Results Of Studies Of Glycemic Control And Microvascular Disease

The ultimate proof that glycemic control is worthwhile has to come from long-term randomized-controlled trials (RCT). We are fortunate that after many decades of observational or retrospective studies, we now have one systematic review and three long-term RCTs showing the benefits of glucose control in both type 1 and type 2 diabetes. There is one major type 1 study and two type 2 studies that will be briefly reviewed. The systematic review by Groeneveld et al. (21) looked at 16 small RCTs in type 1 diabetes, that had a follow-up of 8 to 60 months. The overall conclusion of these studies was that glycemic control was important in reducing the microvascular complications.

The Diabetes Control and Complications Trial (DCCT) was a landmark trial that was designed to finally answer the glycemic control and complications question (22). This was a large multicenter trial with enough statistical power to answer the issue conclusively. The study involved 1441 patients with type 1 diabetes who were randomized to either intensive glucose control or conventional treatment. The intensive therapy regimen was designed to achieve blood glucose levels close to the normal range as possible with three or more daily injections of insulin or an insulin pump. The conventional therapy consisted of one or two insulin injections. The cohorts were studied to answer two different questions that were related to the control and complications debate. One of the study questions was, whether intensive therapy would prevent the development of diabetic retinopathy (primary prevention) and the other whether intensive therapy would affect the progression of early diabetic retinopathy (secondary prevention). While retinopathy was the main outcome, renal, neurologic, cardiovascular, and neuropsychological outcomes and adverse effects of the two treatments were also studied (Table 1). There were 726 patients in the primary arm and 715 in the secondary prevention arm and the mean follow-up was 6.5 years. In the primary prevention cohort the intensive treatment reduced the adjusted mean risk for developing retinopathy by 76% as compared to the conventional therapy group. In the secondary prevention cohort, intensive therapy slowed retinopathy progression by 54% and also reduced the development of proliferative or severe nonproliferative retinopathy by 47%. Furthermore there was a reduction in microalbuminuria (> 40mg/24h) by 39% and of albuminuria (> 300 mg/24h) by 54%. Clinical neuropathy was also reduced 60%. However, it was noted that patients on the intensive treatment did have a three times greater increase in the number of severe hypoglycemic episodes. The hypoglycemia did not result in death or stroke and the mortality did not differ in the two treatment cohorts. Despite the hypoglycemia difference there was no clinically important changes in neuropsychological function between the groups. The patients appeared to adjust well to the demands of the intensive therapy program. Weight gain was a problem in the intensively treated group with a mean gain of 4.6 kg at 5 years. There was no increase in the ketoacidosis rates in either group. This benefit was achieved in the intensive treatment group with a mean blood glucose of 155 mg/dL and HbA1c of ~7.2% with a normal average glucose being ~110 mg/dL and the HbAic < 6.05%.

Another important outcome of the DCCT was the finding that there is no glycemic threshold for the development of long-term complications. In a retrospective Joslin clinic study (23), it has been suggested that a threshold exists for microalbuminuria and that it increases substantially around an HbA1c of ~8%. The prospective Stockholm Study (24), also showed that the risk for microalbuminuria increased substantially once the HbA1c was more than 8.9% to 9%. However, the data from the DCCT refute this idea and indicate that for every 10% reduction in HbA1c there is a 39% reduction in the risk of retinopathy progression throughout the HbA1c range. The relationship also holds for developing microalbuminuria as well as neuropathy, and is continuous but nonlinear. However, the magnitude of the risk reduction (RR) is greater at higher HbA1c levels and at the same time as control improves the risk of hypoglycemia increases with the lower HbA1c levels (25).

In a follow-up study of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study found that the benefits of intensive treatment, persists over the

TABLE 1 Risk Reduction (RR) in Microvascular Complications in the Diabetes Control and Complications Trial
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