initiation of 10-mcg ExBID
(preceded by 4 weeks of 5-mcg exenatide BID) and 1% to
8% upon first initiation of 2 mg ExQW. Concomitant use of
insulin-secretogogue SFU was more often associated with
hypoglycemic events than was concomitant MET use. Insulin was usually, but not always, associated with more hypoglycemia than exenatide. In addition, nocturnal hypoglycemia was significantly more frequent in subjects treated with
insulin glargine or aspart than with exenatide.
In summary, major/severe hypoglycemia has rarely been
observed with ExBID or ExQW use. In the absence of concomitant SFU therapy, the risk of mild-to-moderate hypoglycemia is low. Concomitant SFU increases the risk of hypoglycemic events and SFU discontinuation should be considered when initiating exenatide. ExBID use is associated
with a reduced incidence of nocturnal hypoglycemia compared with insulin.
Pancreatitis
In postmarketing data, exenatide administration has been
associated with acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis. Of note, acute
pancreatitis has been observed in patients treated with exenatide, but it has not been shown that exenatide was causally associated with this adverse event, as will be discussed
below. Patient characteristics associated with an increased
risk of pancreatitis are overweight/obesity, alcohol use,
smoking status, and prior pancreatitis/cholelithiasis/ cholecystectomy [136]. In the MacConell et al. [137] integrated
analysis discussed above, composite exposure-adjusted incidence rates per 100 patient-years for pancreatitis were not
statistically different between the exenatide and pooled comparator groups (0.27 versus 0.18) (Fig. 13). In addition, occurrence of acute pancreatitis was rare, with a comparable
incidence rate of 0.1% in each cohort. In individual phase 3
exenatide clinical trials, pancreatitis was also rare with ExBID or ExQW exposure (Table 3) [86-120].1,2
In an analysis using insurance claims from a large U.S.
commercial health database, patients with T2DM initiating
ExBID were propensity-score-matched with a similar cohort
initiating MET or SFU (glyburide) [140]. In this study, exenatide initiators were more likely to be overweight/obese
with dyslipidemia and hypertension. Baseline prevalences of
gallstone disease (0.8%) and alcohol dependence syndrome
(0.1% to 0.2%) were low and comparable across matchedpairs. The estimated absolute risk of hospitalization associated with a primary diagnosis of acute pancreatitis was
0.13% among patients treated with exenatide compared with
0.13% for the matched MET/Gly cohort suggesting that
there was no apparent difference in risk. One limitation of



181

Table 3. Overview of Nausea, Vomiting, Hypoglycemia, and Selected Treatment-Emergent Adverse Events from Phase 3 Exenatide
Clinical Trials

Nausea
(%)

Vomiting
(%)

Hypo
(%)

Major/
Severe
Hypo?

ExBID+MET+SFU

29

NG

29

No

Aspart QD+MET+SFU

9

NG

56

3.2%

4.02 hypo/subj-y. P=0.0013 vs Ex

Aspart BID+MET+SFU

8

NG

61

4.8%

5.25 hypo/subj-y. P<0.0001 vs Ex

ExBID+MET +/or SFU

14-29

NG

7-12

0.7%

The severe hypo event occurred in a patient
treated with SFU

ExBID+MET

50

NG

8.3

No

Glarg+MET

NG

NG

24.2

No

ExBID+MET

38.1

9.5

19.0

No

Glarg+MET

NG

8.0

28.0

No

ExBID+Glarg

41

18

25.0

No

PBO+Glarg

8

4

29.0

1%

ExBID+MET±SFU

28.0

9.9

34.5

0.9%

LIRA+MET±SFU

25.5

6.0

26.0

No

ExBID+MET +/or SFU

51

13

36

No

5 mcg ExBID+MET +/or SFU

39

10

14

No

PBO+MET +/or SFU

7

2

3

No

ExBID+MET +/or SFU

8-39

NG

<1-13

0.2%

1 severe hypo in 1010 subj-y

ExBID+MET+/or SFU+/or TZD

48.3

NG

50.0

4.2%

Nocturnal hypo: 11.9%.

