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The new place of enterohormones in intestinal failure.
Daoud, DC, Joly, F
Current opinion in clinical nutrition and metabolic care. 2020;(5):344-349
Abstract
PURPOSE OF REVIEW Since the approval of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, for the treatment of patients with short bowel syndrome (SBS) associated with intestinal failure, enterohormone therapy has received significant interest and is becoming the first choice of treatment in selected patients. As such, it is paramount to assess and understand the new place of hormonal therapy in the algorithm of treatments in SBS-intestinal failure. RECENT FINDINGS Specialized intestinal failure units have recently reported their outcomes with teduglutide to evaluate if they are consistent with the phase III trials results. SBS-intestinal failure patients are very heterogenous including their response to this treatment, hence the importance of real-life studies beyond the context of clinical trials. Moreover, it is essential to find a consensus on criteria identifying candidate patients for teduglutide. In addition, the impact of teduglutide on quality of life and its cost-effectiveness are emerging as well as new enterohormone treatments are being studied whether it is long action GLP-2 analog or other ileocolonic break hormones like glucagon-like peptide-1 analog. SUMMARY Hormonotherapy is currently modifying the natural history of patients with SBS-intestinal failure by decreasing their need for parenteral support and possibly even complications associated with long-term parenteral support. Enterohormone treatment is now the cornerstone in SBS-intestinal failure and should be offered as a first-line therapy to selected patients.
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Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.
Naimi, RM, Hvistendahl, M, Enevoldsen, LH, Madsen, JL, Fuglsang, S, Poulsen, SS, Kissow, H, Pedersen, J, Nerup, N, Ambrus, R, et al
The lancet. Gastroenterology & hepatology. 2019;(5):354-363
Abstract
BACKGROUND Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. METHODS In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. FINDINGS Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. INTERPRETATION Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. FUNDING Zealand Pharma.
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Gut hormones in the treatment of short-bowel syndrome and intestinal failure.
Jeppesen, PB
Current opinion in endocrinology, diabetes, and obesity. 2015;(1):14-20
Abstract
PURPOSE OF REVIEW The approval of teduglutide, a recombinant analog of human glucagon-like peptide (GLP) 2, by the US Food and Drug Administration (Gattex) and the European Medicines Agency (Revestive) has illustrated the potential of selected gut hormones as treatments in patients with short-bowel syndrome and intestinal failure. Gut hormones may improve the structural and functional intestinal adaptation following intestinal resection by decreasing a rapid gastric emptying and hypersecretion, by increasing the intestinal blood flow, and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 teduglutide studies, and pilot studies employing GLP-1 and agonists for this orphan condition. RECENT FINDINGS In a 3-week, phase 2, metabolic balance study, teduglutide increased the intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 Kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Adverse events were mainly of gastrointestinal origin and consistent with the known mechanism of action of teduglutide. Pilot studies suggest that GLP-1 may be less potent. Synergistic effects may be seen by co-treatment with GLP-2. SUMMARY Gut hormones promote intestinal adaptation and absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. This will aid the intestinal rehabilitation in these severely disabled short-bowel syndrome patients.
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Growth hormone enhances fat-free mass and glutamine availability in patients with short-bowel syndrome: an ancillary double-blind, randomized crossover study.
Seguy, D, Darmaun, D, Duhamel, A, Thuillier, F, Cynober, L, Cortot, A, Gottrand, F, Messing, B
The American journal of clinical nutrition. 2014;(3):850-8
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Abstract
BACKGROUND Benefits of recombinant human growth hormone (rhGH) alone or combined with glutamine in patients with intestinal failure because of short-bowel syndrome remain controversial. OBJECTIVE We explored effects of rhGH on whole-body protein metabolism in patients with short-bowel syndrome with intestinal failure (SBS-IF) to gain insight into its mechanism of action. DESIGN Eight stable hyperphagic patients with severe SBS-IF received, in a double-blind, randomized crossover study, low-dose rhGH (0.05 mg · kg⁻¹ · d⁻¹) and a placebo for two 3-wk periods. Leucine and glutamine kinetics under fasting and fed conditions, fat-free mass (FFM), and serum insulin were determined on the final day of each treatment. RESULTS rhGH increased FFM and nonoxidative leucine disposal (NOLD; an index of protein synthesis) (P < 0.02), whereas FFM and NOLD were correlated in the fed state (r = 0.81, P = 0.015). With rhGH administration, leucine release from protein breakdown (an index of proteolysis) decreased in the fed compared with fasting states (P = 0.012), which was not observed with the placebo. However, the fast-to-fed difference in leucine release from protein breakdown was not significantly different between rhGH and placebo (P = 0.093). With rhGH, the intestinal absorption of leucine and glutamine increased (P = 0.036) and correlated with serum insulin (r = 0.91, P = 0.002). rhGH increased glutamine de novo synthesis (P < 0.02) and plasma concentrations (P < 0.03) in both fasting and fed states. CONCLUSIONS In SBS-IF patients, feeding fails to decrease proteolysis in contrast to what is physiologically observed in healthy subjects. rhGH enhances FFM through the stimulation of protein synthesis and might decrease proteolysis in response to feeding. Improvements in de novo synthesis and intestinal absorption increase glutamine availability over the physiologic range, suggesting that beneficial effects of rhGH in hyperphagic patients might be achieved without glutamine supplementation.
