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.

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.

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

Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.

Tiessen RG ，Kennedy CA ，Keller BT ，Levin N ，Acevedo L ，Gedulin B ，van Vliet AA ，Dorenbaum A ，Palmer M ... -  《-》

Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes.

Lund SS ，Tarnow L ，Frandsen M ，Smidt UM ，Pedersen O ，Parving HH ，Vaag AA ... -  《-》

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

Wu Y ，Aquino CJ ，Cowan DJ ，Anderson DL ，Ambroso JL ，Bishop MJ ，Boros EE ，Chen L ，Cunningham A ，Dobbins RL ，Feldman PL ，Harston LT ，Kaldor IW ，Klein R ，Liang X ，McIntyre MS ，Merrill CL ，Patterson KM ，Prescott JS ，Ray JS ，Roller SG ，Yao X ，Young A ，Yuen J ，Collins JL ... -  《-》

BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.

Hegade VS ，Kendrick SF ，Dobbins RL ，Miller SR ，Richards D ，Storey J ，Dukes G ，Gilchrist K ，Vallow S ，Alexander GJ ，Corrigan M ，Hirschfield GM ，Jones DE ... -  《-》