Glarg+MET+/or SFU+/or TZD

2.6

NG

59.6

5.3%

Nocturnal hypo: 29.8%. P=0.001 vs Ex

ExBID+MET

45

12

5

No

5 mcg ExBID+MET

36

11

5

No

PBO+MET

23

4

5

No

ExBID+MET

NG

NG

0

NG

Glibenclamide+MET

NG

NG

4.6

NG

ExBID+MET

NG

NG

0

NG

Glibenclamide+MET

NG

NG

5.6

NG

ExBID at B/D+MET± SFU±TZD

22.6

10.0

NG

4.2%

5.21 hypo/subj-y. P=0.393 vs Ex L/D

ExBID at L/D+MET± SFU± TZD

25.1

10.2

NG

0.5%

6.51 hypo/subj-y

ExBID+MET

18.8

9.9

8.0

No

Nocturnal hypo: 3.9%

Aspart+MET

NG

NG

20.5

No

Nocturnal hypo: 7.0%

Citation

Treatment

Other Relevant Observations

EXENATIDE BID CLINICAL TRIALS

Bergenstal 2009
[86]

Blonde 2006 [87]

1.28 hypo/subj-y.

1 pancreatitis, resolved after Ex stopped

Bunck 2009 [88]

Bunck 2011 [89]

1.4 hypo/subj-y
Nocturnal: 17% hypo

Buse 2011 [90]

Buse 2009 [91]

Buse 2004 [92]

Buse 2007 [93]

Nocturnal: 26% hypo
2.6 minor hypo/subj-y. Major hypo had SFU
1.9 minor hypo/subj-y. P=0.0131 vs Ex
1 mild pancreatitis

Davies 2009 [94]

DeFronzo 2005
[95]

Derosa 2010 [96]

Derosa 2011 [97]

Forti 2008 [98]

Gallwitz 2011
[99]


Bhavsar et al.

Table 3. contd…

Citation

Treatment

Nausea
(%)

Vomiting
(%)

Hypo
(%)

Major/
Severe
Hypo?

25.5

15.8

35.5

0.9%


4.4 hypo/subj-y.
ExBID+MET±SFU

MET only: 1.8 hypo/subj-y
MET+SFU: 4.7 hypo/subj-y

Gao 2009 [100]
0.5 hypo/subj-y
PBO+MET±SFU

0.9

0

9.0

0.4%

MET only: 0.22 hypo/subj-y
MET+SFU: 0.54 hypo/subj-y

ExBID+MET +/or TZD

36

NG

7

No

PBO+MET +/or TZD

19

NG

4

No

57.1

17.4

NG

1.4%

Gill 2010 [101]

7.3 hypo/subj-y.
ExBID+MET+SFU

Nocturnal hypo: 21%; 0.9 hypo/subj-y
Heine 2005 [102]
6.3 hypo/subj-y.
Glarg+MET+SFU

8.6

3.7

NG

1.5%
Nocturnal hypo: 43%; 2.4 hypo/subj-y

ExBID+SFU±MET, +SFU±TZD

No

5 mcg ExBID+SFU±MET,
+SFU±TZD

8.1

13.5

43.2

No

2.5 mcg ExBID+SFU± MET,
+SFU±TZD

10.8

5.4

27.0

No

0

0

10.0

No

36.1

16.7

58.3

No

5 mcg ExBID+SFU, +SFU+MET,
+SFU+TZD

25.0

4.2

51.4

No

PBO+ExBID+SFU, +SFU+MET,
+SFU+TZD

8.6

2.9

22.9

No

ExBID+MET+SFU

48.5

13.7

27.8

No

5 mcg ExBID+MET+SFU

39.2

14.7

19.2

4.1%

PBO+MET+SFU

Kendall 2005
[105]

54.1

ExBID+SFU, +SFU+MET,
+SFU+TZD
Kadowaki 2011
[104]

8.1

PBO+SFU±MET, +SFU±TZD

Kadowaki 2009
[103]

35.1

20.6

4.5

12.6

No

59.0

NG

40.0

0.2%

Lower hypo incidence in SFU MIN group

Klonoff 2008
[106]

ExBID+MET+SFU

Liukus 2010
[107]

ExBID+TZD±MET

12

8

4.0

No

PBO+TZD±MET

2

0

2.0

No

ExBID

13

4

4

No

0.52 hypo/subj-y

5 mcg ExBID

3

4

5

No

0.21 hypo/subj-y

PBO

0

0

1

No


33.2

15.0

NG

No

Moretto 2008
[108]

All severe hypo events occurred in patients
treated with SFU

4.7±0.7 hypo/subj-y
ExBID+MET+SFU

Nocturnal hypo: 17%.

Nauck 2007
[109]

5.6±0.7 hypo/subj-y
Aspart+MET+SFU

0.4

3.2

NG

No
Nocturnal hypo: 25%; P<0.038 vs Ex



183

Table 3. contd…

Citation

Treatment

Nausea
(%)

Vomiting
(%)

Hypo
(%)

Major/
Severe
Hypo?

