• Hyperglycemia/Hypoglycemia
• Diabetes Mellitus
• Diabetes & Endocrinology Clinical Trials

TAK-875 is a selective G-protein-coupled receptor 40 (GPR40) agonist that is being developed as an adjunct therapy to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM). Results of a Phase 2 [NCT01007097] trial that has shown the glucose-lowering efficacy, safety, and tolerability of TAK-875 in a clinical setting were presented by Eckhard Leifke, MD, Takeda Pharmaceuticals, Deerfield, Illinois, USA. All doses of TAK-875 produced significant HbA1C lowering compared with placebo after 12 weeks of treatment, with a markedly lower incidence of hypoglycemia relative to glimepiride.

GPR40 is abundantly expressed in the pancreas and functions as a receptor for long-chain free fatty acids (FFAs). Furthermore, long-chain FFAs amplify glucose-stimulated insulin secretion from pancreatic beta-cells by activating GPR40, thus suggesting that GPR40 agonists and/or antagonists have potential as antidiabetic drugs [Itoh Y et al. Nature 2003].

Patients (n=426) with T2DM who previously failed treatment with metformin or diet and exercise alone were randomly assigned (∼60 per group) to receive TAK-875 (6.25 mg, 25 mg, 50 mg, 100 mg, or 200 mg), placebo, or glimepiride (4 mg) once daily for 12 weeks. Subjects mean age was 51.6 years and 52.4% were women. Approximately 75% of patients were on background metformin. The primary efficacy endpoint was change from baseline in HbA1C at Week 12. Other endpoints included changes in HbA1C over time, fasting plasma glucose (FPG), plasma glucose post-oral glucose tolerance testing (OGTT), number of subjects that were rescued due to hyperglycemia, and incidence of hypoglycemia.

All doses of TAK-875 showed significantly (p≤0.001) greater HbA1C reductions at Week 12 compared with placebo. There was a dose-response relationship up to 50 mg TAK-875. The magnitude of decrease in HbA1C that was produced by TAK-875 ≥50 mg was comparable with glimepiride. The percentage of subjects with HbA1C decreases ≥1.5% at Week 12 was 20% to 40% for TAK-875, 30% for glimepiride, and <5% for placebo (all p<0.05 except for 6.25 mg TAK-875). Changes from baseline in FPG and 2-hour OGTT values that were observed with TAK-875 were consistent with changes in HbA1C and occurred with a fast onset of action. The incidence of hypoglycemia (American Diabetes Association criteria) was significantly lower in all TAK-875 groups (mean of 2.3% of subjects) compared with glimepiride (19.4%) and similar to placebo (3.3%). The overall incidence of treatment-emergent adverse events (TEAEs) was similar for the TAK-875 (48.7%) and placebo (47.5%) groups; higher rates of TEAEs were observed in patients who received glimepiride (61.3%). Discontinuations because of AEs were low (1.6% to 3.3%) and similar among all active treatment groups.

Significantly fewer (p<0.05) subjects who received glimepiride and all doses of TAK-875, except the 6.25 mg dose, needed hyperglycemic rescue compared with placebo. At Week 12, TAK-875 (50 mg, 100 mg, and 200 mg) and glimepiride produced significant (p<0.05) increases in HOMA-β. As expected, the greatest increase in body weight (∼1%) occurred with glimepiride. Weight increases with TAK-875 were not dose-dependent. The most common TEAEs, occurring in >5% of subjects, were urinary tract infection (UTI; 5.3%) for TAK-875; headache (8.2%), hyperglycemia (8.2%), and UTI (6.6%) for placebo; and hypoglycemia (19.4%), influenza (8.1%), UTI (8.1%), diarrhea (9.7%), and dizziness (6.5%) for glimepiride.

The results provide evidence of good safety, tolerability, and HbA1C-lowering activity for TAK-875 and are consistent with the glucose-dependent mechanism of action. They support further evaluation of this novel compound in the treatment of T2DM.

• © 2011 MD Conference Express®