Latest results from ACCORD: Mortality signal still there

March 02, 2011

Hamilton, ON - The latest results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of intensive glucose lowering in diabetic patients at high risk of cardiovascular disease, with a median follow-up of five years, show similar findings to the earlier results, with a reduction in MI in the intensive treatment group, but the signal of increased mortality remains[1]. And longer term follow-up has not produced any explanation for this observation.

The five-year results are published in the March 3, 2011 issue of the New England Journal of Medicine by the ACCORD study group, led by Dr Hertzel Gerstein (McMaster University, Hamilton, ON).

Gerstein explained to heartwire that the main results of the trial were reported in 2008 soon after the trial was stopped. At that point, there had been 3.5 years of treatment in the study, with patients randomized to intensive treatment with the aim of lowering glycated hemoglobin (HbA1c) levels to below 6%, or normal treatment with the aim of lowering HbA1c levels to between 7.0% and 7.9%. "After this, there were a couple of additional months of study treatment, and then patients were all switched to the normal regimens. So the current results apply to five years of follow-up, of which 3.7 years were active treatment."

Gerstein notes that the results are very concordant with what was seen in the original report. "There continues to be no clear cardiovascular benefit of intensive treatment. Although there is a definite reduction in MI, a mortality increase is still apparent. The mortality curves remained parallel after the transition of everyone to normal treatment. Therefore, the mortality increase in the intensive group occurred early on in the treatment period and then remained the same throughout the study, even after patients were switched back to regular therapy."

ACCORD trial: Five-year outcomes

Outcome Intensive glucose lowering Standard glucose lowering HR (95% CI) p
Primary outcome*        
Before transition 2.0 2.2 0.90 (0.78-1.03) 0.13
End of study 2.1 2.2 0.91 (0.81-1.03) 0.12
Non fatal MI        
Before transition 1.1 1.4 0.79 (0.66-0.95) 0.01
End of study 1.2 1.4 0.82 (0.70-0.96) 0.01
CV death        
Before transition 0.7 0.6 1.27 (0.99-1.63) 0.07
End of study 0.7 0.6 1.29 (1.04-1.60) 0.02
Any death        
Before transition 1.4 1.2 1.21 (1.02-1.44) 0.03
End of study 1.5 1.3 1.19 (1.03-1.38) 0.02

*Primary outcome=a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes

Intensive treatment better in less hyperglycemic patients?

In this latest paper, the ACCORD authors also report new data on blood pressure and lipid levels in the trial, as well as the effect of intensive vs regular glucose-lowering treatment in various subgroups.

Gerstein pointed out that the effect of intensive treatment was similar in most subgroups. The one exception seemed to be those with lower HbA1C levels at baseline, who appeared to have a greater benefit of intensive treatment on the primary outcome than other groups. "It looks as if the intensive therapy may be more protective in patients who were less hyperglycemic at baseline, but this is only a subgroup observation, and it is not statistically significant so should only be viewed as an interesting observation at this point," he commented.

"Not a black-and-white story"

"The most important message from this trial is that this is not a black-and-white story. There is clear beneficial effect of more intensive therapy on lowering MI, but the mortality signal is going in the wrong direction. There may be some benefit of trying to get HbA1c levels below 6%, but it is not straightforward," he continued.

"We just don't understand why we are seeing this mortality signal, and it is not for lack of looking. We've looked at severe hypoglycemia and it's not that, and it also doesn't seem to be caused by the rapid fall of HbA1c levels. There is no clear explanation emerging for this observation," Gerstein added.

Other trials looking at intensive treatment have not shown a mortality increase. Gerstein said, "ACCORD remains the outlier in this regard. All the trials have also shown a reduction in MI, and we know lower HbA1 c levels are better for microvascular effects, but because of the mortality signal in ACCORD, we cannot recommend aiming for glucose levels in the normal range in diabetic patients. We should stick to the current recommendation of below 7% as a reasonable place to be."

Given that the ACCORD intensive arm involved multiple treatments, Gerstein said the results do not necessarily apply to lowering glucose levels with just one or two drugs. "These results apply to the goals we sought and the tools we used to achieve them. If we use different methods, such as fewer drugs or newer agents, they may not apply. If I have a patient who is doing well with an HbA1c level of 7%, I would not change his treatment. But there seems no reason to worry if a patient is with relative ease getting to levels below 7%. So I would also be happy with someone at a level of 6.8% on one or two drugs."

Gerstein receives consulting/lecture fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Medtronic, Merck, Bayer, Bioavail, Janssen-Ortho, Solvay, Boehringer Ingelheim, Servier, and Takeda and grant support to McMaster University from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Merck, Pronova, Roche, Eli Lilly, and Boehringer Ingelheim.



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