14-33

1-5

NG

No

14-27

NG

8-15

1.0%

Ratner 2006
[110]

ExBID+MET

Riddle 2006
[111]

ExBID+SFU±MET

Zinman 2007
[112]

ExBID+TZD±MET

39.7

13.2

10.7

No

PBO+TZD±MET

15.2

0.9

7.1

No

ExQW+MET

24

11

1

No

SITA+MET

10

2

3

No

PIO+MET

5

3

1

No


EXENATIDE QW CLINICAL TRIALS

Bergenstal 2010
[113]

2 cases of pancreatitis
All hypo events occurred in patients treated
with SFU

14.0
Blevins 2011
[114]

4.7

3.9

No
1 case pancreatitis: resolved while taking
ExQW.

ExQW+D/E, MET, SFU, TZD or
any combo
ExBID+D/E, MET, SFU, TZD or
any combo

35.0

8.9

3.3

No

2 OADs

7.0

6.3

NG

No

ExBID then ExQW, +D/E, MET,
SFU, TZD or 2 OADs

7.7

with SFU
with SFU
Wk 30-52: 10.2% hypo

Buse 2010 [115]
4.6

NG

No

Wk 30-52: 8.0% hypo

ExQW+MET, SFU, TZD or any
comb

9.3

3.7

10.8

No

LIRA+MET, SFU, TZD or any
comb

Buse 2011

with SFU

20.4

10.7

8.9

No

13

4

8

No

1

ExQW+MET±SFU

Hypo with MET: p<0.0001 vs Ex+MET
Diamant 2010
[116]

Hypo with MET+SFU: p=0.0009 vs
Ex+MET+SFU
Glarg+MET±SFU

1

1

26

No

Nocturnal hypo
Hypo with MET: p=0.028 vs Ex+MET
Hypo with MET+SFU: p=0.0005 vs
Ex+MET+SFU

Drucker 2008
[117]

MacConell 20112

2 OADs

26.4

10.8

5.4

No

Hypo with SFU: 14.5% vs 0% without SFU

ExBID then ExQW, +D/E, MET,
SFU, TZD or 2 OADs

34.5

18.6

6.1

No

Hypo with SFU: 15.4% hypo vs 1.1% without
SFU

2 OADs

16 (wks
30- 156)

NG

NG

No


Bhavsar et al.

Table 3. contd…

Nausea
(%)

Vomiting
(%)

Hypo
(%)

Major/
Severe
Hypo?

ExQW

11.3

4.8

5.2

No

MET

6.9

3.3

4.1

No

PIO

4.3

3.1

3.7

No

SITA

3.7

1.8

3.1

No

2 OADs

12*

9*

6.6*

No

Citation

Russell-Jones
2012 [118]

Taylor 2011
[119]

Treatment


*Wk 30-104
Hypo with SFU: 94% (16/17 subj)

ExQW+MET

5.0**

1**

No

**Wk 26-52

SITA then ExQW, +MET

10.8**

3.8**

2**

No

**Wk 26-52

PIO then ExQW, +MET

Wysham 2011
[120]

5.0**

9.6**

2.6**

1**

No

**Wk 26-52

Note: when 'ExBID' is listed without dose, dose was 10 mcg BID. When ExQW listed without dose, dose was 2 mg.
Abbreviations: Aspart insulin aspart; B, breakfast; BID, twice daily; D, dinner; Ex, exenatide; GLARG, insulin glargine; Hypo, hypoglycemic events; hypo/subj-y, number of hypoglycemic events per subject year; L, lunch; MET, metformin; MIN, minimum; Lira, liraglutide; NG, not given; PBO, placebo; PIO, pioglitazone; QW, once weekly; Sita, sitagliptin;
Subj, subject; SFU, sulfonylurea; TZD, thiazolidinedione; vs, versus; Wk, week; Y, year.

