This document reviews the effects of exenatide, a glucagon-like peptide-1 receptor agonist, on weight loss. It summarizes findings from clinical trials that reported consistent weight loss associated with exenatide treatment compared to placebo. Exenatide is thought to cause weight loss by decreasing energy intake through effects on satiety and by possibly increasing energy expenditure, though evidence for each mechanism is inconsistent. Further research is needed to better understand the mechanisms through which exenatide induces weight loss.

1. Nutrition 26 (2010) 243–249
www.nutritionjrnl.com
Review article
Exenatide and weight loss
David P. Bradley, M.D., M.S.a, Roger Kulstad, M.D.b, and Dale A. Schoeller, Ph.D.c,*
a
Division of Endocrinology, University of Wisconsin, Madison, Wisconsin, USA
b
Department of Endocrinology , Marshfield Clinic–Weston Center, Weston, Wisconsin, USA
c
Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, USA
Manuscript received July 9, 2009; accepted July 14, 2009.
Abstract Objective: Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone mainly released from the
distal ileum, jejunum, and colon in response to food ingestion. It is categorized as an incretin due to its
activation of GLP-1 receptors in pancreatic b-cells leading to insulin exocytosis in a glucose-dependent
manner. Exenatide (synthetic exendin-4) is a subcutaneously injected GLP-1 receptor agonist that
shares 50% homology with GLP-1. It is derived from lizard venom and stimulates the GLP-1
receptor for prolonged periods. The present review aims to enumerate exenatide-instigated weight
loss, summarize the known mechanisms of exenatide-induced weight loss, and elaborate on its possible
application in the pharmacotherapy of obesity.
Methods: A search through PubMed was performed using exenatide and weight loss as search terms.
A second search was performed using exenatide and mechanisms or actions as search terms.
Results: In addition to exenatide’s action to increase insulin secretion in individuals with elevated
levels of plasma glucose, clinical trials have reported consistent weight loss associated with exenatide
treatment. Studies have found evidence that exenatide decreases energy intake and increases energy
expenditure, but findings on which predominates to cause weight loss are often inconsistent and
controversial.
Conclusion: Further research on the effects of exenatide treatment on energy intake and expenditure
are recommended to better understand the mechanisms through which exenatide causes weight loss.
Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Obesity; Drug treatment; Glucagon-like peptide-1; Appetite; Energy expenditure
Introduction More than 50% of this total was spent in the United States,
accounting for 10% of the nation’s health budget [4].
Diabetes mellitus affects more than 245 million adults in The ill-toward effects of diabetes mellitus are well docu-
the world [1]. In the United States alone, over 7% of the pop- mented. Diabetes is the fourth leading cause of disease-related
ulation, or 23.6 million people, are affected by diabetes, with death in the world and diabetes-related causes claim a life ev-
more than 90% with type 2 diabetes [2]. In addition, there are ery 10 s [1]. Two major trials concluding in the 1990s com-
currently more than 57 million Americans with impaired fast- pared the ramifications of conventional versus intensive
ing glucose, or ‘‘prediabetes.’’ By 2030, even conservative insulin therapy on the complications of diabetes mellitus.
estimates have diabetes affecting more than 30 million Amer- All the studies had substantial and sustained lowering of he-
icans [3]. This trend is shared globally. The cost of diabetes moglobin A1c in the study participants who underwent the in-
in 2007 was estimated to be approximately $232 billion in di- tensive regimen. In the Diabetes Complications and Control
rect and indirect medical expenses per year worldwide [1]. Trial, lowering blood glucose reduced the risk of eye disease
by 76%, kidney disease by 50%, and clinical neuropathy by
60% [5]. In the United Kingdom Prospective Diabetes Study,
each 1% reduction in mean hemoglobin A1c was associated
* Corresponding author. Tel.: þ608-262-1082; fax: þ608-262-5860. with an overall risk reduction of 35% for microvascular com-
E-mail address: dschoell@nutrisci.wisc.edu (D. A. Schoeller). plications (retinopathy, neuropathy, nephropathy), 25%
0899-9007/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2009.07.008

2. 244 D. P. Bradley et al. / Nutrition 26 (2010) 243–249
reduction in diabetes-related deaths, and 18% reduction in fa- glucose is significantly diminished, suggesting that there
tal and non-fatal myocardial infarction (although not reaching are gut-derived factors playing an important role in postpran-
statistical significance). There was a 7% reduction in all-cause dial glucose control. These gut or incretin hormones were
mortality [6]. subsequently found to be glucagon-like peptide-1 (GLP-1),
Obesity, often coexistent with diabetes, increases health-re- secreted from L-cells of the jejunum, ileum, and colon, and
lated problems exponentially. The World Health Organiza- glucose-dependent insulinotropic polypeptide, secreted
tion’s (WHO) latest projections indicated that globally in from K-cells in the duodenum. In diabetic patients, GLP-1
2005 approximately 1.6 billion adults (!15 y old) were over- concentrations are reduced in response to a meal compared
weight and at least 400 million were obese. The WHO further with non-diabetics. In contrast, glucose-dependent insulino-
projects that by 2015 approximately 2.3 billion adults will be tropic polypeptide concentrations are normal or increased,
overweight and more than 700 million will be obese. At least making GLP-1 the more favorable therapeutic target [12].
