When a landmark trial was stopped early due to a higher death rate in patients randomized to intensive glycemic control, the key question was the medical equivalent of the murder-mystery line, "Who done it?" What caused the higher death rate with intensive control compared with standard glycemic targets?
The randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes (ACCORD), involving 10,251 patients with diabetes who were at high risk for cardiovascular disease, showed a 22% higher all-cause mortality rate among the 5,128 patients whose treatment arm aimed for a hemoglobin A1c level of less than 6% compared with patients whose target HbA1c was in the range of 7%-7.9% (N. Engl. J. Med. 2008;358:2545-59).
Subsequent analyses showed that a rapid drop in glucose wasn’t the cause. Neither was a low HbA1c level in and of itself. "It’s not a problem to get a lower A1c if you’re trying to," explained Dr. Richard M. Bergenstal of the ACCORD study team.
Dr. Richard M. Bergenstal
Neither could weight gain or the use of thiazolidinediones or other medications explain the higher mortality risk with intensive glycemic control.
Episodes of severe hypoglycemia increased the risk for death in both the intensive- and standard-therapy groups, but the general consensus is that severe hypoglycemia did not explain the difference in death rates between those groups, according to Dr. Bergenstal, executive director of the International Diabetes Center at Park Nicollet Health Services, Minneapolis.
Mild hypoglycemia was also investigated as a possible factor in the higher death rates. To get a profile of the potential risk associated with mild hypoglycemia, the ACCORD researchers analyzed more than 9.4 million data points from self-monitored blood glucose tests recorded over an average 2-year period by 5,347 patients, approximately half of the ACCORD cohort, he said at the annual meeting of the American Diabetes Association in San Diego.
What they found was surprising. It wasn’t a high or low HbA1c per se that was most associated with the increased mortality risk in the intensive control group, but unintended high or low blood sugars.
"The more you diverge from what you’re trying to achieve in glycemic targets, the higher the risk of mortality," Dr. Bergenstal said.
In Dr. Bergenstal’s opinion, this implies that clinicians should set a goal not only for HbA1c levels but for blood glucose levels, and they should monitor and evaluate patients’ blood glucose profiles.
"If you’re not achieving the target you set, be careful, and think about whether you want to intensify further if you’re diverging from that," he suggested.
Of the patients with self-monitored blood glucose data, the 2,691 patients in the intensive control group tested their blood sugar levels a mean of 2.7 times per day, compared with 2 times per day for the 2,656 patients with data in the standard control group.
Those who tested more frequently tended to have lower HbA1c levels. In the intensive control group, those who tested blood glucose once per day had a mean HbA1c of 6.9% and those who tested five or more times per day had a mean HbA1c of 6.5%. In the standard control group, those who tested blood glucose once per day had a mean HbA1c of 7.8% and those who tested five or more times per day had a mean HbA1c of 7.3%.
When the investigators analyzed the blood glucose monitoring data by 2-hour intervals, a profile emerged of rising blood sugar levels during the day and a significant drop in glucose levels overnight, in both the intensive and standard control groups.
"The more steep both of those trajectories are, the worse they did," Dr. Bergenstal said.
This indicates that medication approaches are needed to help smooth out this type of curve, he said.
A modal day profile of patients with one or more severe hypoglycemic reactions produced the same pattern but with more instability – a sharper curve of blood glucose values going up during the day, and a sharper curve down overnight. Among patients who died, the modal day profile featured even steeper increases in blood glucose values during the day and sharper drops overnight.
"I can’t say we’ve had the database open long enough to go back and say, ‘At 8 p.m. on March 22, what happened to this person?’ But we will, trust me. We will look even closer at these numbers over time," he said. "I think they’re already giving a sense that it’s probably not a good thing to be going up and down with such velocity."
Difficulties in Controlling Blood Glucose Values