Fig. (13). Adverse events of interest. Exposure-adjusted incidence rate (EAIR) and risk difference of thyroid neoplasm, pancreatitis, renal
impairment, and major adverse cardiac events (MACE). ExBID n=3261. Pooled comparator n=2333. MACE n=2316 and 1629, respectively.
Thyroid neoplasm includes benign neoplasm of thyroid gland and malignant thyroid neoplasm. Pancreatitis includes acute pancreatitis and
chronic pancreatitis. Renal impairment includes renal failure. MACE includes stroke, myocardial infarction, cardiac mortality, acute coronary
syndrome, and revascularization procedures. a95% confidence interval for the risk difference (RD, ExBID incidence rate [%] minus pooled
comparator incidence rate [%]). bMACE analysis: risk ratio (RR) and 95% confidence interval for the RR. PY=patient-years. (Reprinted with
permission from reference [137]).

this study was that claims for medical services may not meet
the strict clinical definition of acute pancreatitis.
In another retrospective analysis of a health insurance
claims database, the risk of acute pancreatitis was significantly higher for adults with diabetes than in normoglycemic
adults (Cox proportional hazard ratio=2.1) [141]. The incidence of acute pancreatitis in the cohort with diabetes was
5.6 cases per 1,000 subject years. Unlike the previous report,
this analysis included patients with evidence of chronic pancreatic disease and estimated the risk of acute pancreatitis
after adjusting for medical conditions and medications asso-

ciated with an increased risk of acute pancreatitis. Among
patients with T2DM, the risk of acute pancreatitis was comparable in the exenatide-treated cohort and the T2DM control cohort (Cox proportional hazard ratio=1.0).
A more recent evaluation of patients with diabetes (types
1 or 2), and without prior insurance claims for pancreatic
disease, found no increased risk of emergency room treatment or hospitalization associated with acute pancreatitis in
patients currently taking exenatide compared with a matched
cohort on other antidiabetes drugs (propensity score adjusted
risk ratio=0.5) [142]. Past exposure to exenatide, defined as


more than 62 days after exhaustion of a patient's drug supply, was associated with an increased risk (risk ratio 2.8).
However, after adjustment for all chart-derived patient characteristics associated with an increased risk of pancreatitis
(overweight/obese, alcohol use, smoking status, and prior
pancreatitis/ cholelithiasis/ cholecystectomy) and contemporaneous claim-identified covariates, the past-time estimate
was consistent with no increased risk for acute pancreatitis
with past exenatide exposure relative to past exposure to
other antidiabetes drugs (odds ratio 1.1).
Based on the medical literature (range 1950 to January
2010), FDA website (range 2005 to August 2008), and
Amylin Pharmaceuticals database, Anderson and Trujillo
[143] published a review of pancreatitis reports associated
with ExBID use. The pancreatitis incident rate during clinical development was 1.8 per 1000 subject years for exenatide, compared with 2.6 per 1000 subject years for PBO
and 0.9 per 1000 subject years for insulin. Among the FDAreviewed post-marketing cases of pancreatitis, all 6 patients
with hemorrhagic or necrotizing pancreatitis required hospitalization and 2 died. For the 30 other cases of pancreatitis,
19 patients were female (63%) with a median age of 60 years
and a time-to-onset of symptoms ranging from 4 to 300 days
after exenatide initiation (median 34 days post-exenatide). In
22 cases of pancreatitis the patients improved after exenatide
discontinuation and in 21 cases of pancreatitis the patients
required hospitalization. Of note, 27 of the 30 patients had at
least one other risk factor for acute pancreatitis.
Elashoff et al. [144] used the U.S. Food and Drug Administration (FDA) adverse event reporting system (AERS)
database to analyze putative associations between exenatide
and cases of pancreatitis, pancreatic cancer, thyroid tumors,
and all cancers. As cautioned by the authors, the FDA AERS
database depends on spontaneous reporting and is thus, subject to reporting biases. The control antidiabetes drugs were
rosiglitazone (TZD), nateglinide, repaglinide, and glipizide
(SFU). Back pain, urinary tract infection, chest pain, cough,
and syncope were prospectively defined as the control adverse events. By design, no comparable analyses were performed to assess the rates of pancreatitis and cancer associated with the control drugs. The fundamental assumptions in
the analysis were no association between the control drugs
and control events, or between exenatide and control events.
The period covered was 2004 through the third quarter of
2009.Within this framework, the authors found an increased
risk of pancreatitis and pancreatic cancer associated with
exenatide compared with the control drugs (odds ratio
10.68). When the subset of pancreatitis reports in 2006 and
prior (before the first cautionary letter from the FDA in
2007) were analyzed, the odds ratio for exenatide, compared
with control drugs, was 2.57 for pancreatitis, 2.95 for pancreatic cancer, 4.73 for thyroid cancer, and 1.08 for all other
cancers. Given the potentially serious safety concerns raised
by Elashoff et al. [144], the European Association for the
Study of Diabetes (EASD) evaluated the report in detail
[145]. The EASD acknowledged the importance of continual
safety monitoring of diabetes therapeutics, but concluded
there was no definitive evidence pointing to an increased
cancer risk with incretin-based medications. The EASD reiterated the incompleteness and bias associated with spontaneous adverse events reporting systems such as the FDA


