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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 thedistal ileum, jejunum, and colon in response to food ingestion. It is categorized as an incretin due to itsactivationofGLP-1receptorsinpancreatic
b
-cellsleadingtoinsulinexocytosisinaglucose-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-1receptor for prolonged periods. The present review aims to enumerate exenatide-instigated weight loss,summarizetheknownmechanismsofexenatide-inducedweightloss,andelaborateonitspossibleapplication 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 elevatedlevels of plasma glucose, clinical trials have reported consistent weight loss associated with exenatidetreatment. Studies have found evidence that exenatide decreases energy intake and increases energyexpenditure, but findings on which predominates to cause weight loss are often inconsistent andcontroversial.
Conclusion:
Further research on the effects of exenatide treatment on energy intake and expenditureare 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
Diabetes mellitus affects more than 245 million adults inthe world[1]. In the United States alone, over 7% of the pop-ulation, or 23.6 million people, are affected by diabetes, withmore than 90% with type 2 diabetes[2]. In addition, there arecurrentlymorethan57million Americanswithimpairedfast-ing glucose, or ‘‘prediabetes.’’ By 2030, even conservativeestimateshavediabetesaffectingmorethan30millionAmer-icans[3]. This trend is shared globally. The cost of diabetesin2007 was estimatedto be approximately $232 billion in di-rect and indirect medical expenses per year worldwide[1].More than 50% of this total was spent in the United States,accounting for 10% of the nation’s health budget [4].The ill-toward effects of diabetes mellitus are well docu-mented.Diabetesisthefourthleadingcauseofdisease-relateddeath in the world and diabetes-related causes claim a life ev-ery 10 s[1]. Two major trials concluding in the 1990s com-pared the ramifications of conventional versus intensiveinsulin therapy on the complications of diabetes mellitus.All the studies had substantial and sustained lowering of he-moglobin A
1c
inthe study participantswho underwent the in-tensive regimen. In the Diabetes Complications and ControlTrial, lowering blood glucose reduced the risk of eye diseaseby 76%, kidney disease by 50%, and clinical neuropathy by60%[5]. In the United Kingdom Prospective Diabetes Study,each 1% reduction in mean hemoglobin A
1c
was associatedwith an overall risk reduction of 35% for microvascular com-plications (retinopathy, neuropathy, nephropathy), 25%
* Corresponding author. Tel.:
þ
608-262-1082; fax:
þ
608-262-5860.
 E-mail address:
dschoell@nutrisci.wisc.edu(D. A. Schoeller).0899-9007/10/$ – see front matter 
Ó
2010 Elsevier Inc. All rights reserved.doi:10.1016/j.nut.2009.07.008Nutrition 26 (2010) 243–249www.nutritionjrnl.com
 
reduction indiabetes-related deaths,and 18%reductioninfa-talandnon-fatalmyocardialinfarction(althoughnotreachingstatisticalsignificance).Therewasa7%reductioninall-causemortality[6].Obesity,oftencoexistentwithdiabetes,increaseshealth-re-lated problems exponentially. The World Health Organiza-tion’s (WHO) latest projections indicated that globally in2005 approximately 1.6 billion adults (
!
