Clinical and Experimental Gastroenterology
`
`Open Access Full Text Article
`
`Dovepress
`open access to scientific and medical research
`
`R E v i E w
`
`Emerging treatment options for short bowel
`syndrome: potential role of teduglutide
`
`Cheng T Tee1,2
`Katharina wallis1,3
`Simon M Gabe1,4
`1Lennard-Jones intestinal Failure Unit,
`St Mark’s Hospital and Academic
`institute, Harrow, UK; 2Antigen
`Presentation Research Group,
`imperial College London, Northwick
`Park and St Mark’s Campus, Harrow,
`UK; 3west Hertfordshire Hospitals
`NHS Trust, watford, UK; 4Division
`of Surgery, Oncology, Reproductive
`Biology and Anaesthetics, imperial
`College Healthcare, London, UK
`
`Correspondence: Cheng T Tee
`Antigen Presentation Research Group,
`Level 7, St Mark’s Hospital and Academic
`institute, watford Road,
`Harrow HA1 3UJ, UK
`Tel +44 0208 869 3651
`Fax +44 0208 869 3532
`Email c.tee@imperial.ac.uk
`
`Introduction: Current medical management of short bowel syndrome (SBS) involves the
`use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important
`intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through
`augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN
`dependence in patients with SBS.
`Areas covered in review: Advancing research of GLP-2 physiology has spurred the growing
`understanding of the diverse effects of GLP-2. The development of the degradation resistant
`GLP-2 analog, teduglutide (GattexTM, NPS Pharmaceuticals, Bedminster, NJ), has allowed its
`exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-
`controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN require-
`ments with good safety profiles. The reparative and immunomodulatory effects of teduglutide
`may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about
`possible carcinogenic properties during long-term use require ongoing evaluation.
`Summary: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for
`its use in other clinical settings like IBD has been shown in small pilot studies.
`Keywords: glucagon-like peptide-2, intestinal failure, intestinal adaptation, parenteral
`nutrition
`
`Introduction
`Short bowel syndrome (SBS) is defined by a combination of symptoms and signs that
`occur after extensive surgical resection of the intestine. This highly disabling condition
`is characterized by malabsorption of both fluid and nutrients and, left untreated, can
`lead to dehydration, malnutrition, and weight loss. The term intestinal failure (IF)
`applies when an adequate balance of nutrients and water cannot be maintained without
`dietary support. IF often remains a short-term problem in the postoperative period.
`However, a small number of patients will require long-term parenteral nutrition (PN)
`or, in selected cases, intestinal transplantation. Such patients will typically have less
`than 100 cm of small bowel leading to an end-stoma or less than 50 cm connected to
`a functioning colon. Although PN has revolutionized IF treatment, it has a significant
`impact on quality of life and carries considerable risks, mainly hepatic failure, central
`vein thrombosis, and recurrent sepsis, all of which will reduce life expectancy. Survival
`following intestinal transplantation is still inferior to that of long-term PN due to the
`high incidence of graft rejection and other postoperative complications.1
`Soon after surgical resection with resulting loss of surface area, the intestine
`physiologically attempts to increase absorption to maintain homeostasis. This process
`
`submit your manuscript | www.dovepress.com
`Dovepress
`http://dx.doi.org/10.2147/CEG.S13906
`
`Clinical and Experimental Gastroenterology 2011:4 189–196
`© 2011 Tee et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
`
`189
`
`Page 1
`
`

`
`Clinical and Experimental Gastroenterology
`
`Open Access Full Text Article
`
`Dovepress
`open access to scientific and medical research
`
`R E v i E w
`
`Emerging treatment options for short bowel
`syndrome: potential role of teduglutide
`
`Cheng T Tee1,2
`Katharina wallis1,3
`Simon M Gabe1,4
`1Lennard-Jones intestinal Failure Unit,
`St Mark’s Hospital and Academic
`institute, Harrow, UK; 2Antigen
`Presentation Research Group,
`imperial College London, Northwick
`Park and St Mark’s Campus, Harrow,
`UK; 3west Hertfordshire Hospitals
`NHS Trust, watford, UK; 4Division
`of Surgery, Oncology, Reproductive
`Biology and Anaesthetics, imperial
`College Healthcare, London, UK
`
`Correspondence: Cheng T Tee
`Antigen Presentation Research Group,
`Level 7, St Mark’s Hospital and Academic
`institute, watford Road,
`Harrow HA1 3UJ, UK
`Tel +44 0208 869 3651
`Fax +44 0208 869 3532
`Email c.tee@imperial.ac.uk
`
`Introduction: Current medical management of short bowel syndrome (SBS) involves the
`use of lifelong parenteral nutrition (PN). Glucagon-like peptide-2 (GLP-2), an important
`intestinotrophic growth factor has been shown to increase intestinal absorption in SBS through
`augmentation of post-resection intestinal adaptation. This may lead to the reduction of PN
`dependence in patients with SBS.
