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Common Sense Prevails: ACCCORD Vs. ADVANCE

Feb 19, 2008

Early results from the largest study ever (ADVANCE) of aggressive measures to control blood sugar in type 2 diabetics has found no sign that intensive treatment increases the risk of death.

Preliminary findings from the ADVANCE trial provide no evidence that intensive treatment to lower blood-glucose levels in type 2 diabetics increases mortality risk, which is in direct conflict with the results of the ACCORD study results.

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.

ADVANCE involves 11,140 high-risk patients with type 2 diabetes who were randomized to intensive or standard glucose-lowering treatments. Study director Dr Anushka Patel (The George Institute commented that, “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. 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."

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 stated 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.

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."

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 drug modified-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.

ACCORD steering committee member Dr John Buse (University of North Carolina, Chapel Hill) pointed out some other differences between the two trials. "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.

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.

In advance of publication