185

database. Also, given the analysis period covered by
Elashoff et al. [144], there was a significant amount of time
before exenatide market introduction when only events with
control therapy were collected, possibly introducing further
bias. In addition, reported events are not evaluated for their
adherence to accepted diagnostic standards. EASD stated
that the only robust way of measuring comparative risk is
within randomized control trials.
In summary, the incidence of acute pancreatitis is rare in
patients with T2DM, whether or not they are being treated
with exenatide or other diabetes drugs. However, additional
monitoring to compile long-term exposure data is warranted,
with randomized, controlled clinical trials as the recommended methodology.
All patients treated with exenatide should be monitored
for the signs and symptoms of pancreatitis, including
persistent severe abdominal pain, possibly radiating to the
back, which may or may not be accompanied by vomiting
[135,146]. If pancreatitis is suspected, exenatide should be
discontinued. If pancreatitis is confirmed, exenatide should
not be restarted. Exenatide should not be used in patients
with a history of pancreatitis.
Neoplasias
In both genders of rats, exenatide caused a dose-related
and treatment-duration dependent increase in the incidence
of thyroid C-cell tumors at clinically relevant exposures
compared to controls [136,146]. A significant increase in
malignant thyroid C-cell carcinomas was observed in female
rats receiving exenatide at 25-times clinical exposure compared to controls and higher incidences were noted in males
above controls in all treated groups at 2-times clinical exposure. Other GLP-1 receptor agonists have also been shown
to induce thyroid C-cell adenomas and carcinomas in male
and female mice and rats at clinically relevant exposures
[144]. It is unknown whether exenatide will cause thyroid Ccell tumors, including medullary thyroid carcinoma (MTC),
in humans, as the human relevance of exenatide-induced
rodent thyroid C-cell tumors could not be determined by
clinical or nonclinical studies..
As to the topic of 'thyroid cancer' in humans raised by the
Elashoff et al. analysis [144], the EASD [145] stated that
there are different categories of thyroid cancer, with different
molecular characteristics and etiologies. The only form possibly mechanistically-related to incretin-based antidiabetic
drugs that could potentially be influenced by therapies leading to enhanced stimulation of the GLP-1R is a cascade leading from C-cell hyperplasia to C-cell adenoma to medullary
thyroid carcinoma. Medullary thyroid carcinoma is one of
the rarer forms of thyroid tumors and it seems counterintuitive that a change in the incidence in medullary thyroid
carcinoma would change the overall incidence of thyroid
carcinomas. A similar viewpoint was expressed by Spranger
et al. [147] for the Drug Commission of the German Medical
Association. According to the authors, the time between tumor induction, tumor development, and metastasis/clinical
diagnosis generally extends more than 10 years. By contrast,
spontaneous adverse drug reactions in the German national
database consistently found the time between initial exenatide exposure and tumor detection to be much shorter (2


Bhavsar et al.

to 33 months). Thus, the authors concluded that a role for
exenatide in tumor induction was doubtful.

percentage of the exenatide cohort than the pooled comparator cohort were free of a primary MACE event over 1 year.

In the MacConell et al. integrated analysis [137], a small
difference was observed between the exenatide BID and
pooled comparator groups in the incidence of thyroid tumors
(0.3% versus 0.0%, respectively).

The effects of 10-mcg ExBID on heart rate was prospectively evaluated in a small, 12-week, PBO-controlled pilot
study [101]. Overweight patients with T2DM with stage-1
hypertension and treated with MET, TZD, or MET+TZD for
their hyperglycemia had no change from baseline in heart
rate in either treatment arm. Exenatide was not associated
with a significant change from baseline in mean 24-hour,
daytime, or nighttime heart rate within or between groups.

