All of the controversy about the impact of glucose control and vascular complications was dramatically answered with the publication of the Diabetes Control and Complications Trial (DCCT) in 1993. The trial showed definitively that stringent blood glucose control could postpone, prevent, or slow the progression of retinal, renal, and neurological complications in individuals with type 1 diabetes. In patients treated with “intensive therapy”—that is, therapy aimed at maintaining blood glucose levels as close to normal as possible—the risk of developing diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy were dramatically reduced compared to conventionally treated patients (figure 1). Moreover, the risk was continuous across the range of A1c – the higher the A1c, the greater the risk (figure 2). Other benefits of intensive diabetes management include improved lipid profiles, reduced risk factors for macrovascular disease, and better maternal and fetal health.
Figure 1a. [A] Cumulative incidence and risk reduction of retinopathy (three-step progression) in the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial (DCCT), and overall cumulative incidence and risk reduction for the need for laser photocoagulation.
![[A] Cumulative incidence and risk reduction of retinopathy (three-step progression) in the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial (DCCT), and overall cumulative incidence and risk reduction for the need for laser photocoagulation.](./figures/figure1a.png)
Figure 1b. [B] Cumulative incidence and risk reduction of microalbuminuria, nephropathy, and clinical neuropathy in the DCCT. Adapted from: The Diabetes Control and Complications Trial Research Group: Progression Of Retinopathy With Intensive Versus Conventional Treatment In The Diabetes Control And Complications Trial. Ophthalmology 1995; 102:647-661. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney International 1995;47:1703-1720. and The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine 1995;122:561-568.
![[B] Cumulative incidence and risk reduction of microalbuminuria, nephropathy, and clinical neuropathy in the DCCT. Adapted from: The Diabetes Control and Complications Trial Research Group: Progression Of Retinopathy With Intensive Versus Conventional Treatment In The Diabetes Control And Complications Trial. Ophthalmology 1995; 102:647-661. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney International 1995;47:1703-1720. and The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine 1995;122:561-568.](./figures/figure1b.png)
Figure 2. Relationship between microvascular complications and A1c in type 1 diabetes. Stylized relative risks for development of various complications as a function of mean A1c during follow-up in the DCCT. For the purposes of illustration, the relative risk of various complications is set to 1 at A1c of 6%. The lines depict a stylized relationship for risk of: (A) sustained progression of retinopathy (), (B) progression to clinical nephropathy (urinary albumin excretion > 300 mg/24 hrs) (), (C) progression to severe non-proliferative or proliferative retinopathy (), (D) progression to clinical neuropathy (), and (E) progression to microalbuminuria (urinary albumin excretion > 40 mg/24 hrs) (). Adapted from: Skyler JS: Diabetic Complications: Glucose Control Is Important. Endocrinology and Metabolism Clinics of North America 1996; 25:243-254.
Since the DCCT was completed in 1993, subjects have been followed in an observational study called Epidemiology of Diabetes Interventions and Complications (EDIC). It was soon observed that the impact of this improved diabetes therapy for an average of 6.5 years (maintaining an A1c of approximately 7% with multiple injections or CSII compared to once or twice daily insulin and an A1c of approximately 9%) had long-lasting effects. Termed “metabolic memory”, there continued to be improvements in microvascular complications eight years after the DCCT ended (figure 3). Despite the fact that A1c levels remained about 8% for both groups after the DCCT, there was reduced risk of progression of retinopathy and nephropathy. Moreover, 11 years after the conclusion of the formal DCCT study, with as long as 20 years of total follow-up, there was demonstrated a risk reduction of 57% for nonfatal myocardial infarction, stroke, or death and a risk reduction of 42% for first of any of the predefined cardiovascular disease outcomes (figure 4). That it took this long for sufficient cardiovascular events to accumulate is not surprising since the mean age of DCCT participants at study entry was only 27 years. The conclusions of this are profound since this was the first study to report a reduction of macrovascular disease with glucose control. Furthermore, these data confirmed the need to control blood glucose as meticulously as possible early in the course of the disease.
Figure 3. Cumulative incidence over 8 years of further progression of retinopathy in the former DCCT conventional-therapy and intensive-therapy groups.. Adapted from: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287: 2563-2569.
Figure 4a. [A] Cumulative incidence of first occurrence of nonfatal myocardial infarction, stroke, or death from cardiovascular disease in the former DCCT conventional-therapy and intensive-therapy groups.
![[A] Cumulative incidence of first occurrence of nonfatal myocardial infarction, stroke, or death from cardiovascular disease in the former DCCT conventional-therapy and intensive-therapy groups.](./figures/figure4a.png)
Figure 4b. [B] Cumulative incidence of the first of any of the predefined cardiovascular disease outcomes in the former DCCT conventional-therapy and intensive-therapy groups. Adapted from: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643-2653.
![[B] Cumulative incidence of the first of any of the predefined cardiovascular disease outcomes in the former DCCT conventional-therapy and intensive-therapy groups. Adapted from: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643-2653.](./figures/figure4b.png)