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Intensive glucose lowering arm of diabetes trial is stopped after excess deaths: ADVANCE study suggests different results
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BMJ 2008;336:407 (23 February), doi:10.1136/bmj.39496.527384.DB
Susan Mayor
1 London
The National Heart, Lung, and Blood Institute, part of the US National Institutes of Health, has stopped the intensive glucose lowering arm of a major trial in type 2 diabetes after more patients died than in the standard treatment group.
The action to control cardiovascular risk in diabetes (ACCORD) study involved 10 251 adults aged 40-82 years with type 2 diabetes who had two or more additional risk factors for heart disease or who already had a diagnosis of heart disease.
They were randomised to intensive glucose lowering treatment, in which the target haemoglobin A1c (HbA1c) concentration was <6%, or to less intensive, standard treatment to reach the average HbA1c (7% to 7.9%) currently achieved in the United States by such treatment.
The Data and Safety Monitoring Board, the independent group that was monitoring the trial, recommended that the trial be stopped when it found that more deaths occurred in the intensive treatment group. A total of 257 patients died in the intensive treatment arm over an average of four years of treatment, whereas 203 in the standard treatment group died. This was a difference of three participants per 1000 each year: 14 per 1000 per year in the intensive group and 11 per 1000 in the standard treatment group. The death rate in each group was lower than that seen in similar groups of participants in other studies, which has typically been about 50 per 1000 per year.
Elizabeth Nabel, director of the institute, said, "A thorough review of the data shows that the medical treatment strategy of intensively reducing blood sugar below current clinical guidelines causes harm in these especially high risk patients with type 2 diabetes."
Dr Nabel suggested that doctors should continue to aim for a target HbA1c of 7% when treating patients with type 2 diabetes. In patients similar to those in the ACCORD study-that is, with an average age of 62, a history of diabetes for an average of 10 years, and with known heart disease or a high risk of heart disease-"less stringent A1c goals are likely appropriate, with an aim for around 7%."
The ACCORD researchers were surprised by the higher number of deaths in the glucose lowering arm, for which they have no reason so far. They say that it could be due to the adverse effects of lowering blood glucose concentrations too much in older diabetic people with heart disease or the adverse effects of a particular drug or drug combination or that it could be a spurious observation that might have disappeared with longer follow-up.
The study was designed to test the strategy of intensive glucose lowering rather than any specific drug treatment. The doctors treating the patients in both arms of the study could use any drugs from all of the major classes of drugs to treat diabetes. A statement from the institute said, "Based on analyses conducted to date, there is no evidence that any medication or combination of medications is responsible."
William Friedewald, chairman of the ACCORD steering committee and clinical professor of medicine and public health at Columbia University, said, "Because of the recent concerns with rosiglitazone, our extensive analysis included a specific review to determine whether there was any link between this particular medication and the increased deaths. We found no link."
He noted that the intensive treatment group had approximately 10% fewer non-fatal cardiovascular events than the standard group but added that when a myocardial infarction did occur it was more likely to be fatal.
Researchers from another study, the action in diabetes and vascular disease: Preterax and Diamicron MR controlled evaluation (ADVANCE) study, which is comparing intensive glucose lowering treatment with less intensive treatment in more than 11 000 patients with type 2 diabetes and a high risk of heart disease, said they had found no evidence of an increased risk of death in patients given intensive treatment. All patients in this group are being treated with modified release gliclazide, while patients not reaching the target HbA1c of <6.5% are also being given a range of other drugs.
Rory Collins, professor of medicine and epidemiology and codirector of the clinical trial service unit at the University of Oxford and principal investigator of the ADVANCE study, said, "The interim results from ADVANCE provide no confirmation of the adverse mortality trend reported from the ACCORD study." He noted that the ADVANCE study's interim results were based on more than twice as much data and similar levels of glucose control as in ACCORD.
Commenting on the ACCORD study, Rury Holman, professor of diabetic medicine at the University of Oxford, said, "This is a very large scale trial, so we have to take the results very seriously."
He said that a great deal of interest exists as to what may have caused the higher mortality in the intensively treated patients, although this will not become clear until full data are available. He considered it unlikely that a very low HbA1c concentration was, in itself, the cause of the higher mortality, as other trials have not shown this effect.
"The only difference is that the patients in ACCORD were very intensively treated-with many on at least three treatments. It may be that many of the patients had borderline, if not occult, hypoglycaemia some of the time. Are they less able to cope with incidents such as myocardial infarction? The data suggest that myocardial infarctions occurred less frequently in the intensively treated group, but when they did they were more likely to be fatal."
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