In summary, a causal relationship between the development of neoplasias and treatment with exenatide or other
diabetes drugs has not been proven in patients with T2DM.
However, additional monitoring to compile long-term exposure data is warranted, with randomized, controlled clinical
trials as the recommended methodology. Patients with a personal or family history of medullary thyroid carcinoma or
multiple endocrine neoplasia syndrome type 2 should not be
treated with exenatide [136,146].
Exenatide Use in Renal Disease
Exenatide is primarily metabolized and cleared in the
kidney [148], and exenatide pharmacokinetics are significantly altered (i.e., reduced clearance rate, increased halflife) in nondiabetic adults with end-stage renal disease [149].
In addition, ExBID may induce nausea and vomiting, resulting in transient hypovolemia possibly leading to worsened
renal function. Therefore, it is prudent to proceed conservatively in patients with moderate renal impairment (creatinine
clearance 30-50 mL/min) and to avoid exenatide use completely in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min)
[136,146].
In the MacConell et al. [137] integrated ExBID analysis,
there was no between-cohort difference in exposure-adjusted
incidence rates per 100 patient-years for renal impairment/failure (1.6 for each cohort).
In summary, caution should be used when initiating or
escalating exenatide therapy in patients with T2DM and
moderate renal impairment. Exenatide should not be used in
patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 ml/min), and should be used
with caution in patients with renal transplantation.
Cardiovascular Effects
Ratner et al. [150] reported a retrospective analysis of
major adverse cardiac events (MACE) in 3945 subjects from
12 randomized exenatide BID clinical trials; 8 PBOcontrolled and 4 active comparator-controlled (Fig. 14). For
this evaluation, MACE included cardiovascular mortality,
stroke, myocardial infarction, acute coronary syndrome, and
revascularization procedures. Of note, in the clinical trials
included in this analysis, patients were excluded from study
participation if they had a significant history of cardiac disease at screening, or active cardiac disease within 1 year
prior to screening. In this population, MACE occurred infrequently. At baseline, mean HbA1c was 8.3% to 8.4%, mean
BMI was 31.3 to 31.5 kg/m2, mean systolic BP was 131 to
132 mmHg, and mean diastolic BP was 79 mmHg. There
were 4 fatal CV events, 2 in each treatment cohort. The exenatide cohort had an exposure-adjusted incidence rate per
100 patient-years of 1.9, versus 2.3 for the comparator cohort. In a weighted Kaplan-Meier plot a significantly higher

Overall, available clinical trial data indicate that treatment with exenatide BID does not increase cardiovascular
risk in patients with T2DM.
Anti-exenatide Antibody Formation and Injection-site
Reactions
Xenogenic peptide therapies, such as exenatide, often
stimulate an antibody response and the clinical impact of this
immune response can range from none to life threatening
[151]. Antibody rates for all xenogenic peptide therapies can
vary from less than 1% to over 70%. However, not all antibodies are neutralizing, nor do all antibody responses result
in attenuation of drug efficacy, altered pharmacokinetics/
pharmacodynamics, or changes in drug clearance. In the majority of cases, the antibody response to xenogenic peptides
is benign, with minimal clinical impact.
In an integrated analysis of patients with T2DM exposed
to ExBID in controlled clinical trials, 35% of all patients
were antibody-positive at endpoint (12 to 52 weeks of treatment); 33% of all patients had low antibody titers ( 125)
[152]. For patients exposed to ExQW in clinical trials, 57%
were antibody-positive at the endpoints of the controlled
periods (24 to 30 weeks); but most (88%) had low antibody
titers. In ExQW patients, 22% with detectable antibodies had
potentially immune-related treatment-related adverse events,
versus 12% in antibody-negative subjects and 10% in the
pooled comparator control group. Injection-site erythema or
pruritus was reported in 13.6% of antibody-positive patients
treated with ExQW, compared with 3.1% of antibodynegative patients and 2.9% of comparator control patients.
No anaphylactic reactions occurred with either exenatide
formulation.
In summary, anti-exenatide antibody responses are common in patients treated with ExBID or ExQW. However, the
incidence of all immune-related adverse events is low. Injection-site erythema or pruritus was observed in patients
treated with ExQW, but no anaphylactic reactions have occurred with either exenatide formulation.
Special Populations
One small PBO-controlled study directly compared exenatide safety in elderly patients with T2DM 75 years of
age (n=15) with middle-aged patients with T2DM 45 to
65 years of age (n=15) [153]. At baseline, the elderly cohort had mild or moderate renal impairment, while the middle-aged cohort had normal renal function. Treatment was
administered over three consecutive days. Nausea and vomiting with ExBID were more prevalent in the elderly cohort
(nausea: 6 patients versus control 3 patients; vomiting: 3



187

Fig. (14). (A) Relative risk of primary MACE and secondary cardiovascular endpoints with ExBID relative to pooled comparators. (B)
Weighted Kaplan-Meier plot for patients without a primary MACE event by treatment in controlled ExBID studies. (Reprinted with permission from reference [150].

