Diabetes management: More than just cardiovascular risk?
Diabetes mellitus and its management have become the center of controversy in recent years. More emphasis is being placed on the potential for adverse cardiovascular outcomes with more aggressive glycemic control as well as on the potential for adverse cardiovascular events with newer antidiabetic therapies, and less on the importance of glycemic control, particularly early in the disease course.
Although it is important to take new data into consideration when managing diabetes, it appears that the results of recent clinical trials are being misinterpreted and incorrectly applied to the wrong patient populations, and in the process, the results of older landmark clinical trials are being neglected. Inadequate glycemic control not only plays a role in cardiovascular risk, it also remains the leading cause of blindness, kidney failure, and nontraumatic lower-limb amputations in the United States.1
Although we need to recognize the potential for adverse cardiovascular outcomes with diabetes and its management, we cannot lose sight of the big picture—ie, that inadequate glycemic control confers both microvascular and macrovascular risk, and that the available data show that restoring near-euglycemia in patients with diabetes considerably reduces the risk of microvascular and macrovascular complications.
Several recently published clinical trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD),2 the Veterans Affairs Diabetes Trial (VADT),3 and the Action in Diabetes and Vascular Disease (ADVANCE)4—failed to demonstrate improved cardiovascular outcomes with improved glycemic control. However, we should not take this to mean that glycemic control is unimportant.
In this article, we will discuss why the results of these recent clinical trials are not valid for the general population of patients with diabetes. We will review evidence from landmark clinical trials that clearly demonstrates that better glycemic control reduces both microvascular and macrovascular complications of diabetes (the “glucose hypothesis”). We contend that excellent glycemic control clearly decreases the microvascular complications of diabetes, and that results from long-term follow-up studies in both type 1 and type 2 diabetes show reduced rates of heart attack and stroke in patients treated intensively earlier in the course of their disease.5,6
EVIDENCE FOR THE GLUCOSE HYPOTHESIS
Diabetes Control and Complications Trial
The first major trial demonstrating that improved glycemic control provides benefit was the Diabetes Control and Complications Trial (DCCT).7 This study enrolled 1,441 patients with insulin-dependent diabetes mellitus, 726 of whom had no retinopathy at baseline (the primary-prevention cohort) and 715 of whom had mild retinopathy (the secondary-intervention cohort).
Patients were randomly assigned to intensive therapy (three or more insulin injections per day or an insulin pump) or to conventional therapy with one or two daily insulin injections. They were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
During the study, the hemoglobin A1c level averaged 9% in the control group and 7% in the intensively treated group. The cumulative incidence of retinopathy was defined as a change of three steps or more on fundus photography that was sustained over a 6-month period.
Effect on retinopathy. At study completion, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50% less than in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% confidence interval [CI] 62%–85%) in the primary-prevention cohort. In the secondary-prevention cohort, intensive therapy reduced the average risk of progression by 54% (95% CI 39%–66%). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47% (P = .011) and that of treatment with photocoagulation by 56% (P = .002).
Effect on nephropathy. Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (P = .04) in the primary-prevention cohort and by 43% (P = .001) in the secondary-intervention cohort. The risk of macroalbuminuria was reduced by 56% (P = .01) in the secondary-intervention cohort.
Effect on neuropathy. In the patients in the primary-prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the incidence of neuropathy at 5 years by 69% (to 3%, vs 10% in the conventional-therapy group; P = .006). Similarly, in the secondary-intervention cohort, intensive therapy reduced the incidence of clinical neuropathy at 5 years by 57% (to 7%, vs 16%; P < .001).
Effect on macrovascular events. In the initial trial, a nonsignificant 41% reduction in combined cardiovascular and peripheral vascular disease events was observed.
DCCT long-term follow-up
After DCCT concluded, the control and treatment groups’ hemoglobin A1c levels converged to approximately 8%. The two groups were then followed to determine the long-term effects of their prior separation of glycemic levels on micro- and macrovascular out comes.5 More than 90% of the original DCCT patients were followed for a mean of 17 years.
Intensive treatment reduced the risk of any cardiovascular disease event by 42% (95% CI 9%–63%; P = .02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI 12%– 79%; P = .02). This result was observed despite separation of glucose control in the two groups only for the first 6.5 years. This beneficial effect of intensive early glycemic control has been termed metabolic memory.
