Preclinical and clinical studies on safety and tolerability of repaglinide.

Repaglinide, an insulinotropic benzoic acid derivative, has been tested extensively in the preclinical and clinical setting for safety and tolerability. In preclinical safety trials, no clinically relevant laboratory or histopathological changes were found and repaglinide was not found to be genotoxic, immunogenic, teratogenic or tumorigenic at levels 50 times greater than the exposure in humans. In an ascending-dose tolerability study in Type 2 diabetic patients, no clinically relevant changes in liver enzymes or ECG occurred during the trial. A total of five active-controlled, long-term trials of identical design have been carried out (with 12 months of maintenance on a fixed, pretitrated dose), including 1228 patients on repaglinide and 597 on sulphonylureas, 417 of whom were on glibenclamide. The most common adverse event in the phase II studies was hypoglycaemia. The frequency of hypoglycaemia was identical for repaglinide and sulphonylureas; however, fewer nocturnal hypoglycaemic events were observed with repaglinide and no increase in the frequency of hypoglycaemic events occurred in elderly patients (> 65 years) compared with younger patients. Severe reactions (assistance required) were approximately twice as frequent in the comparator group. During these studies, two serious hypoglycaemic reactions were reported (coma, seizure or hospitalization), both occurring in patients on glibenclamide. The frequency of serious adverse events and serious cardiovascular events was comparable between repaglinide and sulphonylureas.