Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes

Submitted by:
Leandro Perez, MD, and Jun R. Chiong, MD, MPH, FCCP Steering Committee Member Cardiovascular Medicine and Surgery NetWork
Loma Linda University
Loma Linda, CA

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

DVANCE Collaborative Group, Patel A, MacMahon S N Engl J Med 2008; 358:2560-2572

Introduction:

Vascular complications are the most common cause of death and disability among patients with diabetes. Prospective studies have shown continuous associations of blood glucose and glycated hemoglobin (HbA1C) levels with the risk of major vascular events. However, previously conducted randomized trials evaluating the effects of glycemic control in patients with diabetes have provided inconsistent evidence of effects on vascular disease. Nevertheless, current guidelines recommend a target glycated hemoglobin level of <7.0% for most patients with diabetes.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial investigators sought to answer this question.

In this study, 5,571 patients with type 2 diabetes were randomly assigned to receive “intensive” glucose control targeting an HbA1C level of ≤6.5%; all participants received gliclazide modified release and unrestricted additional antihyperglycemic oral agents and insulin, as needed, to reach the HbA1C goal. The remaining 5,569 patients with diabetes were treated in a standard manner, according to local guidelines, with unrestricted antihyperglycemic therapy, except for the gliclazide modified release. The primary endpoint was a combination of major macrovascular events and microvascular events.

After a median follow-up of 5 years, the mean HbA1C level was significantly lower in the intensively treated group compared with the standard therapy study arm (6.5% vs 7.3%). The major cardiovascular event rate was not different between patients with diabetes who were intensively treated and those receiving standard therapy. There was a statistically significant reduction in microvascular complications, driven entirely by decreases in albuminuria. Neither cardiovascular nor noncardiac-related deaths were different in the two groups. Any hypoglycemia was higher in the intensively treated group, and,severe hypoglycemia, although infrequent, was 87% more frequent in the intensively treated group (0.7 events per patient per year vs 0.4 events per patient per year).

At the end of the study, a little more than 50% of subjects in both groups were taking aspirin, less than half of the patients were using a statin, all patients remained overweight, and mean systolic BP was above 130 mm Hg in 100% of subjects. Although there was an average reduction in low-density lipoprotein (LDL) in both groups (120 mg/dL vs 100 mg/dL), the ideal <70mg/dL goal for this population was not achieved.

Discussion:

This study illustrates the lack of benefit afforded by lowering HbA1C levels to ≤6.5% in terms of overall and cardiac-specific mortality; plus, similar to previous data, there is no apparent advantage of reaching these levels in terms of decreasing the incidence of major cardiovascular events.

These unfortunate events are multifactorial—people who are obese, smoke, dyslipidemic, and who have uncontrolled hypertensive diabetes with previous cardiovascular events, can not expect their macrovascular disease and death rates to substantially drop after a certain HbA1C level has been reached in isolation. The low rate of use of clearly proven, beneficial therapies, such as aspirin and statins, in people with diabetes, is noteworthy.

Clinicians caring for patients with diabetes must not focus solely on one factor but aim to achieve control of all the elements that compose the risk profile for each of these patients.