ADVANCE: Intensive Glucose Control Reduces Diabetic Nephropathy

Jacquelyn K Beals, PhD

June 08, 2008

June 8, 2008 (San Francisco) — Intensive glucose control significantly reduces the risk for nephropathy, according to the results of a 5-year trial to assess the effects of intensive glucose control and blood pressure lowering on vascular complications of type 2 diabetes.

Published early online June 6 in the New England Journal of Medicine and presented here at the American Diabetes Association (ADA) 68th Scientific Sessions, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study is the world's largest diabetes trial, enrolling 11,140 patients with type 2 diabetes at 215 sites in 20 countries.

"Clinicians, diabetes specialists, and indeed the patients whom they look after, urgently need a guidance as to the level of glycemic control that we can safely aim for," Simon Heller, MB BChir, DM, FRCP, study coauthor and management committee member for ADVANCE, said during an ADA media briefing. "I think this study explains really much more clearly now, it makes it more clear for clinicians and their patients the kind of goals that we should be aiming for." Dr. Heller is professor of clinical diabetes, University of Sheffield, and director of research and development, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom.

ADVANCE Study Design

Patients eligible for the ADVANCE trial were at least 55 years old, had been diagnosed with type 2 diabetes at age 30 years or older, and had a history of, or at least 1 risk factor for, vascular disease. Participants were randomly assigned to receive a placebo or a fixed dose of perindopril and indapamide to lower blood pressure, and to undergo intensive control or standard control of blood glucose (the latter determined by local guidelines).

Results of the blood pressure portion of the study were previously published in September 2007. Regardless of initial blood pressure, the blood pressure–lowering regimen in this population reduced their relative risk of death due to cardiovascular disease by 18% (P = .03).

Patients randomized to the intensive-glucose-control group (n = 5571) received gliclazide (modified release, 30 – 120 mg/day) and no other sulfonylureas; other glucose-control agents were prescribed by the treating physicians as needed to achieve the ADVANCE target HbA1c of 6.5% or less. Patients randomized to the standard treatment group (n = 5569) received glucose-lowering agents other than gliclazide as prescribed by their treating physicians, using the current guidelines target for HbA1c of 7.0%.

Reduced Risk for Major Vascular, Microvascular Complications

The ADVANCE study achieved a mean HbA1c of 6.5% in the intensive glucose control group compared with 7.3% in the standard treatment group (P < .001). This decrease was accompanied by a 10% relative risk reduction for major vascular complications (P = .013) and a 14% relative risk reduction for major microvascular events (P = .014). No significant difference was found between the treatment groups for major macrovascular events such as myocardial infarction or stroke (P = .32).

Dr. Heller commented on the absence of macrovascular benefits: "Diabetic nephropathy, and indeed, increased protein excretion in the kidney is a powerful predictor of death from cardiovascular disease. But it's important to remember that this study went on for 4 years or so, and that predicted increase might not be expected until a year or 2 down the line," he said.

"It's worth just pointing out that right at the end of this study, the lines [showing cumulative incidence of major macrovascular events for both treatment groups] are beginning to diverge a little," Dr. Heller noted. "Just a hint that perhaps, if the study had gone on much longer, we might have seen the benefit of macrovascular disease indirectly because of the protection from diabetic kidney disease. But of course that's speculative," he acknowledged.

Most Significant Finding: Reduced Nephropathy Risk

The greatest relative risk reduction in the intensive-glucose-control group was for new or worsening diabetic nephropathy, which decreased 21% compared with the standard treatment group (P = .006). There was also a 9% reduction in new microalbuminuria (P = .02). The study found no evidence that intensive glucose control decreased new or worsening diabetic retinopathy.

Medscape Diabetes & Endocrinology spoke with Anushka Patel, PhD, coauthor and principal clinical coordinator for ADVANCE, about the results for nephropathy and retinopathy.

"Certainly the association between HbA1c and your risk of retinopathy and your risk of nephropathy are very similar," observed Dr. Patel. "The confidence interval for the effect on retinopathy...overlaps quite a lot with the confidence interval of the effects on the renal outcome. So, they are potentially contingent." Dr. Patel is director of the Cardiovascular Division, The George Institute for International Health MD, and in the Department of Cardiovascular Medicine, Royal Prince Alfred Hospital, Sydney, Australia.

"Having said that, though,...the event rate for retinopathy was quite a lot lower than expected, and I think the main reason for that is that it is driven by retinal photocoagulation," Dr. Patel pointed out. "And retinal photocoagulation' is a very specific marker for retinal behavior. You only get it if you have retinal disease. It's not very sensitive. It depends on the availability of treatment."

