NIH's ACCORD Clinical Trial Publishes Results

As AAFP News Now reported earlier this year, the NIH's National Heart, Lung and Blood Institute halted the intensive glucose-lowering arm of the Action to Control Cardiovascular Risk in Diabetes, or ACCORD, trial because of concerns about the number of deaths in patients who were participating. Results from that arm of the study now have been published in the New England Journal of Medicine, but the troubling deaths that led the NIH to halt the study arm have not yet been explained.

The intensive glucose-lowering arm of the ACCORD trial was targeted at reducing blood sugar levels to near normal in adults with type 2 diabetes who were at especially high risk for heart attack and stroke. Patients who participated in this arm of the study were found to have a 22 percent higher risk of death -- a total of 54 more deaths in a cohort of 5,128 participants -- than those who participated in the arm of the study that sought to lower blood sugar to standard treatment levels.

In the new results, the researchers determined that intensive treatment does not significantly reduce the risk of major cardiovascular events, such as fatal or nonfatal heart attacks or strokes; however, compared with standard treatment, it does increase the risk of death.

In addition, although the study targeted adults who were at higher risk for heart attack and stroke, researchers have suggested that the results might not apply to patients who are at lower risk of cardiovascular disease or patients recently diagnosed with type 2 diabetes. On average, ACCORD participants had been diagnosed with diabetes for 10 years at enrollment.

The study researchers are stumped about what caused the higher number of deaths in the intensive treatment group. "Despite detailed analyses, we have been unable to identify the precise cause of the increased risk of death in the intensive blood sugar strategy group," said lead author Hertzel Gerstein, M.D., M.Sc., the Population Health Institute chair in diabetes research at McMaster University in Hamilton, Ontario, in an NIH news release. Gerstein notes that no specific medication or combination of medications is responsible. The researchers think that an unidentified combination of factors tied to the overall medical strategy is likely behind the deaths.

Participants in the intensive glucose-lowering group used more medications and combinations of medications and changed medications and doses more frequently than participants in the standard treatment group. For example, 52 percent of participants in the intensive strategy group were on three oral medications plus insulin compared with 16 percent of participants in the standard treatment group who used that many interventions. Participants in the intensive strategy group experienced more adverse side effects from medications, hypoglycemic events, weight gain and fluid retention.

The researchers also studied whether participants' baseline characteristics at enrollment affected outcomes. They compared outcomes in participants with and without existing cardiovascular disease, women and men, those older and younger than age 65, those with baseline A1c levels lower and higher than 8 percent, and white and nonwhite participants. Among those in the intensive strategy group, death rates were consistently higher regardless of baseline characteristics. However, compared with participants in the standard treatment group, those in the intensive treatment group who began the study with no history of heart attack or stroke or with lower blood sugar levels (A1c level of 8 percent or less) had fewer combined cardiovascular events during the study.

As noted in the previous ANN story, earlier studies had suggested that lowering blood sugar to near-normal levels in people with type 2 diabetes might reduce cardiovascular disease risk. However, the NIH release points out, those were observational studies rather than randomized clinical trials; unlike the ACCORD trial, they did not test treatments to reduce blood sugar.

In addition, intensive blood sugar control has been shown to reduce microvascular complications from diabetes and to lower cardiovascular disease risk in people with type 2 diabetes. However, the levels tested in previous studies were not as low as the level targeted in the ACCORD intensive treatment group.

Future analyses from ACCORD should help determine the effects of the intensive blood sugar strategy on microvascular disease, cognition, quality of life and other outcomes.