ACCORD: Intensive glucose therapy ups mortality risk at 5 years

New 5-year outcomes from the ACCORD trial show that intensive insulin therapy reduced the risk for nonfatal myocardial infarction but raised the risk for all-cause mortality in older patients with type 2 diabetes who have risk factors for cardiovascular disease.

“The higher risk of death from any cause and from CV causes in the intensive-therapy group means that a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be generally recommended in this population,” the ACCORD Study Group wrote in The New England Journal of Medicine.

Researchers examined the effect of intensive glucose lowering (target HbA1c <6%) on mortality and key CV outcomes at 5 years vs. standard therapy (target HbA1c, 7%-7.9%). The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study cohort included patients aged 40 to 79 years with an at least 10-year history of type 2 diabetes. At baseline, all had HbA1c levels of at least 7.5% and had evidence of CVD or were at high risk for disease. The study’s primary outcome was a composite of nonfatal MI, nonfatal stroke or death from any CV causes.

After a mean of 3.5 years, results revealed higher mortality among patients in the intensive-therapy group. Consequently, the intensive-therapy arm was stopped in 2008. The patients were then switched to standard therapy and followed for up to 17 additional months, providing the researchers with 5-year follow-up information.

Before the transition to standard therapy for all patients, the researchers observed no notable differences in the incidence of the primary outcome between the intensive-therapy group and the standard-therapy group (HR=0.9; 95% CI, 0.78-1.03), a result that did not change significantly throughout 5 years (HR=0.91; 95% CI, 0.81-1.03).

However, the researchers noted a disparity between the two groups in the rates of nonfatal MI and mortality at the time of transition. Nonfatal MI was lower among patients assigned to intensive therapy vs. those assigned standard therapy (HR=0.79; 95% CI, 0.66-0.95), a finding that was also present at the study’s conclusion (HR=0.82; 95% CI, 0.70-0.96). Nevertheless, the rate of death from CV causes was nonsignificantly higher (HR=1.27; 95% CI, 0.99-1.63). Again, similar results were found at the study’s conclusion (HR=1.29; 95% CI, 1.04-1.6).

Data also demonstrated that all-cause mortality was higher in the intensive-therapy arm vs. the standard-therapy arm at the time of transition (HR=1.21; 95% CI, 1.02-1.44) and remained higher after the study ended (HR=1.19; 95% CI, 1.03-1.38).

After intensive therapy was discontinued, patients in this group experienced an HbA1c increase from 6.4% to 7.2%. Rates of severe hypoglycemia and other adverse events remained similar between study arms, as did the use of glucose-lowering medications.

“The results of the ACCORD trial suggest a lower limit for glycemic targets, achieved with the use of multiple combinations of currently available approaches,” the researchers concluded.

For more information:

The ACCORD Study Group. N Engl J Med. 2011;364:818-828.

This study provides a little more detail about the 'bottom line' in the ACCORD study, which to me remains caution regarding coaching patients with type 2 diabetes that 'lower is better' with regard to glycemia and HbA1c. Clearly we do not know what is behind the excess event and death rate in patients who receive aggressive therapy, but I think it is biologically plausible to believe that the neurohumoral response to clinically unrecognized hypoglycemia may contribute to silent myocardial ischemia. In the absence of more definitive information, I continue to coach 'lower is better' for those patients with type 2 diabetes and prediabetes/metabolic syndrome who are on antihyperglycemic treatments that pose no risk for hypoglycemia, such as metformin, thiazolidinediones and incretins. For patients who use insulin and/or sulfonylureas, I tend to coach them toward an HbA1c level in the 6.5% to 7% range.

– Stephen A. Brietzke, MD
Endocrine Today Editorial Board member

Disclosure: Dr. Brietzke reports no relevant financial disclosures.

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