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.

Published

Journal Article

AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.

Full Text

Duke Authors

Cited Authors

  • Nunez, DJ; Yao, X; Lin, J; Walker, A; Zuo, P; Webster, L; Krug-Gourley, S; Zamek-Gliszczynski, MJ; Gillmor, DS; Johnson, SL

Published Date

  • July 2016

Published In

Volume / Issue

  • 18 / 7

Start / End Page

  • 654 - 662

PubMed ID

  • 26939572

Pubmed Central ID

  • 26939572

Electronic International Standard Serial Number (EISSN)

  • 1463-1326

Digital Object Identifier (DOI)

  • 10.1111/dom.12656

Language

  • eng

Conference Location

  • England