Intensive Diabetes Treatment and Cardiovascular Disease in Patients With Type 1 Diabetes.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med. 2005;353:2643-2653.

The Diabetes Complications and Control Trial (DCCT) clearly demonstrated that tight glycemic control can prevent or delay the development of diabetic microvascular complications. The relation between glycemic control and cardiovascular disease, however, is less clear. In the DCCT, fewer cardiovascular events were observed in the intensively treated group than in the control group, but this result was not statistically significant because of the relatively young age of the sample and the low base rate of cardiovascular events in this group. Accordingly, one of the aims of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a follow-up to the DCCT, was to examine the effect of tight glycemic control with intensive therapy on the long-term incidence of cardiovascular disease in people with type 1 diabetes.

The DCCT enrolled 1,441 patients with type 1 diabetes and followed them for a period of 6.5 years. Patients with cardiovascular disease, hypertension, and dyslipidemia were excluded from participation. Of these participants, 1,394 (97% of the original cohort) agreed to participate in the EDIC follow-up study, which was conducted from 1994-2005. During the DCCT study, participants were examined and had fasting lipid levels and serum creatinine measured annually. Electrocardiograms were also obtained annually and interpreted by readers who were blind to participant treatment assignments. A1C was assessed on a quarterly basis. In the EDIC study, the DCCT methods were used, but A1C was measured annually, and lipid parameters and renal function were assessed every other year.

In the DCCT, the intensive therapy group self-administered 3 or more daily insulin injections or used an insulin pump. Dose adjustments were made based on at least 4 daily self-monitored glucose measurements. Target A1C was 6.05%, with daily glucose levels ranging from 70 mg/dL to 120 mg/dL. Participants in the conventional group had no glucose goals; instead, they aimed only to prevent symptoms of hyperglycemia and hypoglycemia. Participants in this condition self-administered 1 or 2 daily injections of insulin. At the end of the DCCT, participants in the intensive therapy group had an A1C that was nearly 2% lower than the conventional group (7.4% vs 9.1%, respectively). Following the conclusion of the DCCT, all participants were given the option of intensive therapy, and over time, no significant difference in A1C remained. In this study, the effect of intensive treatment in the DCCT on future cardiovascular events was tested. The primary study endpoint was length of time until any of the following cardiovascular events occurred: nonfatal myocardial infarction (MI) or stroke; death judged to be due to cardiovascular disease; subclinical MI; angina confirmed by ischemic changes on exercise tolerance testing or by clinically significant obstruction on coronary angiography; or need for revascularization with angioplasty or coronary bypass.

In the DCCT, there were no significant differences in baseline cardiovascular risk factors. By the end of the DCCT, the conventional group had significantly more prevalent microalbuminuria, a finding that was observed at the end of the EDIC study. A total of 144 cardiovascular events occurred in 83 patients, with significantly more patients in the conventionally treated group experiencing events compared with their counterparts in the intensively treated group (46 among 31 patients in the intensive group, and 98 among 52 patients in the intensive group), resulting in event rates of .38 per 100 patient years and .80 per 100 patient years, respectively (P<.007). Furthermore, intensive treatment was associated with a 42% reduction in first cardiovascular event compared with conventional treatment, and the risk of first nonfatal MI or cardiovascular death was reduced by 57% in the intensive group compared with the conventional group (P<.02). Reduced A1C during intensive treatment in the DCCT was responsible for a majority of the treatment effect on cardiovascular risk.

This study demonstrated that intensive insulin treatment for a period of 6.5 years was associated with a decreased risk of cardiovascular disease in a long-term follow-up study. These findings reinforce the results of the DCCT, which suggested that intensive insulin therapy should be initiated as early as possible in type 1 diabetes to reduce the risk of diabetic complications.