Significant glucose-lowering and favorable changes in lipid profiles were demonstrated with GPR119 agonist DS-8500a in Japanese patients with type 2 diabetes (T2DM) in a randomized, double-blind, placebo-controlled phase 2b study. DS-8500a acts on the G protein-coupled receptor 119 (GPR119), which has been shown to be highly expressed in the human gastrointestinal tract and in pancreatic β-cells. Based on several in vitro studies, it is expected that GPR119 agonists will reduce blood glucose levels by promoting insulin secretion in a glucose-dependent manner and improve pancreatic β-cell function over long-term treatment. A phase 2a study with DS-8500a (10 or 75 mg) in T2DM patients showed a significant decrease in 24-hour weighted mean glucose levels after 4 weeks of treatment, in both dose groups (-13.3 and -18.9 mg/dL, respectively), compared with placebo.

This 12-week study randomized 368 T2DM patients to placebo (n=73) or one of 3 doses of DS-8500a (25, 50 or 75 mg, with n=73, 74 and 73) or sitagliptin 50 mg (n=75)once daily. The primary efficacy endpoint was change in HbA1c from baseline to the end of the study at week 12. Changes in lipid profiles were among the secondary endpoints and safety endpoints included adverse events, hypoglycemia and clinical/laboratory variables.

At 12 weeks, changes in HBA1c from placebo were -0.23%, -0.37% and -0.44% with DS-8500a 25mg, 50mg and 75 mg, respectively. The change in HbA1c from baseline with sitagliptin was -0.78%. DS-8500a significantly lowered fasting plasma glucose and glucose AUC(0-3h), as well as 2hour-postprandial glucose. These parameters were not lowered to a greater extent with DS-8500a than with sitagliptin. DS8500a 50 mg and 75 mg, as compared with placebo, significantly lowered total cholesterol, LDL-c and triglycerides, and it increased HDL-c. These improvements in lipid parameters were not observed with sitagliptin.

All doses were well tolerated. Two cases of clinically relevant drug-related asymptomatic hypoglycemia were reported in patients taking DS-8500a 50 mg, which resolved without treatment or changes in the study drug dose. No serious adverse events were considered to be related to the study drug.

While the glucose-lowering effects of other GPR119 agonists had been shown to be abrogated after about 2-4 weeks of treatment, in this study the effect on FPG, 2hour-postprandial glucose, glucose-AUC(0-3h) and HbA1c was maintained over time, up to 12 weeks. This may be explained by structural effects between the different GPR119, and the absence of a piperidine ring in DS-8500a, which also results in antagonistic activity in other GPR119 agonists.

Read more about this research online at Adv Ther