title: Glucose and lipid effects of the ileal apical sodium-dependent bile acid transporter inhibitor GSK2330672: double-blind randomized trials with type 2 diabetes subjects taking metformin.
abstract: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D).
  
  
  
  Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days.
  
  
  
  In both studies, GSK672 reduced circulating bile acids and increased serum 7-α-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was ∼40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose.
  
  
  
  In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.
authors.affiliation: GlaxoSmithKline plc, Research Triangle Park, NC and Collegeville, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Nunez
authors.affiliation: Alexion Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.affiliation: Grifols Therapeutics Inc., Research Triangle Park, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: GlaxoSmithKline plc, Research Triangle Park, NC and Collegeville, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Walker
authors.affiliation: Parexel International, Durham, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zuo
authors.affiliation: Nuventra, Inc., Durham, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Webster
authors.affiliation: GlaxoSmithKline plc, Research Triangle Park, NC and Collegeville, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Krug-Gourley
authors.affiliation: GlaxoSmithKline plc, Research Triangle Park, NC and Collegeville, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.affiliation: Pharmaceutical Product Development LLC, Morrisville, NC, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Gillmor
authors.affiliation: Pfizer Inc., Andover, MA, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Johnson
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000378:metabolism; D019540:Area Under Curve; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D008078:Cholesterol, LDL; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting / Q000378:metabolism; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D008744:Methylamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors; D027981:Symporters / Q000037:antagonists & inhibitors; D013841:Thiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: C583160:3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid; D001055:Apolipoproteins B; D001647:Bile Acids and Salts; D001786:Blood Glucose; D008078:Cholesterol, LDL; D007004:Hypoglycemic Agents; D007328:Insulin; D008744:Methylamines; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D013841:Thiazepines; C071908:sodium-bile acid cotransporter; D008687:Metformin
keywords: antidiabetic drug; drug mechanism; lipid-lowering therapy; metformin; phase I-II study; type 2 diabetes