Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial

Rahim Mohammad Naimi, Mark Hvistendahl, Nikolaj Nerup, Rikard Ambrus, Michael Patrick Achiam, Lars Bo Svendsen, Henning Grønbæk, Holger Jon Møller, Hendrik Vilstrup, Adam Steensberg, Palle Bekker Jeppesen, Rahim Mohammad Naimi, Mark Hvistendahl, Nikolaj Nerup, Rikard Ambrus, Michael Patrick Achiam, Lars Bo Svendsen, Henning Grønbæk, Holger Jon Møller, Hendrik Vilstrup, Adam Steensberg, Palle Bekker Jeppesen

Abstract

Background: With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage. We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function.

Methods: Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025.

Findings: Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected.

Interpretation: Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies.

Funding: Zealand Pharma.

Keywords: Indocyanine green; Short bowel syndrome; Soluble CD163; Soluble mannose receptor; Transient elastography.

Conflict of interest statement

RM Naimi was an employee at Zealand Pharma as an industrial PhD fellow during the conduct of this trial. A Steensberg is an employee at Zealand Pharma. PB Jeppesen serves as consultant and trial investigator for Zealand Pharma. The remaining authors have nothing to disclose.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Mean changes from baseline in transient elastography.
Fig. 2
Fig. 2
Mean changes from baseline in ICG-PDR and ICG-R15.
Fig. 3
Fig. 3
Individual serum levels of sCD163 and sMR before and after treatment for each patient.