20 million children younger than 5 y were overweight in The contribution of incretin hormones to the postprandial
2005. Health consequences directly engendered by obesity insulin response was estimated to be 73% in control subjects
can be categorized by the effects of increased fat mass (osteo- compared with 36% in type 2 diabetics, suggesting a signifi-
arthritis, obstructive sleep apnea, social stigmatization, etc.) or cant reduction of the incretin effect [13].
by an increased number of fat cells (insulin resistance leading to Numerous beneficial effects have since been ascribed to
type 2 diabetes, cancer, cardiovascular disease, non-alcoholic GLP-1 (Fig. 1). The hormone has been found to act as an
fatty liver disease, etc.). Obesity is also related to a variety of incretin, thus enhancing the ability of the pancreas to release
other complications through mechanisms sharing a common insulin in response to ingested glucose. This insulinotropic
cause such as poor diet or a sedentary lifestyle. These include action of GLP-1 is glucose-dependent (as glucose approaches
gastrointestinal reflux disease, gout, headache, cellulitis, cere- normal, the effect diminishes), and for GLP-1 to enhance
brovascular incidents, chronic renal failure, hypogonadism, insulin secretion, glucose concentrations must be higher
and erectile dysfunction, among others. than 90 mg/dL, thus theoretically eliminating the risk of
The association between type 2 diabetes mellitus and hypoglycemia [14–17]. GLP-1 has also been shown to elim-
obesity is well acknowledged. In a cross sectional survey inate the inappropriate postprandial glucagon secretion that
utilizing the Behavioral Risk Factor Surveillance System in often leads to glucose excursions after meals. However,
2001, compared with adults with normal weight, adults GLP-1 does not inhibit glucagon secretion when plasma
with a BMI of 40 or higher had an odds ratio (OR) of 7.37 levels are low or normal. GLP-1 also stimulates b-cell prolif-
(95% confidence interval [CI], 6.39–8.50) for diagnosed di- eration and increases b-cell mass. GLP-1 slows gastric emp-
abetes [7]. This is because diabetes and obesity are coupled tying, allowing the rate of glucose release to better match the
by the phenomenon of insulin resistance occurring in periph- rate of glucose utilization in the systemic circulation. The
eral tissues and the central satiety centers of the hypothala- normal physiologic response to hypoglycemia is an acceler-
mus [8]. The mechanism by which obesity fosters a state of ation of gastric emptying, which increases nutrient delivery
insulin resistance continues to be a rapidly evolving area of and restores normal glucose concentrations. In contrast,
interest and the subject of intense research. A full discussion during hyperglycemia, the rate of gastric emptying slows,
is beyond the scope of this review article. Numerous hypoth- improving the match between glucose appearance by means
eses have been postulated including increased adiposity lead- of nutrient absorption from the small intestine and glucose
ing to decreased number of insulin receptors or a failure to disappearance from the circulation. Despite hyperglycemia,
activate tyrosine kinase and phosphatidyl-inositol 3 in the gastric half-emptying time is significantly shorter in
response to insulin receptor binding. Other theories involve patients with type 2 diabetes than in control subjects without
the release of increased amounts of non-esterified fatty diabetes. The mismatch between glucose-appearance and
acids and proinflammatory cytokines (tumor necrosis glucose-disappearance rates contributes to high postprandial
factor-a) or increased inflammation related to macrophage glucose concentrations [18]. GLP-1 slows gastric emptying
accumulation [9]. to reduce the initial postprandial increase in plasma glucose.