patients versus 1 control patient). All other adverse events
were similar in both groups, and none were severe in intensity. There were no reports of hypoglycemia.
FUTURE DIRECTIONS
A once monthly formulation of exenatide (ExQM) is currently undergoing clinical evaluation.4 This formulation uses
the extended-release microspheres of ExQW with a triglyceride-based diluent to enable delivery of higher exenatide
doses less frequently. A 20-week, randomized, open-label,
MacConell L, Malloy J, Huang W, Cirincione B, Shen L, Porter L. Safety
and efficacy of once-monthly exenatide over 20 weeks in patients with type
2 diabetes. Annual meeting of the American Diabetes Association, June
2011.
Late-breaking
abstract
46-LB
accessed
at
http://professional.diabetes.org/Congress_Display.aspx?TYP=9&CID=8245
2.

controlled trial was conducted in 121 patients with T2DM
treated with diet/exercise, MET, TZD (pioglitazone) or
MET+TZD. Three ExQM doses (5, 8, or 11 mg) administered 5 times as directed were compared with ExQW administered 20 times. Sustained plasma exenatide concentrations
were achieved with all ExQM doses, although greater peakto-trough variability in exenatide pharmacokinetic profiles
was observed with ExQM than with ExQW. However, the
mean trough concentrations remained within the therapeutic
range with all ExQM doses. The 8- and 11-mg ExQM doses
achieved plasma exenatide concentrations similar to those of
ExQW. All three ExQM doses reduced mean HbA1c
by -1.3% to -1.5%, compared with an ExQW mean HbA1c
reduction of -1.5%. Seventy percent of patients achieved an
HbA1c<7% on the 11-mg ExQM dose versus 48% with
ExQW. Patients dosed with 11-mg ExQM lost -1.1 kg of
body weight, compared with -1.4 kg in the ExQW group.


The overall safety profile was comparable between ExQM
and ExQW. No hypoglycemia was observed. Based on these
preliminary results, more extensive clinical trials are
planned.
An ongoing, prospective morbidity and mortality outcomes study (EXSCEL) is expected to further elucidate the
potential cardiovascular implications of ExQW in patients
with T2DM.5 The primary outcome measure is the time to
first cardiovascular event in a combined endpoint consisting
of cardiovascular-related death, nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints include the
time to all-cause mortality, time to first cardiovascular event,
time to hospitalization for acute coronary syndrome, and
time to hospitalization for heart failure. Recruitment for this
trial is ongoing.
SUMMARY AND CONCLUSION
This review presents an overview of the evolution of exenatide as a treatment for T2DM beginning with the realization of the importance of the 'incretin effect', through seminal preclinical discoveries, clinical pharmacology investigations, and phase 3 clinical trials. Currently, a twice daily
exenatide formulation is approved for use in patients with
T2DM in the U.S., E.U., Japan, and other countries. More
recently, a once weekly exenatide formulation was approved
for use in the U.S. and EU. In addition, a once-monthly exenatide formulation is undergoing clinical testing. In patients
with T2DM, glycemic control is not always achieved, and
some therapeutic interventions cause hypoglycemia and
weight gain, or possibly exacerbate the risk of CVD. In
clinical trials, exenatide treatment has addressed these unmet
medical needs with T2DM patients experiencing improved
glycemia, weight loss, and a low frequency of hypoglycemia
in the absence of concurrent SFU (insulin secretogogue) use.
The effects of exenatide have been shown to be mediated
through enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed
gastric emptying, and enhanced satiety.

Bhavsar et al.

The most common side effects are gastrointestinal in nature, mild, and transient. Nausea is the most prevalent adverse event and tends to decrease in frequency with continued exenatide exposure. The incidence of hypoglycemia
without concomitant SFU therapy is generally low; hypoglycemia incidence increases when exenatide is used in conjunction with a SFU. Rare cases of pancreatitis have been
reported, typically at the same incidence rate as for other
diabetes drugs. A causal relationship between the development of neoplasias and treatment with exenatide or other
diabetes drugs has not been proven in patients with T2DM.
However, additional monitoring to compile long-term exposure data is warranted, with randomized, controlled clinical
trials as the recommended methodology. Patients with a personal or family history of medullary thyroid carcinoma or
multiple endocrine neoplasia syndrome type 2 should not be
treated with exenatide. No detrimental cardiovascular effects
have been identified. Most patients develop low titer antiexenatice antibodies with little or no physiological consequences. No anaphylaxis has been reported with exenatide
use. Thus, by building upon early observations of antihyperglycemic actions of GLP-1 and Gila monster exendin4, exenatide (synthetic exendin-4) has been successfully developed into a first-in-class diabetes therapeutic.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflicts of interest.
ACKNOWLEDGEMENTS
The authors thank Dr. Loretta L. Nielsen for medical
writing.
ABBREVIATIONS

Exenatide study of cardiovascular event lowering trial (EXSCEL): a trial
to evaluate cardiovascular outcomes after treatment with exenatide once
weekly in patients with type 2 diabetes mellitus. NCT01144338. Accessed
May 14, 2012 at http://clinicaltrials.gov/ct2/show/NCT01144338.

