Effects of a New Oral Hypoglycaemic Agent (CS-045) on Metabolic Abnormalities and Insulin Resistance in Type 2 Diabetes

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Abstract
The effects of a thiazolidinedione antidiabetic agent (CS‐045) on diabetic metabolic abnormalities were studied in a double‐blind clinical trial. Fourteen patients with Type 2 diabetes were selected according to study criteria. Eight were treated with oral CS‐045 at 400 mg daily, and six were given placebo. A multi‐step, hyperinsulinaemic, euglycaemic clamp study, with simultaneous plasma free fatty acid study, and glucagon tolerance test were performed before and after administration of drug. Following 3 months of treatment with CS‐045, there were significant decreases in the mean levels of fasting plasma glucose (from 9.18 ± 0.95 to 7.78 ± 0.44 mmol l−1), postprandial plasma glucose (from 11.8 ± 1.23 to 10.36 ± 1.06 mmol l−1), and haemoglobin A1c (from 9.3 ± 0.4 to 6.8 ± 0.4%). Insulin sensitivity also improved (1st step: from 3.12 ± 0.33 to 4.70 ± 0.47 mg kg−1 min−1 (p < 0.01); 2nd step: from 5.61 ± 0.63 to 7.54 ± 0.58 mg kg−1 min−1 (p< 0.01); 3rd step: from 9.21 ± 0.67 to 11.10 ± 0.87 mg kg−1 min−1). The fasting free fatty acid level decreased significantly from 0.28 ± 0.04 to 0.22 ± 0.02 g l−1. The residual free fatty acid level (%) under insulin infusion clamp conditions decreased significantly from 63.7 ± 9.7 to 45.0 ± 9.2%. CS‐045 treatment was associated with decrease in total cholesterol, total triglycerides, and increase in HDL cholesterol. Basal C‐peptide immunoreactivity level decreased, but there was no change in the peak C‐peptide immunoreactivity value. None of these changes was observed in the placebo group. CS‐045 improved hyperglycaemia as well as insulin resistance. CS‐045 appears to have a different mode of hypoglycaemic action from that of the sulphonylureas.