15 y old) were over-weight and at least 400 million were obese. The WHO further projects that by 2015 approximately 2.3 billion adults will beoverweight and more than 700 million will be obese. At least 20 million children younger than 5 y were overweight in2005. Health consequences directly engendered by obesitycan be categorized by the effects of increased fat mass (osteo-arthritis, obstructive sleep apnea, social stigmatization, etc.) or byanincreasednumberoffatcells(insulinresistanceleadingtotype 2 diabetes, cancer, cardiovascular disease, non-alcoholicfatty liver disease, etc.). Obesity is also related to a variety of other complications through mechanisms sharing a commoncause such as poor diet or a sedentary lifestyle. These includegastrointestinal reflux disease, gout, headache, cellulitis, cere-brovascular incidents, chronic renal failure, hypogonadism,and erectile dysfunction, among others.The association between type 2 diabetes mellitus andobesity is well acknowledged. In a cross sectional surveyutilizing the Behavioral Risk Factor Surveillance System in2001, compared with adults with normal weight, adultswith a BMI of 40 or higher had an odds ratio (OR) of 7.37(95% confidence interval [CI], 6.39–8.50) for diagnosed di-abetes[7]. This is because diabetes and obesity are coupledby the phenomenon of insulin resistance occurring in periph-eral tissues and the central satiety centers of the hypothala-mus[8]. The mechanism by which obesity fosters a state of insulin resistance continues to be a rapidly evolving area of interest and the subject of intense research. A full discussionis beyond the scope of this review article. Numerous hypoth-eses have been postulated including increased adiposity lead-ing to decreased number of insulin receptors or a failure toactivate tyrosine kinase and phosphatidyl-inositol 3 inresponse to insulin receptor binding. Other theories involvethe release of increased amounts of non-esterified fattyacids and proinflammatory cytokines (tumor necrosisfactor-
a
) or increased inflammation related to macrophageaccumulation[9].Given the high prevalence of diabetes and obesity, their causal relation, and the multiple risks associated with either alone or in combination, a dual pharmacologic agent attack-ing both would obviously be of great consequence.
The incretin effect and glucagon-like peptide-1
The incretin effect was first demonstrated in the 1960s[10]. Thebasic principleisthatoral administration ofglucosehasagreaterstimulatoryeffectoninsulinsecretionthanintra-venously administered glucose[11]. In patients with type 2diabetes mellitus this stimulation to orally administeredglucose is significantly diminished, suggesting that thereare gut-derived factors playing an important role in postpran-dial glucose control. These gut or incretin hormones weresubsequently found to be glucagon-like peptide-1 (GLP-1),secreted from L-cells of the jejunum, ileum, and colon, andglucose-dependent insulinotropic polypeptide, secretedfrom K-cells in the duodenum. In diabetic patients, GLP-1concentrations are reduced in response to a meal comparedwith non-diabetics. In contrast, glucose-dependent insulino-tropic polypeptide concentrations are normal or increased,making GLP-1 the more favorable therapeutic target [12].The contribution of incretin hormones to the postprandialinsulin response was estimated to be 73% in control subjectscompared with 36% in type 2 diabetics, suggesting a signifi-cant reduction of the incretin effect [13].Numerous beneficial effects have since been ascribed toGLP-1 (Fig. 1). The hormone has been found to act as anincretin, thus enhancing the ability of the pancreas to releaseinsulin in response to ingested glucose. This insulinotropicactionofGLP-1isglucose-dependent(asglucoseapproachesnormal, the effect diminishes), and for GLP-1 to enhanceinsulin secretion, glucose concentrations must be higher than 90 mg/dL, thus theoretically eliminating the risk of hypoglycemia [14–17]. GLP-1 has also been shown to elim-inate the inappropriate postprandial glucagon secretion that often leads to glucose excursions after meals. However,GLP-1 does not inhibit glucagon secretion when plasma levels are low or normal. GLP-1 also stimulates
b
-cell prolif-eration and increases
b
-cell mass. GLP-1 slows gastric emp-tying, allowing the rate of glucose release to better match therate of glucose utilization in the systemic circulation. Thenormal physiologic response to hypoglycemia is an acceler-ation of gastric emptying, which increases nutrient deliveryand restores normal glucose concentrations. In contrast,during hyperglycemia, the rate of gastric emptying slows,improving the match between glucose appearance by meansof nutrient absorption from the small intestine and glucosedisappearance from the circulation. Despite hyperglycemia,the gastric half-emptying time is significantly shorter inpatients with type 2 diabetes than in control subjects without diabetes. The mismatch between glucose-appearance andglucose-disappearance rates contributes to high postprandialglucose concentrations[18]. GLP-1 slows gastric emptyingto reduce the initial postprandial increase in plasma glucose.In addition, GLP-1 administration has been found to increasesatiety when administered peripherally and centrally, aneffect that will be described in detail later.Inlinewiththesenumerousroles,GLP-1receptorknockout mice have fasting hyperglycemia and abnormal glucose toler-anceand micelackingdipeptidylpeptidaseIV(DPP-IV)showdecreased food intake, improved insulin sensitivity, and de-creased loss of 
b
-cell mass[19].Native GLP-1, however, has a short half-life (1–2 min)due to rapid N-terminal degradation by DPP-IV. Exenatideis a 39-amino acid peptide with 53% homology to GLP-1that is a naturally occurring component of the Gila monster 
 D. P. Bradley et al. / Nutrition 26 (2010) 243–249
244
 
(
 Heloderma suspectum
) saliva. It is resistant to DPP-IVdegradation and thus has a longer half-life with pharmaco-logic action lasting 6 h. It reaches peak plasma concentrationat approximately 2 h. In vitro, exenatide has been shown tobind to and activate the GLP-1 receptor of rat islet cells. It is primarily excreted by glomerular filtration. Exenatidedecreases weight, whereas DPP-IV inhibitors are weight neutral.