=

adverse event reporting system

ALT

=

alanine aminotransferase

ApoB

=

apolipoprotein B

ASPART

=

biphasic insulin aspart 70/30 mix

AST

=

aspartate aminotransferase

B

=

breakfast

BG

=

background

BID

=

twice daily

BL

=

baseline

BP

=

blood pressure

BIM

=

body mass index

Comb

=

combination

CV

=

cardiovascular

CVD

=

cardiovascular disease

D

=

dinner

D/E

In controlled phase 3 clinical trials ranging from 12 to 52
weeks in duration, 10-mcg ExBID reduced mean HbA1c by
-0.8% to -1.7%, accompanied by mean weight loss ranging
from -1.2 kg to -8.0 kg, plus improvements in a broad range
of cardiometabolic risk factors. Efficacy has been demonstrated as monotherapy and in various combinations with
metformin (MET), sulfonylureas (SFU), thiazolidinediones
(TZD), and insulins. During phase 3 clinical evaluation of a
once weekly exenatide (ExQW) formulation in patients with
T2DM in controlled trials ranging from 24 to 30 weeks, 2
mg ExQW reduced mean HbA1c by -1.3% to -1.9%, accompanied by mean body weight reductions ranging from -2.3 to
-3.7 kg; with 70% to 79% having reductions in both HbA1c
and weight. In the DURATION-1 study extension, ExQW
was associated with mean HbA1c reductions of -2.0% at Year
1 and -1.7% at Year 2, on a background of diet/exercise,
MET, SFU, TZD, or 2 oral antidiabetes drugs; the corresponding mean weight reductions were -4.1 kg and -2.6 kg.

AERS

=

diet and exercise

DO

=

study dropout rate

DPP-4

=

dipeptidyl peptidase-IV


Dur

=

DURATION =


duration of clinical trial
Diabetes therapy Utilization Researching changes in HbA1c, weight and other
factors Through Intervention with exenatide ONce weekly

EAIR

=

Exposure-adjusted incidence rate

Ex

=

exenatide

GLP-1

=

glucagon-like peptide-1

EASD

=

European Association for the Study of
Diabetes

189

ROSI

=

rosiglitazone

Rx

=

change or different diabetes medication
prior to randomization

S

=

superiority

SFU

=

sulfonylurea

Sita

=

sitagliptin

Subj

=

subject

T2DM

=

type 2 diabetes mellitus

T50

=

time to achieve 50% stomach emptying

F

=

female

TID

=

thrice daily

FDA

=

U.S. Food and Drug Administration

Tmax

=

GIP

=

glucose-dependent
insulinotrophic
polypeptide/ gastric inhibitory polypeptide

time to reach maximal blood concentration

TSH

=

thyroid stimulatory hormone

TZD

=

thiazolidinediones (TZD)

Geo

=

geometric

VLDL-C

=

very low density lipoprotein cholesterol

GLARG

=

insulin glargine

vs

=

versus

HDL-C

=

high density lipoprotein cholesterol

Wk

=

week

Gli

=

glibenclamide sulfonylurea

Wt

=

weight

HbA1c

=

glycated hemoglobin

Y

=

year

HOMA

=

homeostasis model assessment

Clinical Trial Registration Numbers: See Table 1

hsCRP

=

high sensitivity C-reactive protein

Hypo

=

hypoglycemic events

ILM

=

intensive lifestyle modification

KO

=

knockout

L

=

lunch

LDL-C

=

low density lipoprotein cholesterol

LIRA

=

liraglutide

LS

=

least squares

MACE

=

major adverse cardiac events

MET

=

metformin

MIN

=

minimum

NA

=

not applicable

NG

=

not given

NI

=

non-inferiority

OAD

=

oral antidiabetes drug

PBO

=

placebo

PIO

=

pioglitazone

Pop

=

population

PTH

=

parathyroid hormone

QD

=

once daily

QM

=

once monthly

QW

=

once weekly

oxLDL

=

oxidated low density lipoprotein

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Received: June 27, 2012

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Revised: December 12, 2012

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Accepted: December 14, 2012

Bhavsar et al Curr Diabetes Rev 2013

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