NEJM: Death rates w/ intensive therapy remain high at five years

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An intensive therapy to target normal glycated hemoglobin levels reduced five-year nonfatal rates of MI but increased five-year mortality in patients at a high risk for cardiovascular disease and suboptimally controlled diabetes, according to the ACCORD trial published in the March 3 issue of the New England Journal of Medicine. The intensive treatment arm of the study was terminated after an increased rate of mortality was shown.

To evaluate the outcomes of an intensive glucose lowering therapy on mortality and CV events, members of the ACCORD study group assigned type 2 diabetes patients and patients with either CV disease or CV risk factors to receive intensive therapy targeting a glycated hemoglobin level below 6 percent or standard therapy targeting a level of 7 to 7.9 percent.

The researchers terminated the intensive therapy group after a high mortality rate was noticed in the intensive therapy group. The target glycated hemoglobin level was 7 to 7.9 percent for all participants for the remainder of the trial.

Outcomes of the ACCORD trial have been previously reported, however, the current study used intention-to-treat analyses to report the effect of the mean 3.7-year intensive glycemic intervention and the mean 1.2 years of standard glycemic therapy.

The authors reported that prior to the intensive therapy being terminated, the intensive and standard therapy groups did not differ significantly in terms of the primary outcomes—nonfatal MI, nonfatal stroke or death from CV causes. These rates were 2 percent in the intensive therapy group compared to 2.2 percent in the standard therapy group. However, the intensive therapy group had a higher rate of death from any cause and fewer MIs.

After the researchers terminated the intensive intervention, median glycated hemoglobin levels in the intensive therapy group rose from 6.4 percent to 7.2 percent and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar.

At the time of transition the researchers reported a 21 percent higher rate of death from any cause in the intensive therapy group compared to the standard therapy group. This rate was 19 percent higher at the end of the study.

Additionally, the researchers randomized 4,733 patients to receive either intensive or standard therapy to lower blood pressure and 5,518 patients were randomly assigned to receive a statin plus either fenofibrate or placebo to control lipid levels.

The researchers reported no significant interactions between the glucose-lowering study and the blood pressure study for the primary outcome or between the glucose-lowering study and the lipid study for either the primary outcomes or death.

“Reasons for the higher mortality in the intensive therapy group during the pretransition period remain unclear,” the authors wrote.

"[T]argeting normal glycated hemoglobin levels (i.e., <6 percent) required the use of multiple combinations of glucose-lowering medications in ways that are not used in standard care," the authors wrote. Forty-two percent of the study participants within the intensive therapy group received three or more classes of oral agents either alone (17 percent) or in combination with insulin (25 percent), compared with only 19 percent of patients in the standard therapy group.

"Whether these unconventional combinations were responsible for the results and whether similar findings would have been observed with newer glucose-lowering therapies, different drug combinations, or different target glycated hemoglobin levels is unknown," the researchers concluded.

"[T]he results of the ACCORD trial suggest a lower limit for glycemic targets, achieved with the use of multiple combinations of currently available approaches."