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

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 90mg, twice daily, or placebo for 7 days. The second parallel-group study (n= 75) investigated GSK672 10-90mg twice daily, placebo or sitagliptin for 14 days. Results: In both studies, GSK672 reduced circulating bile acids and increased serum 7-alpha-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 AUC(0-24 h). GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was similar to 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.