Studies of exenatide and weight loss
Three similar phase 3 trials of exenatide were performedin patients with type 2 diabetes mellitus. All had identicalbasic designs but differed in the background oral anti-glyce-mic agent (metformin, sulfonylurea, or metformin plus sulfo-nylurea). All three studies were blinded placebo-controlledstudies conducted over a 30-d period. In the first by Buseet al.[20], with exenatide combined with a sulfonylurea,377 patients were enrolled at 106 sites with changes inbody weight from baseline over time of 
À
1.6
6
0.3 kg inthe 10-
m
g arm (significantly different from placebo),
À
0.9
6
0.3 kg in the 5-
m
g arm (not significantly different from the placebo arm), and
À
0.6
6
0.3 kg in the placeboarm.In thesecond, byDefronzoetal.[21], combiningexena-tide with metformin, 336 patients were enrolled at 82 siteswith changes of 
À
2.8
6
0.5 kg in 10-
m
g arm (
 P
<
0.05),
À
1.6
6
0.4 kg in the 5-
m
g arm (
 P
<
0.001), and
À
0.3
6
0.3 kg in the placebo arm. Weight loss was morepronounced for patients with a higher body mass index.The third study by Kendall et al.[22], combining exenatidewith a sulfonylurea and metformin, involved 733 patients en-rolled at 91 sites, with changes of 
À
1.6
6
0.5 kg in the 10-
m
garm (
 P
<
0.05),
À
1.6
6
0.4 kg in the 5-
m
g arm (
 P
<
0.001),and
À
0.9
6
0.3 kg in the placebo arm. Similar results, detail-ing progressive weight loss over time, have been seen bynumerous other investigators (Table 1)[23–29]. The predominant side effect in these studies was nausea,whichoccurredinadose-relatedpattern.Thishasledtospec-ulation that nausea is a potential theoretical cause of theobserved weight loss. None of these initial studies, however,showed a statistical correlation between the two. Further studies have had conflicting results[27].In contrast to other weight loss therapies, exenatide-in-duced weight loss is not only progressive but persists for at least 2 y[30].
Balance of weight
Bioener getics is the study of the flow and transformationof energy in and between living organisms and between liv-ing organisms and their environment [31]. According to thefirst law of thermodynamics, energy can neither be creatednor destroyed, only transformed from one form to another.Thus, in accordance with this basic principle, the bioenerget-ics of the human body can be measured as a balance betweentwo competing facets: energy intake and energy expenditure.
Fig.1. EffectsofGLP-1onmultipleorgansystems.GLP-1issecretedbyilealL-cellsinresponsetoamealandhasdirectactionsinthebrain,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 includedecreased glucagon secretion, whereas in
b
-cells it leads to increased insulin secretion and decreased apoptosis. GLP-1, glucagon-like peptide-1.
 D. P. Bradley et al. / Nutrition 26 (2010) 243–249
245
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