Randomized,Double-Blind,Dose-Ranging Study of TAK-875, a Novel GPR40 Agonist,in Japanese Patients With Inadequately Controlled Type 2 Diabetes

OBJECTIVE

Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise.

RESEARCH DESIGN AND METHODS

This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose-ranging evaluation of TAK-875 (6.25–200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control.

RESULTS

A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; −0.54, −0.67, −0.88, −1.27, −1.29, and −1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and −1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group.

CONCLUSIONS

TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia.Free fatty acids (FFAs) are not only an important nutritional source—they also act as signaling molecules for a number of cellular processes including insulin secretion (1). There is accumulating evidence that long-chain fatty acids amplify glucose-stimulated insulin secretion from pancreatic β cells, and this effect is mediated through activation of the G-protein–coupled receptor (GPR)40, also known as free fatty acid receptor 1 (2). GPR40, as a potential target for the treatment of diabetes, is receiving much attention, since it is highly expressed in pancreatic β cells (3–5).TAK-875 is an orally bioavailable GPR40 agonist that was chosen as a lead compound for clinical evaluation (6). An initial clinical study of single oral doses of 25–800 mg TAK-875 in healthy volunteers in the U.S. showed no glucose-lowering effects or dose-dependent safety/tolerability changes (7). The authors concluded that these pharmacological properties support the notion that TAK-875, if effective in patients with type 2 diabetes, would have a low risk of provoking hypoglycemia. Recently, results were published from an exploratory randomized, double-blind study in 65 Japanese patients with type 2 diabetes who were treated with placebo or 100 or 400 mg TAK-875 once daily for 2 weeks (8). TAK-875 produced marked dose-dependent glucose-lowering effects and improvements in other indices of glycemic control. TAK-875 was well tolerated, and importantly, no hypoglycemia occurred.Based on the above, the current placebo-controlled study was designed to evaluate the glycemic effects of a range of dosages of TAK-875 (6.25–200 mg) administered once daily for 12 weeks in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. Glimepiride (1 mg) once daily was administered in an open-label fashion to one of the randomized groups as an active control.     

Stromal sarcoma with features of giant cell malignant fibrous histiocytoma

We report a case of primary giant cell malignant fibrous histiocytoma (GCMFH) of the breast. A 56-year-old Japanese woman presented with a firm mass in the right breast. Mammography and ultrasonography revealed a well-circumscribed and lobulated mass in the upper outer quadrant of the right breast, indicative of a benign breast tumor or mucinous carcinoma. Magnetic resonance imaging revealed a restricted breast tumor without intraductal spread. Computed tomography and bone scintigraphy found no sites of distant metastases. Fine needle aspiration biopsy showed several clusters of atypical cells associated with numerous multinucleated giant cells. Breast-conserving surgery with axillary lymph nodes dissection was performed. Histological examination showed primary GCMFH of the breast. No metastases were identified in any of the 15 left axillary lymph nodes resected and surgical margins were free from tumor cells. The tumor was negative for both estrogen and progesterone receptor. Neither adjuvant chemoendocrine therapy nor postoperative radiotherapy was given, and the patient has remained disease free for 30 months postoperatively. To our knowledge, only 30 cases of primary MFH of the breast have been reported in the literature.     

Clinical studies on the complaints of survivors living more than 3 months after total gastrectomy

From 1973 to 1983, 802 patients with gastric cancer were operated on. Out of them, 292 (36.4%) received total gastrectomy. Reconstruction was performed mainly by the Billroth II procedure associated with the closure of the afferent loop according to Plenk's method. 90 patients living more than 3 months complained of the following: heartburn, 18 (20%); reflux, 12 (13.3%); retrosternal pain, 3 (3.3%); stenotic sensation, 23 (25.6%); diarrhea, 10 (11.1%); abdominal pain, 14 (15.6%); and dumping syndrome, 6 (6.7%). It seems to indicate that the quality of life after total gastrectomy is satisfactory.     

Quality of life of patients after esophagectomy for esophageal cancer

Quality of life of 79 patients who underwent esophagectomy for esophageal cancer and survived more than one year was evaluated by a questionnaire method. About 90% of patients had a good appetite, taking ordinary solid foods, and 69% were satisfied with the daily amount of foods. About 40% of patients complained of passage disturbance on swallowing, abdominal pain or diarrhea after meal. Fifty seven per cent of patients had frequent episodes of cough and sputum, and 20% were not able to go up the stairs to the third floor because of short breath. Thirty two per cent of patients with recurrent nerve paresis and even 5% without paresis had a trouble in daily conversation. These physical distresses were thought to be useful indicators for the doctor to evaluate the quality of life of patients. Additionally, about 30% of patients had a tendency of mental depression postoperatively. Fifty six per cent of patients who had worked before operation returned to work or were doing a lighter work than before. The psychological factor and social rehabilitation were suggested to be very important, when evaluated from the patient's side. Especially in case of aggressive surgery for esophageal cancer, postoperative quality of life of patients should be carefully considered from the viewpoints of both the patient and doctor.     

Prospective randomized controlled study of bestatin in gastric cancer surgery

The effectiveness of bestatin combined with mitomycin C and tegafur as an adjuvant to surgery for gastric cancer was investigated in a prospective randomized controlled study. All patients underwent curative gastrectomy during the period from November 1980 to April 1984. Five-year survival rate revealed no significant difference between groups with or without bestatin. The effectiveness of bestatin was suggested in postoperative peritoneal recurrence in cases with positive histological invasion into the veins of the stomach wall.     

Adenoma of the Nipple: Report of a case

We report a case of an adenoma of the nipple in a 33-year-old Japanese woman who presented with a 2-year history of itching, eczema, and discharge from the left nipple. Examination revealed a firm, well defined and erosive tumor measuring 10 x 11 mm that was sore, crusted, and indurated. There was a slight serosanguineous discharge from the tumor. Cytological material from the tumor obtained from the discharge and by fine needle aspiration (FNA) and scraping showed a papillary cell cluster thought to be a benign papilloma.We performed a tumor resection with preservation of the nipple. The histological diagnosis was adenoma of the nipple. The patient was left with a cosmetically well-preserved nipple. No recurrent tumor has been observed for two years after surgery.     

Phase II study on MCNU in patients with advanced or recurrent gastrointestinal cancer

A phase II study on MCNU (Methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside) was performed in 33 patients with advanced or recurrent gastrointestinal cancer under the cooperation of eight institutions in Hiroshima Prefecture. MCNU was given by means of intravenous drip infusion and the 33 cases were divided into three groups according to the method of administration; (A) 50mg/m2 every 1 or 2 weeks, (B) 70mg/m2 every 2 weeks or (C) 90mg/m2 every 6-8 weeks. Among 28 evaluable cases, 1 complete response (CR) and 1 partial response (PR) were observed and these two cases were gastric cancer patients. Platelet nadir occurred at the 3rd or fifth week after MCNU administration, but the leukocyte count was not so decreased. Subjective side effects were nausea, general fatigue and vomiting, but these were observed to be only mild.