NEW ORLEANS — Updated information from two major trials sheds new light on the role of intensive glucose control in patients with type 2 diabetes.
During a press briefing at the annual scientific sessions of the American Diabetes Association, investigators from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial reported that low blood glucose levels do not explain the excess deaths seen in the intensive control group of that study.
“We have been investigating a number of different candidates for such a cause,” Dr. Matthew C. Riddle, professor of medicine at Oregon Health and Science University, Portland, and a member of ACCORD's Glycemia Management Group, said during a press briefing. “The leading candidates are hypoglycemia, which can be harmful for high-risk individuals; change of weight, which would change the metabolic situation of these people; different drugs or combinations of drugs; and rapid changes or low levels of glucose.”
ACCORD incorporated three complementary strategies for intensive or standard control of blood sugar levels, blood pressure, or lipids in 10,251 adults. For diabetes treatment, physicians could choose from any of the approved drug classes.
The goal of the trial was for the intensive-treatment group to reach a hemoglobin A1c level of less than 6% and for the standard-treatment group to reach a level between 7.0% and 7.9%, but findings showed a 20% increased mortality risk in the intensive-treatment group (N. Engl. J. Med. 2008;358:2545-9). Analyses of the interim results could find no specific reason for the increased risk of death from intensive glycemic control.
According to data presented at the meeting, the excess mortality risk in the intensively treated patients occurred among those who failed to reach HbA1c levels close to 6%, and under 7%. “This is a paradox, because the intensive-treatment strategy was aimed at lowering HbA1c, yet increased the risk of death,” Dr. Riddle said. “We don't know why this is, but we think this has important clinical implications: that people who easily achieve HbA1c values below 7% do not necessarily have an increase of cardiovascular risk. But the ones who struggle to improve their glucose control appear to be at risk.”
Dr. Denise Bonds, a medical officer for ACCORD at the National Heart, Lung, and Blood Institute, in Bethesda, Md., presented findings related to hypoglycemia.
Among the 451 deaths that occurred in both groups combined, 7% had at least one severe hypoglycemic event that required medical assistance. Women, African Americans, and those who had diabetes complications, who were older, and who had low education levels, had a higher risk of hypoglycemia.
Within both the intensive- and standard-treatment arms, having a hypoglycemic episode was associated with an increased risk of death. This risk was greater among standard-arm participants. It did not reach statistical significance among intensive-arm participants.
“However, among participants who had experienced an episode of severe hypoglycemia, the risk of death was greater among standard-arm participants,” Dr. Bonds said. “Thus, at this point, we do not believe that severe hypoglycemia is responsible for the increased risk of death seen among intensive-arm participants.”
Analysis of data from the Veterans Affairs Diabetes Trial (VADT) found that the risk of cardiovascular events, including death, was 40% lower in adults who initiated intensive glucose control in the first 15 years after a diagnosis of type 2 diabetes, but this pattern was not seen in adults who initiated intensive glucose control 16–20 years after diagnosis.
Moreover, initiation of intensive control 20 or more years after diagnosis was associated with an increased risk of cardiovascular events, including death, reported Dr. William C. Duckworth, cochair of the trial and director of diabetes research at the Carl T. Hayden VA Medical Center in Phoenix.
The study enrolled 1,791 patients from 20 VA medical centers nationwide. Their mean age at study entry was 60 years, and 97% were men. More than one-third (40%) had prior cardiovascular events, 80% had hypertension, and more than 50% had lipid abnormalities. Most were obese and their average HbA1c level was 9.5% (N. Engl. J. Med. 2009;360:129-39).
Patients were allocated to an intensive or standard glucose-lowering therapy; most received two to three oral antidiabetes agents plus insulin.
The main factor associated with reduced mortality was the patient's level of HDL cholesterol. Dr. Duckworth and his associates observed an 80% decrease in the risk of cardiovascular events, including mortality, for every 10-mg increase in HDL cholesterol above each patient's baseline, a 50% decrease in risk of a first primary cardiovascular event for every 10-mg increase in HDL, and a 55% decrease in risk of all-cause mortality for every 10-mg increase in HDL. “The benefit was as high as a reduction of 90% in some deaths with an improvement in HDL,” Dr. Duckworth said. “Both treatment groups had strong benefits from the HDL.”
Severe hypoglycemia was also associated with increased risks of adverse events and death. In both groups combined, patients who had experienced hypoglycemia severe enough to cause changes in consciousness had an 88% increase in primary cardiovascular events and a threefold increase in cardiovascular death. “Multiple hypoglycemic events strongly increased the risk of death” in both groups, he said. The findings “may provide clues to breaking down diabetes into manageable subgroups. In the short term, I strongly encourage that we avoid severe hypoglycemia whenever possible,” said Dr. Duckworth.
A key message from the trial is to treat diabetes “early, and treat carefully,” adjust HbA1c goals to the individual patient, and encourage patients to report all episodes of hypoglycemia, he concluded.
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