Given the high prevalence of diabetes and obesity, their In addition, GLP-1 administration has been found to increase
causal relation, and the multiple risks associated with either satiety when administered peripherally and centrally, an
alone or in combination, a dual pharmacologic agent attack- effect that will be described in detail later.
ing both would obviously be of great consequence. In line with these numerous roles, GLP-1 receptor knockout
mice have fasting hyperglycemia and abnormal glucose toler-
The incretin effect and glucagon-like peptide-1 ance and mice lacking dipeptidyl peptidase IV (DPP-IV) show
decreased food intake, improved insulin sensitivity, and de-
The incretin effect was first demonstrated in the 1960s creased loss of b-cell mass [19].
[10]. The basic principle is that oral administration of glucose Native GLP-1, however, has a short half-life (1–2 min)
has a greater stimulatory effect on insulin secretion than intra- due to rapid N-terminal degradation by DPP-IV. Exenatide
venously administered glucose [11]. In patients with type 2 is a 39-amino acid peptide with 53% homology to GLP-1
diabetes mellitus this stimulation to orally administered that is a naturally occurring component of the Gila monster

3. D. P. Bradley et al. / Nutrition 26 (2010) 243–249 245
Fig. 1. Effects of GLP-1 on multiple organ systems. GLP-1 is secreted by ileal L-cells in response to a meal and has direct actions in the brain, stomach, and a- and
b-cells of the pancreas. In the brain GLP-1 acts to increase satiety. In the stomach it acts to decrease gastric emptying. Effects on a-cells of the pancreas include
decreased glucagon secretion, whereas in b-cells it leads to increased insulin secretion and decreased apoptosis. GLP-1, glucagon-like peptide-1.
(Heloderma suspectum) saliva. It is resistant to DPP-IV pronounced for patients with a higher body mass index.
degradation and thus has a longer half-life with pharmaco- The third study by Kendall et al. [22], combining exenatide
logic action lasting 6 h. It reaches peak plasma concentration with a sulfonylurea and metformin, involved 733 patients en-
at approximately 2 h. In vitro, exenatide has been shown to rolled at 91 sites, with changes of À1.6 6 0.5 kg in the 10-mg
bind to and activate the GLP-1 receptor of rat islet cells. It arm (P < 0.05), À1.6 6 0.4 kg in the 5-mg arm (P < 0.001),
is primarily excreted by glomerular filtration. Exenatide and À0.9 6 0.3 kg in the placebo arm. Similar results, detail-
decreases weight, whereas DPP-IV inhibitors are weight ing progressive weight loss over time, have been seen by
neutral. numerous other investigators (Table 1) [23–29].
The predominant side effect in these studies was nausea,
Studies of exenatide and weight loss which occurred in a dose-related pattern. This has led to spec-
ulation that nausea is a potential theoretical cause of the
Three similar phase 3 trials of exenatide were performed observed weight loss. None of these initial studies, however,
in patients with type 2 diabetes mellitus. All had identical showed a statistical correlation between the two. Further
basic designs but differed in the background oral anti-glyce- studies have had conflicting results [27].
mic agent (metformin, sulfonylurea, or metformin plus sulfo- In contrast to other weight loss therapies, exenatide-in-
nylurea). All three studies were blinded placebo-controlled duced weight loss is not only progressive but persists for at
studies conducted over a 30-d period. In the first by Buse least 2 y [30].
et al. [20], with exenatide combined with a sulfonylurea,
377 patients were enrolled at 106 sites with changes in Balance of weight
body weight from baseline over time of À1.6 6 0.3 kg in
the 10-mg arm (significantly different from placebo), Bioenergetics is the study of the flow and transformation
À0.9 6 0.3 kg in the 5-mg arm (not significantly different of energy in and between living organisms and between liv-
from the placebo arm), and À0.6 6 0.3 kg in the placebo ing organisms and their environment [31]. According to the
arm. In the second, by Defronzo et al. [21], combining exena- first law of thermodynamics, energy can neither be created
tide with metformin, 336 patients were enrolled at 82 sites nor destroyed, only transformed from one form to another.
with changes of À2.8 6 0.5 kg in 10-mg arm (P < 0.05), Thus, in accordance with this basic principle, the bioenerget-
À1.6 6 0.4 kg in the 5-mg arm (P < 0.001), and ics of the human body can be measured as a balance between
À0.3 6 0.3 kg in the placebo arm. Weight loss was more two competing facets: energy intake and energy expenditure.

