A PILOT CLINICAL-TRIAL OF A NEW ORAL HYPOGLYCEMIC AGENT, CS-045, IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

CS-045, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-thiazolidinedione, lowers plasma glucose in several animal models of non-insulin dependent diabetes mellitus (NIDDM) presumably by increasing insulin sensitivity. Little adverse effect was found in a phase 1 study on healthy male subjects. In order to test its efficacy in lowering plasma glucose in NIDDM in man, a pilot multi-center clinical trial of CS-045 was carried out in 146 patients with NIDDM whose glycemic control was inadequate (FPG > 140 mg/dl) on diet and/or other oral hypoglycemic agents. CS-045 was given orally in a daily dose of 200 mg or 400 mg for 12 weeks in addition to the previous treatment. The mean fasting plasma glucose (FPG) and fructosamine began to decrease within 2 weeks and the mean HbA1c within 8 weeks. After 12 weeks, the FPG fell from 192 +/- 41 to 155 +/- 45 mg/dl (P < 0.01), fructosamine from 3.7 +/- 0.6 to 3.3 +/- 0.6 (P < 0.01), and HbA1c from 8.9 +/- 1.5% (P < 0.01). The drug was effective in 39% of patients in that FPG fell by more than 20% of the initial value. This rate of efficacy was the same when CS-045 was given alone or together with other oral hypoglycemic agents. The drug was more effective in a dosage of 400 mg than with 200 mg (the rate of efficacy 46% vs 25%) and more effective in obese patients than in lean patients (46% vs 25%). This is the first clinical study of CS-045. The data indicates that CS-045 has a dose-dependent hypoglycemic effect in NIDDM patients. It is more effective in obese patients suggesting an effect on improvement in insulin sensitivity.