References

    1. Cavicchi M., Beau P., Crenn P., Degott C., Messing B. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann. Intern. Med. 2000;132(7):525–532.
    1. Kelly D.A. Intestinal failure-associated liver disease : what do we know today? Gastroenterology. 2006;130(2 Suppl 1):70–77.
    1. Lim D.W., Wales P.W., Josephson J.K. Glucagon-like peptide 2 improves cholestasis in parenteral nutrition-associated liver disease. JPEN J. Parenter. Enteral Nutr. 2016;40(1):14–21.
    1. Pereira-Fantini P.M., Lapthorne S., Joyce S.A. Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease. J. Hepatol. 2014;61(5):1115–1125.
    1. Sasdelli A.S., Agostini F., Pazzeschi C., Guidetti M., Lal S., Pironi L. Assessment of intestinal failure associated liver disease according to different diagnostic criteria. Clin. Nutr. 2018;S0261–5614(18):30170–30175.
    1. Van Gossum A., Pironi L., Messing B. Transient Elastography (FibroScan) is not correlated with liver fibrosis but with cholestasis in patients with long-term home parenteral nutrition. JPEN J. Parenter. Enteral Nutr. 2015;39(6):719–724.
    1. Hukkinen M., Kivisaari R., Lohi J. Transient elastography and aspartate aminotransferase to platelet ratio predict liver injury in paediatric intestinal failure. Liver Int. 2016;36(3):361–369.
    1. Alvarez D., Orozco F., Mella J.M., Anders M., Antinucci F., Mastai R. Meal ingestion markedly increases liver stiffness suggesting the need for liver stiffness determination in fasting conditions. Gastroenterol. Hepatol. 2015;38(7):431–435.
    1. Barone M., Iannone A., Brunetti N.D. Liver stiffness and portal blood flow modifications induced by a liquid meal consumption: Pathogenetic mechanisms and clinical relevance. Scand. J. Gastroenterol. 2015;50(5):560–566.
    1. Levesque E., Martin E., Dudau D., Lim C., Dhonneur G., Azoulay D. Current use and perspective of indocyanine green clearance in liver diseases. Anaesth Crit Care Pain Med. 2016;35(1):49–57.
    1. Møller S., la Cour Sibbesen E., Madsen J.L., The Bendtsen F. Indocyanine green retention test in cirrhosis and portal hypertension. Accuracy and relation to severity of disease. J. Gastroenterol. Hepatol. 2018:1–7.
    1. Andersen E.S., Rødgaard-Hansen S., Moessner B., Christensen P.B., Møller H.J., Weis N. Macrophage-related serum biomarkers soluble CD163 (sCD163) and soluble mannose receptor (sMR) to differentiate mild liver fibrosis from cirrhosis in patients with chronic hepatitis C: a pilot study. Eur. J. Clin. Microbiol. Infect. Dis. 2014;33(1):117–122.
    1. Lim D.W., Wales P.W., Mi S. Glucagon-like Peptide-2 alters bile acid metabolism in parenteral nutrition–associated liver disease. JPEN J. Parenter. Enteral Nutr. 2016 jan;40(1):22–35.
    1. Guan X., Karpen H.E., Stephens J. GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology. 2006;130(1):150–164.
    1. Guan X., Stoll B., Lu X. GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets. Gastroenterology. 2003;125(1):136–147.
    1. Høyerup P., Hellström P.M., Schmidt P.T. Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients. Regul. Pept. 2013;180:12–16.
    1. Jeppesen P.B., Pertkiewicz M., Messing B. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143(6):1473–1481.e3.
    1. Schwartz L.K., O'Keefe S.J., Fujioka K. Long-term Teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome. Clin. Transl. Gastroenterol. 2016;7
    1. Naimi R.M., Hvistendahl M., Enevoldsen L.H. Glepaglutide, a novel long-acting glucagon-like peptide-2 analogueue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2019;1253:1–10.
    1. Castera L., Forns X., Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J. Hepatol. 2008;48(5):835–847.
    1. Boursier J., Zarski J.P., de Ledinghen V. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology. 2013;57(3):1182–1191.
    1. Cheung T.T., Chan S.C., Chok K.S. Rapid measurement of indocyanine green retention by pulse spectrophotometry: a validation study in 70 patients with child-Pugh a cirrhosis before hepatectomy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2012;11(3):267–271.
    1. Purcell R., Kruger P., Jones M. Indocyanine green elimination: a comparison of the LiMON and serial blood sampling methods. ANZ J. Surg. 2006;76(1–2):75–77.
    1. Sakka S.G., Reinhart K., Meier-Hellmann A. Comparison of invasive and noninvasive measurements of indocyanine green plasma disappearance rate in critically ill patients with mechanical ventilation and stable hemodynamics. Intensive Care Med. 2000;26(10):1553–1556.
    1. Møller H.J., Hald K., Moestrup S.K. Characterization of an enzyme-linked immunosorbent assay for soluble CD163. Scand. J. Clin. Lab. Invest. 2002;62(4):293–299.
    1. Rødgaard-Hansen S., Rafique A., Christensen P.A. A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness. Clin. Chem. Lab. Med. 2014;52(3):453–461.
    1. Karlas T., Petroff D., Sasso M. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J. Hepatol. 2017;66(5):1022–1030.
    1. Møller H.J. Soluble CD163. Scand. J. Clin. Lab. Invest. 2012;72(1):1–13.
    1. Beath S., Pironi L., Gabe S. Collaborative strategies to reduce mortality and morbidity in patients with chronic intestinal failure including those who are referred for small bowel transplantation. Transplantation. 2008;85(10):1378–1384.
    1. Pironi L., Arends J., Baxter J. ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults. Clin. Nutr. 2015;34(1):171–180.
    1. Kjærgaard M., Thiele M., Jansen C. High risk of misinterpreting liver and spleen stiffness using 2D shear-wave and transient elastography after a moderate or high calorie meal. PLoS One. 2017;12(4)
    1. El Kasmi K.C., Anderson A.L., Devereaux M.W. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology. 2012;55(5):1518–1528.
    1. Mutanen A., Lohi J., Heikkilä P., Jalanko H., Pakarinen M.P. Liver inflammation relates to decreased Canalicular bile transporter expression in pediatric onset intestinal failure. Ann. Surg. 2018;268(2):332–339.
    1. Etzerodt A., Maniecki M.B., Møller K., Møller H.J., Moestrup S.K. Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163. J. Leukoc. Biol. 2010;88(6):1201–1205.

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