`Areas covered in review: Advancing research of GLP-2 physiology has spurred the growing
`understanding of the diverse effects of GLP-2. The development of the degradation resistant
`GLP-2 analog, teduglutide (GattexTM, NPS Pharmaceuticals, Bedminster, NJ), has allowed its
`exploration as a therapeutic agent in a variety of clinical settings. Recent multicenter, placebo-
`controlled studies of GLP-2 in SBS patients demonstrate meaningful reductions in PN require-
`ments with good safety profiles. The reparative and immunomodulatory effects of teduglutide
`may also be beneficial in patients with inflammatory bowel disease (IBD). Safety concerns about
`possible carcinogenic properties during long-term use require ongoing evaluation.
`Summary: GLP-2 appears to offer a novel adjuvant treatment modality for SBS. Promise for
`its use in other clinical settings like IBD has been shown in small pilot studies.
`Keywords: glucagon-like peptide-2, intestinal failure, intestinal adaptation, parenteral
`nutrition
`
`Introduction
`Short bowel syndrome (SBS) is defined by a combination of symptoms and signs that
`occur after extensive surgical resection of the intestine. This highly disabling condition
`is characterized by malabsorption of both fluid and nutrients and, left untreated, can
`lead to dehydration, malnutrition, and weight loss. The term intestinal failure (IF)
`applies when an adequate balance of nutrients and water cannot be maintained without
`dietary support. IF often remains a short-term problem in the postoperative period.
`However, a small number of patients will require long-term parenteral nutrition (PN)
`or, in selected cases, intestinal transplantation. Such patients will typically have less
`than 100 cm of small bowel leading to an end-stoma or less than 50 cm connected to
`a functioning colon. Although PN has revolutionized IF treatment, it has a significant
`impact on quality of life and carries considerable risks, mainly hepatic failure, central
`vein thrombosis, and recurrent sepsis, all of which will reduce life expectancy. Survival
`following intestinal transplantation is still inferior to that of long-term PN due to the
`high incidence of graft rejection and other postoperative complications.1
`Soon after surgical resection with resulting loss of surface area, the intestine
`physiologically attempts to increase absorption to maintain homeostasis. This process
`
`submit your manuscript | www.dovepress.com
`Dovepress
`http://dx.doi.org/10.2147/CEG.S13906
`
`Clinical and Experimental Gastroenterology 2011:4 189–196
`© 2011 Tee et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
`which permits unrestricted noncommercial use, provided the original work is properly cited.
`
`189
`
`Page 1
`
`

`
`Tee et al
`
`Dovepress
`
`of intestinal adaptation occurs through structural (villous cell
`hyperplasia, increased crypt depth, and intestinal dilatation)
`and functional (increased mucosal enzyme activity and
`reduction of intestinal transit) mechanisms leading to a
`gradual increase in absorptive capacity. This period of
`adaptation is thought to last up to 24 months. Nutritional
`(eg, glutamine) and non-nutritional (eg, growth factors)
`substances have been implicated in promoting this adaptive
`response. In the last decade, most IF research has been
`focused on exploring the potential of these substances as
`supportive IF treatment. However, clinical trials so far have
`not demonstrated reproducible or meaningful clinical benefits
`with the use of glutamine or growth hormone.2–5
`Current supportive medical management includes the
`use of agents that reduce secretion (H2 receptor blockers,
`proton pump inhibitors, and octreotide) and motility (codeine,
`opium, lomotil, and loperamide).6 The goal is to reduce the
`total stool output to ,2 L per day. Dietary advice to maximize
`intestinal absorption is highly beneficial but needs to be
`tailored to the anatomy of the residual bowel.
