OBJECTIVE: To assess the effective longevity of combination double oral therapy before insulin or triple oral therapy is needed in patients with type 2 diabetes mellitus. METHODS: We retrospectively reviewed the outcomes of our first 100 patients with type 2 diabetes who were successfully transferred from twice-daily mixed NPH and regular insulin to a combination of metformin and a sulfonylurea. RESULTS: Of the 100 study patients, 40 had well-controlled plasma glucose (glycosylated hemoglobin levels <8.0%) with use of metformin and a sulfonylurea. Good glycemic control was achieved with triple oral therapy (a sulfonylurea, metformin, and a thiazolidinedione) in 14 patients and with a sulfonylurea, metformin, and evening-administered mixed NPH and regular insulin in 7. In addition, plasma glucose was effectively controlled with twice-daily mixed NPH and regular insulin in conjunction with metformin or a thiazolidinedione (or both) in 22 patients and with twice-daily mixed NPH and regular insulin alone in 17. The mean time (+/- standard error) from primary failure of sulfonylurea monotherapy to the time when a third hypoglycemic agent was needed was 7.9 +/- 1.1 years (95% confidence interval, 5.7 to 10.1). CONCLUSION: When oral monotherapy fails (that is, glycosylated hemoglobin values exceed 8.0%) in patients with type 2 diabetes, combination therapy with a sulfonylurea and metformin is potentially effective in maintaining glycemic control and avoiding the addition of insulin or a thiazolidinedione for a mean duration of 7.9 years.