4. 246 D. P. Bradley et al. / Nutrition 26 (2010) 243–249
Table 1
Randomized control trials of exenatide with concomitant therapy, frequency of nausea, and amount of weight loss
Study Duration of study Concomitant therapy Frequency of nausea (%) Weight loss (kg)
Placebo 5-mg dose 10-mg dose 5-mg dose 10-mg dose
Buse et al. [20] 30 wk Sulfonylurea 7 39 51 0.9 1.6
Defronzo et al. [21] 30 wk Metformin 23 36 45 1.6 2.8
Kendall et al. [22] 30 wk Metformin þ sulfonylurea 21 39 49 1.6 1.6
Heine et al. [23] 26 wk Metformin þ sulfonylurea 8.6 57 N/A 2.3 N/A
Davis et al. [26]* 16 wk None 12.5 N/A 48.5 N/A 4.2
Barnett et al. [27]* 16 wk Metformin or sulfonylurea 3.1 N/A 42.6 N/A 0.8
Zinman et al. [28] 16 wk Thiazolidinedione 15.2 N/A 40 N/A 1.51
Nauck et al. [29]* 52 wk Metformin þ sulfonylurea 0.4 N/A 33 N/A 2.5
N/A, not available
* Studies administered exenatide 5 mg two times daily for 4 wk and then 10 mg two times daily until completion.
Energy intake is composed of the caloric contents of ingested after intravenous infusion of exendin-4. Other studies have
food, whereas energy expenditure is composed of three echoed this effect on decreased oral intake. A meta-analysis
subsets: the resting metabolic rate (RMR), defined as the en- of seven studies on ad libitum energy intake after intravenous
ergy required for maintenance of normal bodily functions GLP-1 infusion showed that energy intake decreased by 727
such as respiration, circulation, and body temperature; the kJ, or 11.7% [33]. This finding in human subjects, however,
thermic effect of a meal, defined as the energy expended was challenged by the observation that GLP-1 receptor–
above RMR due to absorption, metabolism, and storage of deficient mice have normal intake and body weight [34].
dietary nutrients; and the physical activity energy expendi- The anorectic effects of GLP-1 are not well understood.
ture, defined as the energy expended from physical activity, The regulation of feeding and energy balance involves
which includes exercise and activities of daily living. The hormonal and neural inputs and is quite complex. The phys-
components and their relative contributions to total energy iologic role of GLP-1 and the mechanism responsible for
expenditure can be seen in Figure 2. weight loss with adjunctive exendin-4 are an area of consid-
erable research.
Bioenergetics and exenatide Possible mechanisms to explain the observed decrease in
oral intake include exenatide-induced nausea, decreased
Sustained progressive weight loss is an objective in gastric emptying, and increased satiety. Although nausea is
obesity and insulin resistance-related diabetes mellitus. common with exenatide use and may singularly lead to
Therefore, mechanisms to aid in this process are constantly decreased intake, studies have failed to demonstrate a correla-
under investigation. Most studies to date have examined tion between the presence of, or the degree of, nausea and
the role of GLP-1 and exenatide in the reduction of oral in- lowering of body weight.
take. Edwards et al. [32] found that healthy volunteers con- In addition, decreased oral intake with exenatide may
sumed 19% fewer calories at a free-choice buffet lunch involve the ‘‘ileal brake’’ and its relation to retarded gastric
emptying. The ileal brake is the primary inhibitory feedback
mechanism, neural and hormonal, to control transit of a meal
through the gastrointestinal tract to optimize nutrient diges-
tion and absorption. Ingested food activates distal intestinal
signals that inhibit gastrointestinal motility and thus prolong
emptying. This effect is thought to be mediated by vagal
efferent nerves, activated by gastric distention and gastroin-
testinal hormones, that are transmitted to the solitary nucleus
of the brainstem [35]. In fact, GLP-1–induced anorexia is
abolished by vagal transection [36]. The rate of gastric emp-
tying is a key determinant of glucose levels after a meal and is
often abnormal and frequently accelerated in individuals with
diabetes [37–39]. This acceleration disrupts the ileal brake.
GLP-1 slows gastric emptying to reduce the initial postpran-
dial increase in plasma glucose.
Fig. 2. Components of total energy expenditure by approximate percentage. Another possible mechanism involves increased satiety.