`
`The naturally occurring gut hormone, glucagon-like
`peptide-2 (GLP-2), is a pleiotropic intestinotrophic hormone
`that enhances digestive and absorptive capacity.7 Recent
`advances in our understanding of the basic science of GLP-2
`have led to its exploration as a potential ‘first in class’
`therapeutic drug for SBS.
`
`Glucagon-like peptide-2
`and teduglutide
`Glucagon-like peptide-2 is a 33-amino acid peptide with
`an estimated molecular mass of 3765.8.8 GLP-2 is derived
`from the post-translational processing of pro-glucagon, a
`large prohormone that is mainly expressed in the pancreas,
`intestine, and brain (Figure 1). In the intestine, biologi-
`cally active GLP-21–33 is secreted from enteroendocrine
`L-cells of the ileum and colon in response to nutritional,
`hormonal, and neural stimulation. Human and animal
`studies have revealed that dietary fiber and short-chain
`fatty acids, carbohydrates, and fats are potent stimulators
`of GLP-2 secretion.9
`
`33
`
`61
`
`72
`
`107
`
`GRPP
`
`Glucagon
`
`IP1
`
`GLP-1
`
`Pancreas
`
`Intestine
`and
`CNS
`
`1
`
`1
`
`1
`
`1
`
`30
`
`64
`
`69
`
`69
`
`72
`
`158
`
`Glicentin
`
`MPGF
`
`GRPP
`
`Glucagon
`
`IP1
`
`GLP-1
`
`IP2
`
`GLP-2
`
`158
`
`Proglucagon
`
`69
`
`78
`
`106/107
`
`126
`
`158
`
`Glicentin
`
`GLP-1
`
`IP2
`
`111 123
`
`GLP-2
`
`GRPP
`
`Oxyntomodulin
`
`1
`
`30 33
`
`69
`
`Figure 1 Proglucagon contains three homologous hormonal sequences, glucagon/GLP-1/GLP-2, and is separated by intervening peptides iP1/iP2. Proglucagon is processed
`differentially in pancreas, intestine, and CNS.
`Abbreviations: CNS, central nervous system; GLP, glucagon-like peptide; GRPP, glicentin-related polypeptide; iP, intervening peptide; MPGF, major proglucagon fragment.
`
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`Teduglutide and short bowel syndrome
`
`GLP-2 exerts a wide variety of effects on the gastrointestinal
`tract and is a key mediator of intestinal adaptation.10 In ani-
`mal studies, GLP-2 treatment induces mucosal growth in
`the small and large intestine through an increase in crypt
`cell proliferation and a reduction of villous cell apoptosis
`(Figure 2).11,12 This increase in mucosal mass is accompanied
`by enhanced functional absorptive capacity.13 Other GLP-2-
`mediated effects include inhibition of gastric emptying and
`acid secretion,14,15 reduction of intestinal permeability,16,17
`anti-inflammatory actions,18 and stimulation of mesenteric
`blood flow.19
`Specific G-protein coupled GLP-2 receptors (GLP-2Rs)
`are found in abundance in the proximal small intestine and
`have been demonstrated on enteroendocrine cells,20 enteric
`neurons,19 and subepithelial myofibroblasts.21 The apparent
`lack of GLP-2Rs on the proliferative crypt cells suggests that
`the effects of GLP-2 are mediated through a variety of down-
`stream effectors (Figure 3).22 Insulin-like growth factor-1
`appears to be essential for GLP-2-induced intestinal epithe-
`lial proliferation,23 and nitric oxide might be a key mediator
`in GLP-2-induced upregulation of intestinal blood flow.19
`Vascular endothelial growth factor and transforming growth
`factor-β have been linked to GLP-2-induced wound repair.24
`The release of vasoactive intestinal peptide (VIP) from enteric
`neurons appears to mediate some of the anti-inflammatory
`effects of GLP-2.25 For further, in-depth discussion into the
`complex interplay of GLP-2 and its downstream mediators
`the authors of this paper recommend a recent review by
`Rowland and Brubaker.26
`GLP-2 has a short half-life of approximately 7 minutes
`in humans and undergoes N-terminal truncation by the
`proteolytic enzyme dipeptidyl peptidase IV (DPPIV) to the
`
`A
`
`B
`
`Figure 2 Effect of GLP-2 on murine small intestine. Histological appearance of small
`intestine epithelium from control (A) and GLP-2-injected (10 days) (B) mice.
