Diabetes Journal Club Julie Shah

Free fatty acid receptor Activation of FFAR1 by fatty acids or synthetic ligands results in increased insulin secretion, but only in the presence of rising glucose concentrations.

Study Design TAK-875 is an oral, highly potent, and selective FFAR1 agonist that was the first of its class tested for glucose-lowering ability in patients with type 2 diabetes. Aim- to assess the efficacy and safety of TAK-875 compared with placebo and glimepiride in patients whose type 2 diabetes was inadequately controlled by diet and exercise or treatment with a stable metformin dose This is a phase 2, randomized, double-blind, placebo-controlled, and active-comparator-controlled multicenter study between Nov 17, 2009, and Sept 29, 2010, at 95 sites in the USA, Mexico, and Guatemala. 12 week treatment period and 2 week follow up period Weekly visit to review log book and glucometer Blood tests ( HbA1c, insulin, proinsulin, c-peptide and glucagon levels) were obtained at baseline, week 4,8,12)

Results -1.05% 1.0% with TAK

Changes relative to placebo group are significant

Patient log showed consistent dose dependent decrease in fasting and postprandial BG compared to placebo

Overall incidence of adverse reaction was similar in TAK group vs placebo; much higher in glimepiride group

Bodyweight changes- Average increase of 0. 86 – 1 Bodyweight changes- Average increase of 0.86 – 1.27kg in TAK group vs 1.59kg in Glimepiride group

Discussion There was a dose dependent improvement in glycemic control 33- 48% of patients reached target HbA1c < 7 at 12 weeks of treatment with TAK 875 25mg or higher Adverse events profile similar to placebo group and lower than glimiperide group due to reduced risk of hypoglycemia

Conclusion The restricted distribution of FFAR1 receptors, their distinct activation of Gαq, and the apparent glucose-dependent potentiation of insulin secretion by FFAR1 agonists might underlie the salutary effects on glucose control in patients with type 2 diabetes without heightening the risk of hypoglycemia and excessive weight gain, and with an adverse event profile that is similar to that for placebo.