Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes

Introduction:  The Action in Diabetes and Vascular Disease:  Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial investigated the effects of intensive blood glucose control on vascular outcomes for patients with type 2 diabetes.

Methods:  11,140 patients with type 2 diabetes were randomly assigned a blood glucose control strategy.  They were assigned to undergo either a standard blood glucose control strategy, or an intensive blood glucose strategy.  In the intensive blood glucose strategy, gliclazide (modified release) plus other drugs were used to achieve a glycated hemoglobin (HbA1c) of 6.5% or less.

The primary end points assessed were:  composites of major macrovascular events (death caused by a cardiovascular event, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening retinopathy or nephropathy).  Theses primary end points were assessed both jointly and separately.

Results:  The median follow-up in the ADVANCE trial was 5 years.  After that time, intensive-control group had a lower mean HbA1c (6.5%) than the standard-control group (7.3%).

It was seen that intensive blood glucose control reduced the incidence of combined major macrovascular and microvascular events (18.1% vs. 20.0% with standard blood glucose control; hazard ratio, 0.90; 95% CI, 0.82-0.98; p=0.01).  The intensive-control group also showed a reduced incidence of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77-0.97; p=0.01), mostly caused by a reduced incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66-0.93; p=0.006).  There was no significant effect on retinopathy (p=0.50) in the intensive-control group.

The blood glucose control strategies had no significant effects on major macrovascular events (hazard ratio with intensive blood glucose control, 0.94; 95% CI, 0.84-1.06; p=0.32), nor did the control strategy have a significant effect on death from cardiovascular causes (hazard ratio with intensive blood glucose control, 0.88; 95% CI, 0.74-1.04; p=0.12) or on death from any cause (hazard ratio with intensive blood glucose control, 0.93; 95% CI, 0.83-1.06; p=0.28).

Severe hypoglycemia was uncommon, but it was more common in the intensive-control group (2.7% vs. 1.5% in the standard blood glucose control group; hazard radio, 1.86; 95% CI, 1.42-2.4; p<0.001).

Conclusions:  An intensive blood glucose control strategy (using modified-release gliclazide and other drugs as needed) lowered the HbA1c level to 6.5% and showed a 10% relative reduction in the combined outcome of major macrovascular and microvascular events.  This was seen mainly as a result of the 21% relative reduction of nephropathy.