February 6, 2008 (Bethesda, MD) – The blood-glucose-lowering part of the ACCORD trial in patients with type 2 diabetes at especially high risk of heart disease has been stopped prematurely because of a higher rate of mortality in the patients in the intensive arm vs that in the standard arm .
Patients in the standard-treatment group will continue treatment without changes, but patients in the intensive-treatment group will now be transitioned to the standard treatment.
The trial was a study of strategy rather than specific drug therapy, and many diabetes agents were used to reach glycemic targets. The higher death rate in the intensive group was not due to episodes of hypoglycemia or to any single drug, including rosiglitazone, or to a combination of drugs, ACCORD investigators said.
ACCORD is an National Heart, Lung, and Blood Institute (NHLBI) study of approximately 10 000 patients with type 2 diabetes and either heart disease or two risk factors for heart disease. The trial has a double 2X2 factorial design. All patients were participating in the glycemic-control part of the trial, which was testing whether an intensive strategy that targets a HbA1c level of <6.0% reduces the rate of cardiovascular events more than a standard strategy that targets an HbA1c of 7.0% to 7.9%.
Then, depending on their blood-pressure and cholesterol levels, patients are assigned to two other parts of the trial. These are testing the combination of a fibrate (to raise HDL and lower triglycerides) and a statin (to lower LDL) vs a statin alone, and lowering systolic blood pressure to a target of below 120 mm Hg vs a target of 140 mm Hg. These blood-pressure and lipid arms of the study will continue until the study ends as planned, in June 2009.
In the glycemic-control part of the study, the median A1c level achieved in the intensive-treatment group was 6.4%, vs 7.5% in the standard group. The trial was stopped because of an excess of three deaths per 1000 participants per year in the intensive group vs the standard group, over an average of four years of treatment.
ACCORD: Deaths in Intensive vs Standard Glycemic Control Groups
|Standard Glycemic Control||Intensive Glycemic Control|
|Deaths, n||203 (11/1000/y)||257 (14/1000/y)|
In a conference call on February 6, Dr Elizabeth Nabel, director of the NHLBI, pointed out that the death rate in both arms was lower than that previously observed in individuals with type 2 diabetes at especially high risk for heart disease, who generally have a risk of death of approximately 50/1000 per year. She also reported that there was a trend toward benefit in the intensive arm in terms of nonfatal cardiovascular events, but that this was outweighed by the increased mortality.
"This is an important finding that shows that if you have type 2 diabetes and are at especially high risk for heart disease, very intensive glucose-lowering treatments aimed at normalizing blood glucose to an A1c of less than 6% may be detrimental," Nabel stated.
She stressed that these results were applicable only to those individuals who are similar to the ACCORD participants--who had had type 2 diabetes on average for 10 years at the time of enrollment, had higher HbA1c levels than most type 2 diabetes patients in the US today (average of 8.2% at baseline), and had known heart disease or at least two risk factors in addition to diabetes, including high blood pressure, high cholesterol levels, obesity, and smoking.
She added that patients should not change their diabetes treatment without consulting with their healthcare provider and that the NHLBI concurs with the general recommendation of the American Diabetes Association that patients with diabetes should aim for an A1c level of less than 7%. "However, for this special group of individuals with diabetes, as exemplified in the ACCORD population, who were average age of 62, had diabetes for an average of 10 years, and had known heart disease or were at high risk, less stringent A1c goals are likely appropriate, with an aim for around 7%."
Reduction in Nonfatal Events?
Expanding on the study findings, chair of the ACCORD steering committee, Dr William Friedewald (Columbia University, New York), said the intensive group showed approximately 10% fewer nonfatal cardiovascular events such as MIs compared with the standard-treatment group, but that it appeared that, if an MI did occur, it was more likely to be fatal. In addition, the intensive-treatment group had more unexpected sudden deaths.
Not Linked to Rosiglitazone
Friedewald noted that because of recent concerns about rosiglitazone, they had specifically analyzed the data to try to determine whether there was any link between this particular medication and the increased deaths in the intensive-treatment group, but so far no link has been found, and the use of rosiglitazone does not seem to explain the increased mortality.
Some Benefits Seen in Other Populations
Dr Hertzel Gerstein (McMaster University, Hamilton, ON), who led the group that designed the glycemic-control approaches used in ACCORD, gave some background to the study. He noted that a large body of research has shown that higher glucose levels predict a higher likelihood of fatal and nonfatal cardiovascular events and that studies have shown that lowering blood glucose levels can significantly lower the risk of certain complications of diabetes, such as eye, nerve, and kidney diseases. In addition, a major study in people with type 1 diabetes has suggested that intensive blood-sugar-lowering strategies reduce the risk of cardiovascular disease and death, and a study in patients with more recent onset of type 2 diabetes than ACCORD participants showed a trend toward a reduction in MI.
"This body of research strongly suggests that lowering glucose levels to levels that are typically observed in people without diabetes could reduce the risk of cardiovascular disease in people with established type 2 diabetes. But, until ACCORD, no major clinical trial had studied whether lowering a raised blood-sugar level to a level similar to that seen in people without diabetes reduces the risk of cardiovascular disease in people with type 2 diabetes. In addition, no clinical trial has studied the effects of intensive blood-sugar lowering in people with longstanding type 2 diabetes who already have cardiovascular disease or who have multiple risk factors for cardiovascular disease in addition to diabetes," Gerstein stated. This was the rationale for ACCORD.
How ACCORD Differs From Previous Studies
Dr Judy Fradkin (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD) reviewed how ACCORD differs from earlier studies of intensive glycemic control. She noted that a crucial difference was that ACCORD studied the effects of lowering glucose to a near-normal level, a lower level than that targeted in earlier studies. In addition, patients enrolled into ACCORD were older (average 62 years), had had diabetes for a longer time (an average of 10 years), and were at a higher risk for cardiovascular disease than patients enrolled in earlier studies of intensive glucose control.
"It is not yet known whether controlling glucose to near-normal levels will prevent heart disease and extend life in other groups such as younger people with diabetes, those earlier in the course of disease and in whom glucose is easier to control, and those without established cardiovascular disease," she said. The results also cannot be extrapolated to patients with type 1 diabetes, she added.
National Heart, Lung, and Blood Institute. ACCORD telebriefing prepared remarks. February 6, 2008. Available at: http ://www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm.
Heartwire from Medscape © 2008 Medscape
Cite this: Sue Hughes. Intensive-Glycemic-Control Arm of ACCORD Stopped - Medscape - Feb 06, 2008.