ADVANCE: Intensive blood glucose control has renal benefits

June 6, 2008

Intensive blood glucose control in patients with type 2 diabetes resulted in a significant reduction in the risk of microvascular complications compared with standard blood glucose control. This was driven by a reduction in the occurrence of nephropathy, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) study.

Intensive blood glucose control in patients with type 2 diabetes resulted in a significant reduction in the risk ofmicrovascular complications compared with standard blood glucose control. This was driven by a reduction in the occurrence ofnephropathy, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE)study.

No evidence of an increased risk of death was observed among ADVANCE patients randomized to intensive blood glucose control.This contrasts with the results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which wasterminated prematurely earlier this year due to an increased rate of death in patients whose blood glucose was intensivelycontrolled. (The final results from ACCORD are being presented June 10.)

There was no significant effect of intensive blood glucose control on macrovascular risk in ADVANCE, but the aggressivetreatment of cardiovascular risk factors in the group randomized to standard control and the smaller-than-targeted differencein achieved hemoglobin A1c levels between the two randomized groups may have contributed to this lack of a significanteffect, according to Anushka Patel, MBBS, PhD, study director of ADVANCE, and director of the cardiovascular division at TheGeorge Institute for International Health, and associate professor at the University of Sydney, Australia.

ADVANCE was an international study funded by the Australian Government's National Health and Medical Research Council andServier. It was carried out independently of the government and industry sponsor. It included 11,140 high-risk patients withtype 2 diabetes who were randomized to a target hemoglobin A1c level of 6.5% or lower (intensive control) or standardguidelines-based A1c targets.

Participants were also randomized to intensive blood-pressure lowering or placebo; as reported in the Lancet in 2007, afixed-dose combination of perindopril and indapamide reduced the risk of vascular events by 9% and cardiovascular death by18% over 5 years.

"The intensive glucose control strategy we're reporting is a pragmatic, flexible approach that in many ways reflects theapproach to glucose control practiced by diabetologists, family doctors, and many others," said Stephen MacMahon, DSc, PhD,MPH, co-principal investigator of ADVANCE, and professor of cardiovascular medicine and epidemiology, University ofSydney.

Treatment strategy

The achieved average A1c levels were 6.5% in the intensive arm and 7.3% in the standard arm (the average difference in A1cbetween the two arms over the course of the trial was 0.7%).

The incidence of combined major macrovascular and microvascular events was reduced by 10% (p = 0.01) in theparticipants randomized to intensive blood-glucose lowering.

The intensive control strategy was associated with a 14% reduction (p = 0.01) in the risk of microvascular events (aco-primary endpoint) compared with standard control, driven by a 21% reduction (p = 0.006) in the risk of the development orprogression of kidney disease in the intensive arm. There was no significant effect of the intensive intervention onretinopathy.

The incidence of a composite of death and macrovascular complications, the other co-primary outcome, was not significantlyaffected by intensive glucose control: 10% in the intensively treated group and 10.6% in the standard treatment arm achievedthis outcome (p = 0.32).

The overall rate of cardiovascular events was only 2.2% per year, much lower than the anticipated 3% per year, which may haveprevented the study from having sufficient power to detect a difference in cardiovascular events between the two strategies.Further,the final difference in A1c levels between the two groups (0.7%) was less than the 1% difference in A1c the investigatorssought to achieve.

As expected, the incidence of hypoglycemia was higher in the intensive group. Severe hypoglycemic events occurred in 2.7% ofthe intensive arm versus 1.5% in the standard arm (p < 0.001).

"The study makes it clear for clinicians and their patients the kind of goals that we should be aiming for, We can concludethat getting them down to HbA1c levels of less than 7% or even approaching 6.5%, can benefit patients [with regard to]diabetic kidney disease, and essentially protect one in five over a few years from developing this very bad complication, which is afeared complication indeed," said Dr. MacMahon.