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New approaches to the treatments of short bowel syndrome-associated intestinal failure.
Jeppesen, PB
Current opinion in gastroenterology. 2014;(2):182-8
Abstract
PURPOSE OF REVIEW Teduglutide, a recombinant analog of human glucagon-like peptide 2, has recently been approved in the US and Europe (Gattex and Revestive, respectively) as the first targeted treatment of short bowel syndrome-associated intestinal failure (SBS-IF). Glucagon-like peptide 2 improves structural and functional intestinal adaptation following intestinal resection by decelerating a rapid gastric emptying, by decreasing gastric hypersecretion, by increasing intestinal blood flow and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 studies preceding the US Food and Drug Administration and the European Medicines Agency approval of subcutaneous teduglutide for this orphan condition. RECENT FINDINGS In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide had an acceptable tolerability profile, where adverse events generally were of gastrointestinal origin consistent with the known mechanism of action. SUMMARY Teduglutide will add incremental benefit to the limited medical treatment armamentarium in SBS patients by maximizing intestinal absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. Future research should target and implement other key hormones with similar and possible additive or synergistic effects, thereby further promoting structural and functional adaptation and intestinal rehabilitation in these severely disabled SBS patients.
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Treatment of adult short bowel syndrome patients with teduglutide.
Nørholk, LM, Holst, JJ, Jeppesen, PB
Expert opinion on pharmacotherapy. 2012;(2):235-43
Abstract
INTRODUCTION Parenteral support is lifesaving in short bowel syndrome patients with intestinal failure (SBS-IF), who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Mutually, the symptoms of SBS-IF and the inconveniences and complications in relation to parenteral support may cause impairment of the quality of life of SBS-IF patients. Conventional treatments include dietary manipulations, oral rehydration solutions, antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited, and treatments improving structural and functional integrity of the remaining intestine are desired. Teduglutide , an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by inhibiting gastric emptying and secretion, which in turn reduces intestinal losses and promotes intestinal absorption. AREAS COVERED This paper reviews the following findings: in a 3-week, Phase II balance study, teduglutide reduced diarrhea by ∼ 700 g/day and fecal energy losses by ∼ 0.8 MJ/day, and in a randomized, placebo-controlled, 24-week, Phase III study, corresponding reductions in the need for parenteral support were obtained. EXPERT OPINION Teduglutide seems to be safe and well-tolerated and demonstrates restoration of structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for parenteral support in SBS-IF patients.
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Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease.
Kaser, S, Ebenbichler, CF, Tilg, H
International journal of clinical practice. 2010;(7):968-83
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a disease spectrum ranging from simple steatosis and steatohepatitis to cirrhosis. Based on its strongest risk factors namely visceral obesity and insulin resistance, NAFLD is thought to be the hepatic manifestation of the metabolic syndrome and is considered to be the most common liver disorder in Western countries. Pathophysiological mechanisms include an enlarged pool of fatty acids, subclinical inflammation, oxidative stress and imbalances of various adipocytokines such as adiponectin. Accordingly, targets for therapeutic interventions are miscellaneous: amelioration of obesity by pharmacological, surgical or lifestyle intervention has been evaluated with success in numerous, but not all studies. Some efficacy was reported for metformin and short-term glitazone treatment. In a large recently reported trial, vitamin E supplementation improved biochemical and histological markers in subjects with non-alcoholic steatohepatitis. Blockade of the endocannabinoid system has been proposed to be a promising target in NAFLD; however, very recently the cannabinoid receptor blocker rimonabant has been withdrawn because of central nervous system toxicity. Cytoprotective therapies and statins have been mainly ineffective in NAFLD. New but so far insufficiently studied therapeutic approaches include inhibitors of the renin-angiotensin system as well as incretin mimetics respectively.