`Reproduced with permission from Drucker et al.11
`© Copyright 1996 National Academy of Sciences, USA.
`Abbreviation: GLP, glucagon-like peptide.
`
`Villlus
`epithelium
`
`SEMFs
`
`?
`
`A
`
`Crypt
`epithelium
`
`IGF-1
`+ other
`growth
`factors (?)
`
`B
`
`VIP
`
`NO
`
`?
`
`Immune
`cell
`
`Blood
`vessel
`
`GLP-2
`
`C
`
`Muscularis
`
`Enteric
`neuron
`
`Figure 3 Proposed model for the indirect mechanisms of GLP-2 action in the
`intestine. Expression of the GLP-2R in intestinal endocrine cells (A), intestinal
`SEMFs (B), and enteric neurons (C) suggests that GLP-2 acts indirectly to produce
`its diverse actions in the intestine. iGF-i is critical for the ability of GLP-2 to induce
`intestinal growth and activate crypt cell proliferation. GLP-2-mediated enteric
`neuronal signaling enhances intestinal blood flow through a mechanism involving
`NO production and has anti-inflammatory actions through VIP.
`Used with permission from Dubé et al, American Journal of Physiology – Endocrinology
`and Metabolism, vol 293; E460–E465, 2007.22
`Abbreviations: GLP-2, glucagon-like peptide-2; GLP-2R, glucagon-like peptide-2
`receptor; iGF, insulin-like growth factor; NO, nitric oxide; SEMF, subepithelial
`myofibroblast; VIP, vasoactive intestinal polypeptide.
`
`biologically inactive form GLP-2.3–33 Blocking of DPPIV
`degradation, either through glycine substitution in position 2,
`as in teduglutide, or through adjuvant use of DPPIV inhibitors
`extends the use of GLP-2 half-life and confers greater
`biological potency. DPPIV inhibition enhances the intesti-
`notrophic effect of GLP-2 in rats and mice.28
`
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`Teduglutide [Gly] GLP-2 (GattexTM, NPS Pharmaceuticals,
`Bedminster, NJ), a DPPIV-resistant analog of GLP-2 lacking
`the N-terminal DPPIV cleavage site, has received orphan
`drug designation for the treatment of SBS from the United
`States Food and Drug Administration (FDA) and the
` European Medicines Agency. In 2007, NPS Pharmaceuticals
`granted Nycomed the rights to teduglutide outside of North
`America.
`
`Clinical trials of glucagon-like
`peptide-2 in SBS
`The production of GLP-2 occurs in both the small and large
`bowel via the proglucagon-expressing enteroendocrine
`L-cells but is most abundant in the distal ileum. This may
`explain why functional adaptation appears more effective
`when the residual intestine is ileum rather than jejunum.
`Those with end jejunostomy and no colon, who have the
`poorest intestinal adaptation, have a markedly impaired
`postprandial GLP-2 response, presumably caused by a lack of
`functioning L-cells.29 In contrast, SBS patients with preserved
`colon exhibit increased fasting GLP-2 levels with a postpran-
`dial profile comparable to that of healthy controls.30 These
`findings, combined with strong evidence of a correlation
`between GLP-2 and intestinal adaptation in animal models,13
`have raised hopes that GLP-2 therapy might be able to pro-
`duce clinically meaningful enhancement of intestinal mass
`and function in patients with SBS.
`Results of clinical trials so far have been encouraging. In
`initial uncontrolled open label studies of SBS patients, native
`GLP-2 and the long-acting analog teduglutide significantly
`improved intestinal wet-weight absorption by up to 1 L
`per day. This occurred in patients with end jejunostomy as
`well as in patients with a preserved colon, despite the latter
`group having near normal endogenous GLP-2 levels.31,32 The
`effects have been shown to be maintained for up to 2 years
`of treatment but will quickly wear off following treatment
`termination. The effect on energy absorption appears to
`be minor.
