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- 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.
- Authors
Nunez, D. J.; Yao, X.; Lin, J.; Walker, A.; Zuo, P.; Webster, L.; Krug‐Gourley, S.; Zamek‐Gliszczynski, M. J.; Gillmor, D. S.; Johnson, S. L.
- Abstract
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.
- Subjects
GLUCOSE; LIPIDS; BILE acids; PHARMACOKINETICS; CONFIDENCE intervals; TRIGLYCERIDES; METFORMIN
- Publication
Diabetes, Obesity & Metabolism, 2016, Vol 18, Issue 7, p654
- ISSN
1462-8902
- Publication type
Article
- DOI
10.1111/dom.12656