ADVANCE Does Not Confirm ACCORD Results

Sue Hughes

February 14, 2008

February 14, 2008 (Sydney, Australia) - Preliminary findings from the ADVANCE trial provide no evidence that intensive treatment to lower blood-glucose levels in type 2 diabetics increases mortality risk.

The ADVANCE study is similar to the blood-glucose-lowering part of the ACCORD trial, which was stopped last week because of a higher number of deaths in patients allocated to intensive glucose lowering rather than standard treatment.

In a press release released by the ADVANCE group, principal investigator Prof Stephen MacMahon (The George Institute, Sydney, Australia) stated that "Due to the unexpected report from the ACCORD trial, we felt it was in the public interest for us to ask our data monitoring and safety committee to make a statement as to whether the available data from ADVANCE provide any support for the suggestion that intensive blood-glucose lowering may increase mortality."


ADVANCE management committee chair Prof John Chalmers (The George Institute) commented: "Doctors and patients should feel reassured that the mortality trend reported by the ACCORD study has not been found in the interim results from ADVANCE. However, we need to await more definitive analyses and reports from both studies before drawing final conclusions."

ADVANCE involves 11 140 high-risk patients with type 2 diabetes who were randomized to intensive or standard glucose-lowering treatments. The study is just coming to an end, but the database is still locked and the investigators still blinded while the data are checked and cleaned up, study director Dr Anushka Patel (The George Institute) told heartwire . The database will be unlocked in March and the analysis will begin at that point. She added that the data were now "more than 99% complete and so we are confident that the interim findings communicated here are a reliable guide to the final results."

Twice as much data as in ACCORD

In the press release, data safety and monitoring board (DSMB) chair, Prof Rory Collins (University of Oxford, UK), said the data provided "no confirmation" of the adverse mortality trend reported from the ACCORD study. He also noted that the ADVANCE interim results were based on more than twice as many data and similar levels of glucose control as in ACCORD.

Patel told heartwire that only the DSMB has seen the data and the ADVANCE investigators have not had access to the study results. "We do not know if the mortality results show a benefit for intensive glucose lowering or a neutral effect. But we understand that there is no indication of harm," she said. She added that no information on any other outcome, other than mortality, was yet available.

Same A1C level as ACCORD in intensive arms

She noted that the intensive arm was aiming for HbA1C levels of 6.5% or below, and they actually achieved 6.4%--exactly the same level as the intensive arm in ACCORD. The standard-treatment arm achieved an A1C level of 7%, slightly below the 7.5% reached in ACCORD.

Patel said she "couldn't even begin to speculate" on reasons why the mortality results were different between the two trials. "It's far too early. We haven't even seen the data yet. We don't know enough information. The ACCORD investigators have done some analyses, but we haven't even started our analyses yet."

Differences between the trials

While ACCORD and ADVANCE are similar in that they both investigated intensive vs standard glucose lowering in type 2 diabetes, there are many differences between the two trials. ACCORD allowed any treatment whatsoever to reach target glucose levels, whereas in ADVANCE, all patients in the intensive group started treatment with the sulfonylurea drugmodified-release gliclazide. But Patel noted that the vast majority of patients could not reach target levels on this one drug alone, and so other treatments were added and, like ACCORD, many therapies were used. "There was probably a similar range of treatments used in the two studies, but there will be some differences. For example, ACCORD applied more stringent drug therapy to reach targets than we did, and there was probably more use of thiazolidinediones in ACCORD than in ADVANCE."

She said the patient population was "broadly similar" in the two studies, with around one-third of patients in both studies having a prior history of cardiovascular disease, but the average age in ADVANCE was slightly higher (66 vs 62 years in ACCORD), and patients had had diabetes for a shorter time in ADVANCE (eight years vs 10 years in ACCORD). In addition, A1C levels were a bit lower at baseline in ADVANCE patients, but their blood pressure was a little higher than those in ACCORD.

Less intensive intervention in ADVANCE?

ACCORD steering committee member Dr John Buse (University of North Carolina, Chapel Hill) pointed out some other differences between the two trials to heartwire . "ADVANCE included a population with milder diabetes that I suspect required a less intensive effort to get the A1C to 6.4%. They were aiming only for 6.5%, while we were aiming for <6.0%," he said. While the two populations arguably had similar cardiovascular risk, none of the ADVANCE patients are in the US and thus will be socially and culturally quite different, he added.

"I think ADVANCE supports the notion that it is the intensity of the medical intervention and not the A1C level achieved on average that is the problem, but we'll know for sure in a few weeks," Buse commented.

Asked whether the ACCORD investigators considered asking for ADVANCE data before stopping the study, Buse replied: "The decision to stop the study was made by the [National Heart, Lung, and Blood Institute] NHLBI. As an investigator, they did not discuss it with me before the decision was final." He noted that the ACCORD and ADVANCE investigators had met from time to time during the past five years and have some joint analyses planned.

Buse, who is also president of medicine and science at the American Diabetes Association (ADA), said he did not feel patients should be confused by the differing results of the two studies. "We have really tried to encourage people not to read between the lines. We tried as hard as we could to make the point that the study was stopped due to a safety concern but that it should in no way affect current ADA guidelines. The only cautionary note we sounded was using very intensive programs of glucose lowering in patients at very high risk of CVD. From what I know about ADVANCE, they did not use a very intensive glucose-lowering program," he told heartwire .

The NHLBI told heartwire that the ADVANCE and ACCORD studies have agreed to share data and that although there may be several differences between the studies that need to be examined, hopefully a consensus can be reached on the conclusions.

ADA statement

In a statement, the ADA said it "believes that the information from ADVANCE is very important and further magnifies the uncertainty over whether intensive glucose control may harm some people with diabetes." The association notes that results of a third trial, the VA Diabetes Trial, which also examined the relationship between intensive glycemic control and cardiovascular outcomes in type 2 diabetes, are due out soon. "The ADA plans to critically examine the final data from these studies once they are publicly available later this year and will issue further recommendations at that time. In the meantime, the ADA continues to advise most people with diabetes to strive for an A1C of less than 7% but as always stresses individualization of treatment goals. People with type 2 diabetes who have existing CVD or multiple CVD risk factors should consult with their healthcare team about their treatment goals," it adds.

ADVANCE was funded by the National Health & Medical Research Council of Australia and Servier, the manufacturer of modified-release gliclazide. The trial also included an investigation into more intensive blood-pressure lowering. This part of the trial, which showed a benefit with the combination of perindopril and indapamide, was reported last year.

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