`A recently published large multinational, random-
`ized, placebo-controlled clinical trial of teduglutide in 83
`post-resection SBS patients requiring PN at least three
`times per week for a minimum of 12 months, has also
`reported a positive outcome. Following a maximum 8-week
`optimization of PN with a 4–8-week stabilization period,
`patients were randomized into a 24-week treatment protocol
`with placebo (n = 16), 0.05 mg/kg/day teduglutide (n = 35)
`or 0.10 mg/kg/day teduglutide (n = 32). The main measure
`of treatment response was a reduction in parenteral nutrition
`
`requirements from baseline of more than 20%. The PN
`reductions were made in standardized fashion when the
`urine volume increased to a certain threshold. The increased
`urine production was considered as a surrogate marker for
`increased intestinal wet-weight absorption. The reported
`primary efficacy endpoint of the study, was based on a
`graded response score (GRS) that accounted for both inten-
`sity (reduction from baseline of 20%–100%) and duration
`of response (response at weeks 16, 20, and 24). Although no
`statistical significance could be shown for the 0.10 mg/kg/
`day dose group, the GRS in the lower 0.05 mg/kg/day dose
`group were significantly better than in the placebo group
`(P = 0.007). Also, a .20% reduction of PN was achieved in
`significantly more patients treated with the 0.05 mg/kg/day
`teduglutide compared with placebo (46% (16/35) vs 6%
`(1/16), P = 0.005).33 The difference between 0.10 mg/kg/day
`teduglutide and placebo was not significant (25% vs 6.3%
`responders: P = 0.161). Three patients were weaned off
`PN completely (two in the low- and one in the high-dose
`treatment group).
`The apparent lack of significant treatment response using
`0.10 mg/kg/day teduglutide is thought to be related to protocol
`restrictions that could not take into account decreased oral
`fluid intake, which occurred significantly more often in the
`high dose patient group, as well as a trend towards higher
`baseline PN requirements and shorter remnant short bowel.
`Post hoc evaluation of the net effect of teduglutide estimates a
`similar efficacy of both treatment doses resulting in increased
`liquid absorption of approximately 700 mL (4.9 L per week),
`which is very much in keeping with the results of the open-
`label trials. The investigators also argue that the therapeutic
`benefit of teduglutide might have been underestimated by
`considering PN reduction as isolated endpoints, rather than
`taking into account additional positive effects on hydration
`and renal function. Teduglutide led to a significant increase in
`urine excretion in the low-dose group, and despite a reduced
`oral intake, urine output was maintained in the high-dose
`group. Although energy absorption was not quantified in this
`study, there was a small increase in body weight and lean
`body mass in both treatment groups, despite reduction in PN
`calorie provision.34 Plasma citrulline, a sensitive marker for
`enterocyte mass and function, increased with low- and high-
`dose treatment but not with placebo, indicating a teduglutide-
`related intestinotrophic effect. Accordingly, increased villous
`height was documented in both treatment groups.
`The aforementioned study was followed up with a
`28-week extension study that enrolled 65 patients that
`had completed the initial trial. The aim was to investigate
`
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`Teduglutide and short bowel syndrome
`
`whether the PN reductions could be maintained for up to
`1 year, as well as evaluate drug safety and tolerability. The
`results have been published in abstract form, and the final
`publication is anticipated.35 Patients previously on active
`treatment were maintained on their dose, and the placebo-
`treated patients were randomized to teduglutide 0.05 or
`0.10 mg/kg/day. In the low-dose group, 12/16 (75%) of
`initial responders maintained the PN reduction; ten of these
`had further reductions. In the high-dose group, 6/8 (75%)
`of initial responders maintained the reduction, and two of
`these had a further reduction. Among the initially placebo-
`treated subjects, 6/6 (100%) responded to low-dose and 2/7
`(28%) to high-dose teduglutide. Mean absolute (relative) PN
`reductions from weekly baseline volume were 4.5 L (51%,
`low-dose group) and 3.0 L (24%, high-dose group). Four
`actively treated subjects were weaned off parenteral nutrition
`over the 1-year trial period.
