title: Specific inhibition of bile acid transport alters plasma lipids and GLP-1.
abstract: BACKGROUND
  Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC.
  
  
  METHODS
  Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1.
  
  
  RESULTS
  In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02).
  
  
  CONCLUSIONS
  Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans.
  
  
  BACKGROUND
  ClinicalTrial.gov: NCT01069783 and NCT01038687 .
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, Metabolism Unit, Center for Endocrinology, Metabolism, and Diabetes, Karolinska Institute at Karolinska University Hospital Huddinge, S-141 86, Stockholm, Sweden. mats.rudling@ki.se.|Department of Medicine, and Molecular Nutrition Unit, Karolinska Institute at Karolinska University Hospital Huddinge, S-141 86, Stockholm, Sweden. mats.rudling@ki.se.|Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, S-141 86, Stockholm, Sweden. mats.rudling@ki.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.affiliation: Mayo Clinic, Rochester, MN, USA. camilleri.michael@mayo.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Albireo, Göteborg, Sweden. Hans.Graffner@albireopharma.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Graffner
authors.affiliation: NNF Center for Basic Metabolic Research, the Panum Institute, University of Copenhagen, Copenhagen, Denmark. jjholst@sund.ku.dk.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Albireo, Göteborg, Sweden. Leif.Rikner@albireopharma.com.
authors.forename: Leif
authors.initials: L
authors.lastname: Rikner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002783:Cholestenones / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002908:Chronic Disease; D003248:Constipation / Q000097:blood / Q000188:drug therapy*; D004151:Dipeptides / Q000009:adverse effects / Q000627:therapeutic use*; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D013841:Thiazepines / Q000009:adverse effects / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D002783:Cholestenones; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004151:Dipeptides; D008055:Lipids; D013841:Thiazepines; D014280:Triglycerides; C002656:7 alpha-hydroxy-4-cholesten-3-one; C581303:elobixibat; D052216:Glucagon-Like Peptide 1