The Diabetes Control and Complications Trial (DCCT), published in the early 1990s, is still relevant today because it relates the importance of a patient's systemic health to eye health and confirms that controlling blood sugar is critical to decreasing disease progression, particularly eye disease.1 Before the DCCT, animal studies and observational studies linked elevations in blood glucose to severity of diabetic disease complications.2-7 It was the DCCT, however, that strove to validate the glucose hypothesis by looking directly at an intervention to control and lower blood sugar and ask if it reduces the morbidity associated with diabetes. Fortunately for ophthalmologists, eye disease, because it is so readily classifiable, was the primary endpoint in the DCCT as investigators used ophthalmic variables to monitor treatment efficacy.

STUDY DESIGN AND ELIGIBILITY
This study involved individuals who had type 1 diabetes. A total of 1,441 relatively young patients without hypertension, significant kidney disease, or hypercholesterolemia were about equally divided between 2 cohorts. Within each cohort, subjects were randomly assigned to intensive or conventional management of their glycemia.

The primary cohort joined the study with no retinopathy, and the question they served to address was: By instituting tight control, could you decrease the development of diabetic eye disease? The secondary cohort joined the study with mild or moderate nonproliferative disease, and the question they helped answer was: By instituting tight control, could you slow the rate at which the eye disease would progress?

CONVENTIONAL VS INTENSIVE THERAPY
In the mid-1980s, the goal of conventional therapy was to avoid symptoms of hyperglycemia or hypoglycemia. That meant using injections of insulin once or twice a day; daily self-monitoring of control, blood or urine testing; quarterly feedback of control, using glycosylated hemoglobin (HbA1c) levels; general information about the importance of diet and exercise; and an office visit four times a year. The annual price tag for that type of regimen in late- 1980s dollars was about $1700.

In contrast, the goal of intensive treatment in the DCCT was to keep blood glucose values as close to normal as possible, 24/7. To do that, individuals could self-select use of multiple doses of insulin (MDI) per day, or they could use an external insulin pump. They were required to monitor their glycemia levels by finger-stick blood determinations a minimum of four times a day. They received monthly feedback of their HbA1c levels; they were supported monthly with calls from nutritionists and nurse practitioners; and they had monthly clinic visits. The annual cost to deliver that type of care was two to three times more than conventional therapy: $4000 (MDI), $5800 (pump).

FOLLOW-UP
Seven-field photographs were taken annually and read at a masked reading center. Three steps of progression on the retinopathy scale (1 to 25 steps) was considered progression (Figure 1).

Figure 2 shows how well the intensive treatment regimen worked to control blood sugar levels over 24 hours. Even though the intensive group was aiming for preprandial blood glucose concentrations between 70 and 120 mg/dL, they do not quite achieve it, but they are much lower and closer to normoglycemia than the value of 231 ±55 mg/dL obtained in the conventional group.

Figure 3 shows the HbA1c profiles over the 10 years of the study. On average, HbA1c levels were 7% for the intensive therapy group and 9% for the conventional therapy group with no overlap between the groups. So the intensive regimen used in the DCCT was effective at decreasing glycemia.

Figure 4 shows the primary cohort and the proportion of people who developed a sustained 3 step progression in eye disease, meaning these eyes enrolled without any retinopathy and they progressed to mild non-proliferative disease. Comparing conventional therapy to intensive therapy, there was a five-fold reduction in progression of diabetic eye disease by intensive management. This is very clinically relevant and obviously statistically significant. You can prevent development of mild disease with intensive control. In the secondary cohort (Figure 5), by 10 years, there was a three-fold reduction in progression of diabetic eye disease by intensive management.

Figure 6 shows another important endpoint: the need for photocoagulation. Again, there was a three-fold reduction of rates at which these patients required laser treatment.

ADVERSE EVENTS
With tight glycemic control, the risk of a significant hypoglycemic event increases, and there was a three-fold increase in the incidence of hypoglycemia in the intensive therapy group. Another adverse effect with intensive therapy was an increase in body weight. With tight control, patients are less prone to lose glucose in their urine, rather they are forced to metabolize it, so there is greater potential for weight increase. The intensively managed individuals gained more weight gain, and that can be a real problem among young type 1 diabetics, particularly women.

CONCLUSIONS FROM THE DCCT
There is undeniable evidence from the DCCT that tight glycemic control reduces the morbidity associated with diabetes. A general recommendation to every patient with diabetes—as we extrapolate DCCT data to individuals with type 2 diabetes, as well—is to maintain the best control possible, safely within their sensitivity levels to detect impending hypoglycemia, to try to decrease long-term organ damage. In the interest of time, we did not review the DCCT data in depth, which would have emphasized that the benefits get wider and more substantial over time. The DCCT provided positive data monitoring participants over one decade. Imagine how these graphs might continue to separate if participants were monitored for a second or third decade of tight control.

Additionally, benefits were seen over a range of ophthalmic endpoints and over the gamut of retinopathy. What's more, investigators looked at kidney disease, cardiovascular disease, and cognitive functioning, all of which showed benefits with tight control.

POST-TRIAL OBSERVATIONAL STUDY
At the conclusion of the DCCT, most patients agreed to further follow-up within an observational study called the Epidemiology of Diabetes Interventions and Complications (EDIC) study.8 At entry into the EDIC study, all patients were advised to aim for tight control, but they no longer received assistance through the study.

The patients originally assigned to conventional management tried to follow the instructions, and their HbA1c levels fell to 8% over the 4-year period. Lacking their accustomed support, the patients who had been in the intensive management group in the DCCT saw their HbA1c levels drift upward. So 4 years after the DCCT, HbA1c levels for both groups were equivalent at 8% in the EDIC study. Despite that, patients who had been in the intensively managed group of the DCCT continued to show a reduction in disease progression, even after they “slacked off” to a degree. This shows us that a big investment up front still pays dividends in the later years, even if control becomes less stringent. ■

1. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
2. Engerman R, Bloodworth JM Jr, Nelson S. Relationship of microvascular disease in diabetes to metabolic control. Diabetes. 1977;26:760-769.
3. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control. Diabetes. 1987;36:808-812.
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8. EDIC Research Group. Retinopathy and nephropathy in patients with Type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000; 342:381-389.