`Prior to application for FDA licensing of teduglutide
`as a first-in-class treatment for SBS, a further confirmatory
`Phase 3 study (STEPS – Study of Teduglutide in PN-
`dependent Short-bowel syndrome) has just been completed.
`This study randomized 86 SBS patients to either 0.05 mg/kg
`of teduglutide Gattex or placebo over a 24-week period. The
`following unpublished data has been extracted from a recent
`NPS Pharmaceuticals press release (January 31, 2011).36 The
`primary efficacy endpoint was defined as the percentage
`of patients who achieved a 20% or greater reduction in
`weekly PN volume at weeks 20 and 24. In an intention-
`to-treat analysis, 63% (27/43) of teduglutide-treated patients
`responded compared with 30% (13/43) of placebo-treated
`patients (P = 0.002). Absolute weekly reduction of PN
`volume was also greater in the teduglutide group compared
`with placebo; 4.4 L (baseline of 12.9 L) vs 2.3 L (baseline
`of 13.2 L). Teduglutide was well tolerated with only four
`patients discontinuing the study due to adverse events (one
`teduglutide treated and three placebo treated). The adverse
`events were consistent with the pharmacological effects of
`the drug. More than 97% of the eligible participants opted
`to participate in the STEPS 2 open-label continuation study
`where all participants will receive an additional 24 months
`of teduglutide therapy.
`These clinical studies indicate that teduglutide treatment
`can achieve clinically useful reductions of PN requirements
`in SBS patients, considered being stable on optimal
`conventional management.
`Metabolic bone disease is highly prevalent in SBS
`patients on long-term PN. A mediating role for GLP-2 in the
`postprandial decrease in bone resorption has been suggested
`
`because GLP-2 injection reduces bone resorption marker
`s-CTX in healthy postmenopausal women.37 In a small group
`of SBS patients with jejunostomy, 35-day GLP-2 treatment
`decreased bone resorption markers and increased bone mass
`and bone mineral density (BMD).38 However, other studies
`were unable to replicate the beneficial effect of GLP-2 on
`bone BMD in SBS patients.39,40 The clinical role of GLP-2 in
`the treatment of osteoporosis therefore remains uncertain.
`Crohn’s disease is a leading cause for adult SBS.
`Accumulating evidence that GLP-2 has anti-inflammatory
`and reparative properties promoted the expansion of GLP-2
`research into inflammatory bowel disease (IBD). Bioactive
`GLP-2 circulating concentrations are elevated in patients
`with active IBD compared with healthy controls, indicating
`an innate adaptive mechanism to the associated IBD intes-
`tinal damage.41 A pilot, proof of concept study was carried
`out on patients with moderate to severely active Crohn’s
`disease. This 8-week, randomized, placebo-controlled,
`dose-ranging trial, which recruited 100 patients, suggests
`a dose-dependent benefit in the reduction of the Crohn’s
`Disease Activity Index (CDAI) score. In the highest dose
`group, 55.6% of patients went into remission vs 33.3% of
`the placebo group. No statistical significance was observed,
`however, and further research must determine whether these
`results relate to symptomatic disease control (by decreasing
`diarrhea) or reflect decrease in inflammatory activity and
`improved mucosal healing. The authors acknowledged the
`pilot nature of the study as well as the use of CDAI as the
`primary outcome.42 Further clinical studies with greater
`statistical power and more effective primary endpoints and
`longer trial period are much needed. Nevertheless, this trial
`provided promising data for the use of teduglutide as a novel
`treatment of intestinal diseases associated with compromised
`repair of the intestinal mucosa.
`There has been a number of studies looking at rodent
`models of intestinal injury to explore the mechanisms
`of anti-inflammatory actions of GLP-2.18,25,44 One such
`study carried out by Sigalet et al, investigated the effects
`of GLP-2 treatment on rats with trinitrobenzene sulfonic
`acid-induced ileitis or dextran sulfate sodium-induced
`colitis.25 Apart from trophic effects of GLP-2, treatment
`also resulted in significant reduction in inflammatory mark-
`ers, interleukin (IL)-1ß, interferon-γ, and tumor necrosis
`factor-α, along with reduction in neutrophil activity. The
`use of a VIP antagonist confirmed that VIP appeared
`to mediate the anti-inflammatory properties of GLP-2.
