Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

OBJECTIVE—To evaluate the safety and efficacy of treatment with insulin alone, insulin plus metformin, or insulin plus troglitazone in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 88 type 2 diabetic subjects using insulin monotherapy (baseline HbAlc 8.7%) were randomly assigned to insulin alone (n = 31), insulin plus metformin (n = 27), or insulin plus troglitazone (n = 30) for 4 months. The insulin dose was increased only in the insulin group. Metformin was titrated to a maximum dose of 2,000 mg and troglitazone to 600 mg. RESULTS—HbAlc levels decreased in all groups, the lowest level occurring in the insulin plus troglitazone group (insulin alone to 7.0%, insulin plus metformin to 7.1%, and insulin plus troglitazone to 6.4%, P < 0.0001). The dose of insulin increased by 55 units/day in the insulin alone group (P < 0.0001) and decreased by 1.4 units/day in the insulin plus metformin group and 12.8 units/day in the insulin plus troglitazone group (insulin plus metformin versus insulin plus troglitazone, P = 0.004). Body weight increased by 0.5 kg in the insulin plus metformin group, whereas the other two groups gained 4.4 kg (P < 0.0001 vs. baseline). Triglyceride and VLDL triglyceride levels significantly improved only in the insulin plus troglitazone group. Subjects taking metformin experienced significantly more gastrointestinal side effects and less hypoglycemia. CONCLUSIONS—Aggressive insulin therapy significantly improved glycemic control in type 2 diabetic subjects to levels comparable with those achieved by adding metformin to insulin therapy. Troglitazone was the most effective in lowering HbAlc, total daily insulin dose, and triglyceride levels. However, treatment with insulin plus metformin was advantageous in avoiding weight gain and hypoglycemia.

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OBJECTIVE -To evaluate the safety and effectiveness of triple therapy using insulin, metformin, and a thiazolidinedione following a course of dual therapy using insulin and metformin or insulin and a thiazolidinedione in type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty-eight type 2 diabetic subjects using insulin monotherapy (baseline HbA lc level 8.5%) who had been randomly assigned to insulin (INS) and metformin (MET) (INS ϩ MET, n ϭ 14) or INS and the thiazolidinedione troglitazone (TGZ) (INS ϩ TGZ, n ϭ 14) (dual therapy) for 4 months were given INS, MET, and TGZ (triple therapy: INS ϩ MET, add TGZ; or INS ϩ TGZ, add MET) for another 4 months. The INS dose was not increased. CONCLUSIONS -Triple therapy using INS, MET, and TGZ resulted in lower HbA lc levels and total daily insulin dose than during dual therapy. The use of triple therapy resulted in 100% of subjects achieving an HbA lc Ͻ7.0%, while decreasing the dose of INS. Weight gain was avoided when MET therapy preceded the addition of TGZ therapy. The addition of TGZ resulted in the greatest reductions in HbA lc levels and insulin dose. Triple therapy using INS, MET, and a thiazolidinedione (such as TGZ) can be a safe and effective treatment in type 2 diabetes. RESULTS Diabetes Care 27:1577-1583, 2004R esearch in the previous decade has conclusively demonstrated the benefit of improved blood glucose control in the prevention of diabetes complications (1,2). Efforts to advance our ability to achieve near normal glycemic control have resulted in an array of pharmaceutical interventions that not only lower blood glucose levels, but also have beneficial effects on comorbid conditions such as hypertension and hyperlipidemia. In the treatment of type 2 diabetes, health care providers have the option of using insulin (INS), sulfonylureas, thiazolidinediones, biguanides such as metformin (MET), and other oral agents to achieve treatment goals (3,4).MET has been shown to lower blood glucose levels by sensitizing the liver to the effects of insulin, thus suppressing hepatic glucose output. It also has mild effects on promoting glucose utilization (5,6). Thiazolidinediones, like troglitazone (TGZ), improve insulin sensitivity by enhancing insulin-mediated glucose disposal, resulting in reduced plasma insulin concentrations. Thiazolidinediones may also have modest effects on lowering hepatic glucose production (7-9). In addition, studies have shown that thiazolidinediones enhance ␤-cell responsiveness and may prolong ␤-cell survival (10,11). Several randomized, placebocontrolled studies have demonstrated the effectiveness of dual therapy using oral sulfonylureas or INS in combination with either MET or TGZ in lowering blood glucose levels in type 2 diabetic subjects (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Studies of the combined use of MET plus a thiazolidinedione have also shown improved glycemic control when compared with MET alone (23-26). Thiazolidinediones added to treatment with sulfonylureas and MET resulted in significant improvements in HbA 1c leve...