PAEE, physical activity energy expenditure; RMR, resting metabolic rate; The GLP-1 receptor is mainly distributed in the pancreatic
TEM, thermic effect of a meal. islets and gastric glands [40], but has also been found in

5. D. P. Bradley et al. / Nutrition 26 (2010) 243–249 247
various regions of the central nervous system [41] with ways. Most data are accumulated from indirect resting calo-
a wide distribution throughout the rostrocaudal extent of rimetry. Indirect calorimeter studies estimate heat production
the hypothalamus and, in particular, dense accumulations from measurements of oxygen consumption and carbon
in the paraventricular and arcuate nucleus [42]. This area dioxide production while a subject is enclosed in a ventilated
has been found to be crucial to the regulation of appetite. Di- hood. It allows measurements of the RMR and the thermic
rect administration of GLP-1 into the central nervous system effect of a meal but does not provide a free-living environ-
or transmission to the hypothalamus after peripheral admin- ment for which to measure physical activity (physical activity
istration by the vagus nerve appears to result in decreased ca- energy expenditure) and thus does not allow for a calculation
loric intake. The appearance of c-fos expression, a marker of of total energy expenditure. This technique has been utilized
GLP-1 activating the neuron, after intracerebroventricular by several investigators. Shalev et al. [46] found that GLP-1
injection of GLP-1 provides evidence that GLP-1–induced infusion increased RMR. Flint et al. [47,48] reported that
anorexia may be at least partly mediated by the central hypo- GLP-1 infusion also increased RMR and resulted in a de-
thalamus. Schick et al. [43] first reported reduction of food creased thermic effect of a meal in non-obese and obese
intake after intracerebroventricular injection of GLP-1 to patients. Pannacciulli et al. [49] similarly found that GLP-1
rats in 1992. The first evidence of the effect of GLP-1 on increased short-term RMR after adjusting for age, sex, and
feeding behavior in humans was reported in 1998 by Flint body composition.
et al. [44], who found increased feelings of satiety and full- The global burden of obesity and diabetes has accelerated
ness and reduced feeling of hunger after intravenous admin- research into the development of a large number of pharma-
istration of GLP-1. Studies of exenatide relating to satiety cologic agents that target excess weight or insulin action.
have similarly demonstrated an increased sense of fullness Among those agents that have reached market, exenatide is
and reduced sensation of hunger. interesting because it acts to stimulate insulin production as
A summary of the effects of GLP-1 on appetite, feeding intended, but also has been found to cause weight loss. It is
behavior, and body weight in humans is presented in Table 2. not clear, however, how much of the weight loss is due
Glucagon-like peptide-1 and exenatide have also been to an incretin effect on energy intake or expenditure. The lat-
shown to result in decreased levels of ghrelin, a potent orexi- ter has been difficult to access until the development of
genic hormone [45]. The extent to which ghrelin and its inter- methods for measuring energy expenditure in free-living
action with other satiety factors contributes to weight loss is subjects. To date, there are to our knowledge no published
unknown. studies that provide information regarding total energy ex-
In terms of energy expenditure, there are limited studies to penditure after exenatide administration, although several
this point. Energy expenditure can be assessed in a variety of are ongoing and will likely provide further clarification
Table 2
Current studies of effects of glucagon-like peptide-1 on appetite, feeding behavior, and body weight in humans
References Dose (pmol $ kgÀ1 $ minÀ1) Duration Route Subjects Effects P
Flint et al. [44] 0.7 4h IV 20 healthy Reduction of energy 0.0002
intake 21%
Decreased sensation 0.012
of hunger
Enhanced fullness 0.028
Enhanced satiety 0.013
Gutzwiller et al., 1999 [50] 0–1.5 2h IV 16 healthy Reduction of food <0.001
intake 35%
Reduction of caloric <0.001
intake 32%
Reduction of fluid <0.01
intake 18%
Toft-Nielsen et al., 1999 [51] 2.4 48 h SC 6 diabetics Decreased feeling <0.05
of hunger
Decreased future <0.05
food intake
Fullness not affected —
Hellerstrom et al., 1999 [52] 0.75 8h IV Obese Reduced caloric intake —
Reduced sensation —
of hunger
Zander et al., 2001 [53] 2.4 6 wk SC 10 diabetics Reduction of body 0.02
weight 1.9%
Reduction of appetite 21% 0.01
IV, intravenous; SC, subcutaneous

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