`Subsequently, Ivory et al confirmed the anti-inflammatory
`actions of GLP-2 via use of IL-10 knockout (IL-10-/-)
`
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`mouse model. This study showed that GLP-2 altered the
`mucosal response of inflamed intestinal epithelial cells and
`macrophages by activation of the suppressor of cytokine
`signaling-3 pathway, which antagonizes the IL-6-mediated
`increase in signal transducers and activators of transcription
`3 signaling. The study also confirmed that this immuno-
`modulatory effect was IL-10 independent.18 Translation
`studies “from bench to bedside” may allow the clinical use
`of teduglutide as both a trophic and an immunomodulatory/
`immunosuppressive therapy in patients with SBS, in
`particular those who develop SBS from complications of
`Crohn’s disease.
`
`Safety consideration
`Clinical studies so far report good drug compliance,
`tolerance, and safety of native GLP-2 and teduglutide, with
`no significant increase of serious adverse events. Most
`commonly reported adverse events are abdominal pain,
`bloating, constipation, nausea, injection site erythema, lower
`limb edema, stoma swelling, headache, and nasopharyngitis.
`Caution is suggested in patients with a history of abdominal
`pain and recurrent subacute obstruction. In cardiac failure,
`increased fluid absorption might lead to decompensation
`and fluid overload.
`The therapeutic use of GLP-2 may require lifelong admin-
`istration. Because of concerns that permanent stimulation of
`epithelial proliferation might initiate or accelerate malignant
`growth, research into the role of GLP-2 in carcinogenesis
`is ongoing. Low level GLP-2R expression has been dem-
`onstrated in cancer cell lines and human tumors including
`colonic adenocarcinomas.43,45 GLP-2 also exerts a direct
`proliferative effect on transformed cell lines despite apparent
`lack of a specific receptor.46 Recent in vivo studies in mouse
`cancer models have added to concerns that GLP-2 may play
`a role in both tumor initiation and progression. Mice that
`were pretreated with carcinogen azoxymethane showed
`an increase in number and size of aberrant crypt foci,
` presumed precursors of tumor development, when they were
`subsequently treated with GLP-2 vs controls treated either
`with saline or the GLP-2R antagonist GLP-2.3–33 Loss of
`mucin production in aberrant crypts (considered an important
`marker of dysplasia) and formation of adenocarcinomas
`were almost exclusively observed in GLP-2-treated mice
`but not in controls.47 In another model, GLP-2 injections
`increased the number and size of colonic adenomas in mice
`pretreated with the carcinogen 1,2-dimethylhydralazine.48
`It has been argued that the effects of GLP-2 are present
`at the early stage of carcinogenesis, with no effect when
`
`adenomas and microadenomas have already developed, as
`in the APC min/+ mice model.45 The precise implications of
`such studies for the development of colon cancer in humans
`remain incompletely understood. Until a clear safety profile
`for the long-term use of GLP-2 is established, a high level
`of vigilance is required. This should include mandatory
`screening of prospective patients for pre-malignant lesions
`(particularly colonic adenomas).
`
`Conclusion
`The ability of GLP-2 to enhance intestinal adaptation has
`been demonstrated in numerous animal models. There is
`now mounting clinical evidence that it can provide a new
`therapeutic strategy in SBS patients in whom it may pave
`the path towards reducing PN dependence. This, in turn,
`may lead to a reduction in PN-related complications as well
`as improving patients quality of life. GLP-2 appears safe
`and well tolerated in the short and medium term. Optimal
`indications, timing, and dose as well as possible gains from
`coadministration with other growth factors will need to be
`studied further, and long-term colonic surveillance studies
`must be considered to abate safety concerns.
`Promising results of the ability of GLP-2 to restore
`mucosal integrity and possible immunomodulatory effects
`bade the question of its use in IBD.
`
`Acknowledgment
`The St Mark’s Research Foundation has supported this
`work.
`
`Disclosure
`Dr Tee, Dr Wallis, and Dr Gabe have been investigators in
`the multinational trial of teduglutide in the management of
`SBS, sponsored by NPS Pharmaceuticals.
`
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