Is there sustained renal benefit from previous intensive insulin therapy in people with type 1 diabetes?

Writing Team for the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type I diabetes mellitus on development and progression of diabetic nephropathy. JAMA 2003;290:2159-67.

Background: The benefits of intensive insulin therapy for type 1 diabetes mellitus to prevent microvascular complications have been established.1 However, it is unknown whether these benefits persist when insulin therapy becomes less intensive and begins to approximate that of conventional treatment.

Design: In a randomized controlled trial, 1441 patients with type 1 diabetes were randomly assigned to receive either intensive insulin therapy to achieve normal glycosylated hemoglobin (HbA_1C) levels or conventional therapy (1 or 2 daily injections of insulin) without specific goals for glycemic control. Patients were eligible if they had no advanced diabetes complications and normal renal function. Following completion of the trial, a follow-up study of the cohort was begun in which patients who had been receiving the intensive therapy were encouraged to continue it and those in the conventional treatment arm were encouraged to switch to intensive treatment. Of the original 1441 subjects, 1375 agreed to participate in the follow-up study. No treatment intervention was involved, and participants were assessed for renal outcomes over 7–8 years.

Results: After completion of the initial randomized controlled trial, patients in the intensive therapy arm had significantly lower HbA_1C levels and a lower incidence of microalbuminuria than those receiving conventional treatment did (Table 1). The glomerular filtration rate and creatinine clearance were identical in both groups.

The difference in HbA_1C levels between the 2 groups began to narrow during the follow-up study, although the modest difference remained statistically significant. More impressive was that the patients in the intensive treatment arm had significantly lower incidences of microalbuminuria, clinical albuminuria, hypertension and creatinine levels of more than 177 mmol/L (Table 1).

Commentary: The results of this study suggest that the benefits of strict glycemic control on renal function are long-lasting. A similar observation has been made regarding diabetic retinopathy.2 These results lend support to the hypothesis that diabetic complications are invoked by a “metabolic memory” effect (one or more processes set in motion by previous periods of poor metabolic or glucose control and that culminate in tissue damage). One example is the formation of advanced glycation end products, which can have extremely long half-lives.3 Alternatively, it is possible that excellent glycemic control merely delays the development of diabetic complications.

That the investigators used the surrogate end point of albuminuria rather than a clinical end point is not a crucial concern, because albuminuria is known to be strongly predictive of end-stage renal disease.4 Also, although the difference in mean HbA_1C levels between the 2 groups was statistically significant over the course of the study, it was very small and unlikely to account for the results. Finally, because the study population had been carefully screened to capture individuals with high motivation, it is not representative of the entire population with type 1 diabetes.

Practice implications: Provided there are no contraindications to intensive therapy (poor compliance, advanced diabetic complications or hypoglycemic unawareness) all patients with type 1 diabetes should be considered for intensive insulin therapy. Physicians and diabetic patients should be gratified to learn from this study that, even if a patient's intensive therapy must be abandoned one day, it will likely continue to confer benefits long afterward.

Steven L. Shumak Division of General Internal Medicine, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ont.