A substudy is being conducted with 2000 patients in which retinas were examined at the beginning of the study and again at the end. "We'll report later in the year. That will give us a much better idea of what's going on with retinal disease." Dr. Patel said.

The reduction in nephropathy remains the most significant finding of the study. As Dr. Heller said in the media briefing, "[G]etting down to [these kinds] of HbA1c levels — less than 7.0% or even approaching 6.5% as authorities around the world prove — can benefit patients from diabetic kidney disease and essentially protect 1 in 5 over a few years from developing this very bad complication."

ADVANCE and ACCORD: Conflicting or Complementary?

"I think [the findings] have to be put into perspective," Harold E. Lebovitz, MD, chair of the ADA Scientific Sessions Planning Committee and moderator of the ADA media briefing, told Medscape Diabetes & Endocrinology about ADVANCE and another recently reported large type 2 diabetes trial.

Several ADA scientific sessions focused on ADVANCE and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. ACCORD was supported by the National Heart, Lung, and Blood Institute, and it enrolled 10,251 patients with type 2 diabetes. ACCORD was suspended in February 2008 after approximately 3.5 years of follow-up as a result of significantly more deaths in the intensive-glucose-control group than in the standard-therapy group (P = .04).

There was no evidence of increased risk of death in the ADVANCE intensive-glucose-control group. The investigators attempted to explain factors in these 2 large studies that would account for their different outcomes.

ADVANCE and ACCORD have several fundamental differences: Primary endpoints of ADVANCE were major microvascular events and/or major macrovascularevents, assessed jointly and separately; primary endpoints for ACCORD were macrovascular events. Mean baseline HbA1c level in ADVANCE participants was 7.5%; in ACCORD, mean baseline HbA1c level was 8.3%. Mean body mass index was 28 kg/m2 in ADVANCE participants and 32 kg/m2 in ACCORD participants.

Among ACCORD participants, 28% in the intensive-treatment group gained 10 kg or more; 14% in the standard treatment group gained 10 kg or more. Dr. Patel noted: "We were half expecting that we might see some increase in body weight with the intensive-glucose strategy in ADVANCE. In fact, there [was] no change in body weight in the intensive group and...there was a slight reduction in weight in the standard group over the period of follow-up. So by the end of follow-up, there was an average difference between the 2 groups of only 0.75 kg."

The glucose-lowering strategy in each study was quite different. ADVANCE was pragmatic in trying to achieve tight glucose control, and it took 2 or 3 years to separate groups and devise strategies — adding more drugs and encouraging investigators to do more lifestyle modifications. The ACCORD approach was more aggressive, using more agents from the start with multiple injections.

Denise G. Simons-Morton, MD, PhD, project officer for ACCORD at the National Heart, Lung, and Blood Institute in Bethesda, Maryland, pointed out, "Neither study found a significant reduction in the competent macrovascular outcomes from intensive glycemia lowering. That's the similarity between the findings." She attributed the problems with ACCORD to a combination of 3 factors: the strategy used, the goal achieved, and the population in which it was achieved.

Implications for Practice

"The purpose of [ADVANCE] was to address whether getting very tight control of the glucose, rather than ordinary control, made a difference," Dr. Lebovitz said during the media briefing. "[W]e would not conclude that glucose makes no difference, but we would say that attempting to get very very tight glucose control may not give you added benefit for cardiovascular disease." Dr. Lebovitz is a professor of medicine in the Division of Endocrinology and Metabolism/Diabetes at the State University of New York Health Sciences Center in Brooklyn, New York.

Dr. Lebovitz continued, "On the other hand, remember that 50% of all the people who enter a dialysis program in the west have diabetes as the cause of their kidney disease. don't have to get so tight in the control to get a better effect on cardiovascular [events], but you do if you want to really reduce kidney disease, which is a very important endpoint."

Dr. Heller reports receiving consulting fees from Novo Nordisk, Eli Lilly, and Amylin; lecture fees from Novo Nordisk, Eli Lilly, Servier, and Merck; and grant support from Novo Nordisk and GW Pharmaceuticals. Dr. Patel reports receiving lecture fees from Servier, Pfizer, and Abbott, and she has received grant support from Pfizer, Servier, and Sanofi-Aventis. Dr. Lebovitz is a consultant for Novartis Pharmaceuticals Corporation and sanofi-aventis. He is also on the advisory board of Amylin Pharmaceuticals, Inc; in the speakers bureau of GlaxoSmithKline; and a stockholder of Amylin Pharmaceuticals, Inc, GlaxoSmithKline, and sanofi-aventis. Dr. Simons-Morton has disclosed no relevant financial relationships.

N Engl J Med. 2008;358:2560-2572.
American Diabetes Association 68th Scientific Sessions. Presented June 6, 2008.


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