RR 76%







Abbreviations: DDCT, Diabetes Control and Complications Trial; RR, risk reduction.

Abbreviations: DDCT, Diabetes Control and Complications Trial; RR, risk reduction.

4 years of follow-up (26). After the initial study was completed the patients in the control group were offered intensive therapy and all patients now received care from their own physicians. Retinopathy and nephropathy were assessed based on fundus photographs and urine specimens, respectively. The median HbA1c, which was on average 9.1% and 7.2% in the control and intensive therapy groups in the DCCT narrowed during this follow-up. The median during the 4 years was 8.2% in the control group and 7.9% in the intensive therapy group. Despite this worsening in the glycemic control in the intensive treatment group the proportion of patients having worsening of retinopathy, including proliferative changes as well as macula edema, and the need for laser treatment was less. There was also a significantly lower increase in urinary albumin excretion in the intensive treatment group. Therefore, in contrast to the DCCT, where the benefits of intensive therapy were not evident until 3 or 4 years of treatment, in the EDIC the benefits persisted despite an increase in the HbA1c. Another interesting finding of the DCCT was that for primary prevention of the complications intensive therapy should be started within the first 5 years of the onset of the disease.

In another study Ohkubo and colleagues from Kumamoto, Japan also demonstrated the benefits of intensive insulin therapy in a group of thin type 2 patients (27). A total of 110 patients with type 2 diabetes were randomized to intensive treatment with multiple insulin injections (MIT) or conventional insulin therapy (CIT). The MIT consisted of premeal rapid acting insulin and intermediate insulin at bedtime and goals of fasting glucose of less than 140mg/dL and postprandial levels of 200mg/dL or less. In addition the HbA1c goal was 7% or less. The CIT group was treated with one or two injections of intermediate insulin and was to try and keep the fasting glucose close to less than 140 mg/dL. There was a primary prevention and secondary prevention group based on the presence of diabetic retinopathy and urinary albumin excretion. After 6 years the mean HbA1c was 7.1% in the intensive group and 9.4% in the control group. In the primary prevention cohort there was a 7.7% development of retinopathy in MIT group after 6 years compared with 32% in the CIT group. In addition in the secondary prevention cohort, in the MIT group, 19.2% had progression of retinopathy compared to 44% in the CIT group. Similar reductions in both the primary as well as secondary cohorts were found for nephropathy and neuropathy. Overall the investigators stated that from this study the glycemic threshold to prevent the onset and progression of diabetic microangiopathy was an HbA1c <6.5%, fasting blood glucose < 110mg/dL and a 2h postprandial blood glucose of < 180 mg/dL. Over the entire study period 6 patients in the MIT group and 4 patients in the CIT group had one or more, mild hypoglycemic reactions with no coma or seizures or need for assistance from another person.

After the publication of these two studies there was still an ongoing discussion on the applicability of the results to the larger group of patients with type 2 diabetes mellitus. In part the issue has to do with the complications as they develop in type 2 diabetes mellitus. As noted earlier most patients with this form of diabetes die from cardiovascular disease and to date we have no data like the DCCT to support the role of glucose control alone in reducing the risk. On the other hand the long-term microvascular complications are identical in both type 1 and type 2 diabetes. Overall the prevalence of these complications is similar and the major difference is that at the time of diagnosis more patients with type2 diabetes have evidence of complications. This is due to the fact that they tend to have the disease for at least 5 to 7 years before clinical diagnosis. The higher prevalence of macrovascular disease is probably due in part to the older age of the patients as well the associated risk factors like hypertension, dyslipidemia, obesity, and the changes in fibrinolysis and coagulation, that are part of the insulin resistance syndrome.

However, we are now able to answer this issue of microvascular complications with another landmark study led by Robert Turner from Oxford, which studied patients with type 2 diabetes. The UKPDS is the largest type 2 diabetes study ever done (28). This clinical study was designed to assess the effects of intensive treatment with four pharmacological monotherapies versus a diet only control group, on cardiovascular and microvascular complications of type 2 diabetes (Table 2). In the study 3867 patients with newly diagnosed type 2 diabetes were randomly assigned to two treatment groups: one group, the intensive treatment policy took one of three oral sulfonylurea drugs (cholorpropamide, glibenclamide, or glipizide) or insulin; and a second group, whose only initial treatment was dietary

TABLE 2 U.K. Prospective Diabetes Study. Risk Reduction for Diabetes-Related Endpoints During Intensive Therapy with Sulfonylureas and Insulin
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