Sulfonylureas: Effects in Vivo and in Vitro

To evaluate the effects of therapy on the vascular complications of adult diabetes, the University Group Diabetes Program (UGDP) carried out a prospective double-blind study in 12 centers of 823 newly diagnosed adult-type diabetics, who were randomly assigned to different treatment groups. Over a period of 8 years the overall incidence of nonfatal complications were the same for all groups, irrespective of the therapy—oral placebo, oral sulfonylureas, a small fixed dose of insulin, or a variable dose of insulin sufficient to normalize the blood glucose. Only the variable-dose insulin group maintained nearly normal blood glucose concentrations. In contrast to this, the sulfonylurea-treated group had a significantly increased incidence of fatal cardiovascular events. In vitro, sulfonylureas inhibited the important regulatory enzyme, cyclic AMP phosphodiesterase, in the pancreatic beta cell and in all other tissues tested, including the heart and platelets. In addition to inhibiting phosphodiesterase, sulfonylureas affected other processes in the platelet and in heart muscle. These studies confirm, in vitro, the direct multiple effects of sulfonylureas in many tissue sites outside of the beta cell.