Low HbA1c not linked to mortality

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Our findings show that neither a rapid early reduction of glucose, and thus HbA1c, nor a sustained near-normal level of HbA1c were associated with the excess mortality accompanying intensive glycemic treatment,” Matthew C. Riddle, MD, professor of medicine at Oregon Health and Science University, told Endocrine Today. “Instead, findings show that the excess risk occurred among participants who could not reduce HbA1c very much despite vigorous efforts to do so.”

The ACCORD glucose control clinical trial investigated whether an intensive strategy targeting HbA1c levels of less than 6% would reduce the risk for cardiovascular disease in patients with type 2 diabetes at high risk for CVD. Researchers randomly assigned 10,251 patients to a standard strategy (target HbA1c, 7% to 7.9%) or an intensive strategy (target HbA1c, <6%). The data and safety monitoring board advised stopping intensive glycemic treatment in ACCORD in February 2008 after 3.4 years because of increased mortality in the intensive treatment arm (257 deaths vs. 203 deaths).

Data presented at the American Diabetes Association’s 69th Scientific Sessions in June revealed that lower HbA1c levels were associated with lower mortality in patients assigned to both strategies. Each 1% higher HbA1c level was associated with a statistically significant 66% higher RR for mortality in the intensive group and a trend in the same direction in the standard group. In addition, patients who rapidly lowered their HbA1c levels during the first year of treatment appeared to have a lower risk for death. Excess mortality in the intensive control group occurred among those who were unsuccessful in reaching a target goal at or near 6%.

New analysis of ACCORD data

The current analysis “explored whether on-treatment HbA1c itself had an independent relationship with mortality.” The researchers analyzed data obtained during 3.4 years of follow-up before the intensive arm was halted.

According to the researchers, “these analyses implicate factors associated with persisting higher HbA1c levels, rather than low HbA1c per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.”

The increased risk started to emerge within one to two years after the strategy began to aggressively lower the participants’ blood glucose levels. According to the researchers, a higher average on-treatment HbA1c was a stronger predictor of mortality than HbA1c for the last interval of follow-up or the decrease of HbA1c in the first year. Further, higher average HbA1c was associated with a greater mortality risk.

The analysis suggested that mortality risk with the intensive strategy increased linearly from 6% to 9% HbA1c and appeared to be greater with the intensive strategy compared with the standard strategy only when average HbA1c was less than 7%.

“Targeting 7% HbA1c or lower continues to be an evidence-based goal of treatment in type 2 diabetes in general, but ACCORD suggested that a subgroup of patients should seek less ambitious HbA1c goals. Our findings support the view that we will have to consider different HbA1c targets and perhaps different treatment strategies for different groups of patients,” Riddle said in the interview.

The most recent analysis of ACCORD data appear to answer the question of whether rapidly reducing HbA1c levels, or achieving low HbA1c levels, can be seriously harmful, but it does not provide answers as to what caused the excess mortality, Riddle said.

“We still don’t know why more patients in the intensive group died. We wish we knew what it was about this group that caused the additional risk, but we don’t,” Riddle said in a press release. One practical question for future analyses is how to identify the people for whom an intensive regimen may be risky, he told Endocrine Today.

Riddle said his team will continue to investigate potential causes of the increased mortality, including the role of weight gain during the study. The researchers “still need to understand whether changes of weight or use of specific drugs may be associated with either greater or lesser risk during use of the intensive treatment strategy,” he said.

Another question that remains is whether hypoglycemia contributed to the risk. Although analyses to date do not show a link between severe hypoglycemia and higher mortality with an intensive strategy, the data “do not entirely rule out the possibility that repeated mild or moderate hypoglycemia was related to risk in some way,” Riddle said.

In an accompanying editorial, Edward J. Boyko, MD, MPH, professor of medicine, University of Washington, and chief of the general internal medicine section, VA Puget Sound Health Care System, said another possible clue may be the higher mortality associated with resistance to glucose control.

“Whether continuing to pursue intensive treatment in patients in whom no improvement in glucose control leads to more harm than good should be pursued as a possible explanation for the puzzling findings of ACCORD,” Boyko wrote. – by Katie Kalvaitis