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World's largest Trial of Intensive Glucose Control in Type 2 Diabetes Shows Reduced Risk of Complications by 21%: ADVANCE Study

Posted: Wednesday, June 11, 2008

The world's largest diabetes trial has shown intensive blood glucose can reduce the risk of kidney disease by 21% with no evidence of any increased risk of death when blood glucose was intensively controlled. 

“The results clearly demonstrate that intensive control of blood glucose, as recommended by most current clinical guidelines, has an important role in the prevention of renal complications of type 2 diabetes. The other major finding of the trial was that major macrovascular events – heart attack, stroke and death from cardiovascular disease – were not significantly reduced with intensive glucose control, although there was a trend towards improvement in these outcomes. However, the results suggest that a multifactorial approach addressing all the major risk factors including blood pressure and blood lipids is required to prevent macrovascular disease,” said Anushka Patel, MBBS, SM, PhD, Study Director of the ADVANCE trial, and Director, Cardiovascular Division,

The George Institute for International Health, which conducted the study, in a recent interview. “The key message is that the study confirms the current approach that intensively controlling blood glucose has an important role inthe prevention of the microvascular complications of diabetes.”

There was no evidence of an increased risk of death among ADVANCE patients receiving intensive treatment to lower blood glucose, in contrast to the similar ACCORD trial in the U.S., which was discontinued prematurely earlier this year due to an increased rate of death in its intensive arm. microvascular complications by 10%, but that was driven largely by the microvascular results,” said Dr Patel.  “Further, the 14% reduction in microvascular risk was driven mainly by nephropathy rather than retinopathy. We found that intensively controlling blood glucose reduces risk of the development or progression of kidney disease by 21%.”

ADVANCE did not show a statistically significant effect of intensive glucose control on cardiovascular disease (10% in the intensively treated group vs., 10.6% in the standard group). “We believe a protective effect remains plausible since we were aiming for a 1% difference in A1C levels between the standard and intensive groups, but achieved an average of a 0.7% difference over the course of the trial,” said Dr. Patel. “Further, the rate of cardiovascular events was only 2.2% per year rather than the expected 3% per year, possibly due to more aggressive treatment of blood pressure and lipids.” She also noted that the wide confidence interval in the trial’s results does not exclude the benefits that epidemiologic evidence predicts.

The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) trial was an international study involving 11,140 high-risk patients with type 2 diabetes based at 214 centers in 20 countries worldwide.  “ADVANCE was designed to address two of the major uncertainties in the prevention of the vascular complications of diabetes: whether important clinical benefits would result from reducing A1C to 6.5% or lower and from intensive blood pressure lowering, whether or not the patient had had hypertension,” said Stephen MacMahon, DSc, PhD, MPH, Co-Principal Investigator of the study.

In a factorial design, patients received blood-pressure-lowering treatment with a fixed-dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide or a placebo, and diabetes treatment with gliclazide MR, plus other anti-diabetic drugs as needed. The average age of participants was 66, with 46% coming from Europe, 37% from Asia, 13% from Australia and New Zealand, and 4% from North America. At the outset, 32% of the participants had already had a cardiovascular event, such as a stroke or heart attack, and the balance were already at high risk due to such risk factors as a history microalbuminuria (protein in the urine), proliferative diabetic retinopathy, current cigarette smoking, elevated total cholesterol, or low HDL (the “good” cholesterol).

“The key objective was to get the intensive group patients down to an A1C of 6.5%, which the trial achieved,” said Dr. MacMahon. The investigators did not have a particular target for the standard group so they did not have control of what the standard group would achieve. At baseline, the average A1C of all participants was 7.5%,” said Dr. MacMahon. “Physicians treating those in the standard group could give them any medications they chose according to the guidelines in the local country. Physicians treating those in the intensive group were required to use gliclazide MR first and then up to three oral agents, followed by insulin in order to reach the goal of an A1C of 6.5% or lower. Sulfonylureas, thiazolidinediones, acarbose, metformin, and insulin were commonly used in both arms of the study. Aside from gliclazide MR, all medication choices were left to the treating physician.” “At the end of the five years of follow-up, the average A1C in the intensive group was 6.5% and in the standard group was 7.3%,” he reported. “However, the average difference in A1C over the course of the trial was 0.7%.”

There were two primary outcomes: first, a composite of death and macrovascular complications – death, cardiovascular death, nonfatal heart attacks, and nonfatal stroke; second, a composite of microvascular complications – new or worsening renal disease (nephropathy) or diabetic eye disease (retinopathy). It was prespecified that the outcomes would be analyzed both jointly and separately. “As expected, patients in the intensive group had more hypoglycemia (episodes of low blood glucose), but the overall incidence was actually quite low,” he said. The incidence of severe hypoglycemic events was 2.7% in the intensive group and 1.5% in the standard group, and this difference was statistically significant.

 “It’s more challenging today than it has ever been in the past to demonstrate a benefit for glucose control first because the standard group was in such good control. Patients getting standard treatment are already in good glycemic control today and are also getting good treatments for cholesterol and blood pressure and are getting aspirin,” said Dr. MacMahon. “So the overall rate of heart attacks is low, which means we might need a much larger group and a much longer study to detect the effects of glucose lowering on macrovascular outcomes.” “If there is any effect of glucose control using currently available drugs on heart attacks, it’s going to be small, and therefore the key message with heart attacks and strokes is that diabetes patients need comprehensive treatment to control all risk factors including blood pressure and cholesterol,” said Dr. MacMahon.

Source: Diabetes In Control: Presented at the ADA's 68th Annual Scientific Sessions.

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