Rationale for the association of sulfonylurea and insulin.

Approximately 20-30% of patients with non-insulin-dependent diabetes mellitus (NIDDM) started on sulfonylureas fail to respond to treatment (primary failure); in the remaining patients, secondary failure to sulfonylurea therapy occurs at a rate of 5-10% per year. On the other hand, in insulin-treated NIDDM patients a progressive increase in insulin requirement can occur without significant improvement in glucose control. In these patients the combination of oral agents with insulin therapy may be useful. The rationale behind this therapeutic approach resides in the synergistic action of the two agents on specific mechanisms responsible for glucose intolerance and hyperglycemia. Long-acting insulin, administered as a single dose at supper or bedtime, should restrain excessive overnight hepatic glucose production, thus allowing a significant reduction in fasting glucose concentrations. A lower ambient glucose level should favor the stimulatory effect of sulfonylureas on insulin secretion. Sulfonylurea treatment should increase the portal inflow of secreted insulin with a resultant increase in insulin levels draining into liver, thus reducing postprandial hepatic glucose output. Moreover, sulfonylureas might improve insulin action on its target tissue (i.e., muscle), thus increasing overall insulin-mediated glucose metabolism. The reduction in prevailing plasma glucose levels will reduce the toxic effect of hyperglycemia on the beta-cell and on insulin-sensitive tissues. On this basis, NIDDM patients with secondary failure of monotherapy may benefit from combined therapy. Nevertheless, the effects of combined therapy should be strictly monitored and intensive insulin therapy promptly started if poor control persists.