ACCORD: Intensive Glucose-Lowering Reduces Ischemic Cardiovascular Events

December 03, 2014

HAMILTON, ON — An analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggests that intensively lowering glucose concentrations in diabetic patients might reduce the risk of ischemic heart disease[1].

The trial's strategy of using multiple agents to achieve intensive glycemic control was associated with a significant 13% relative reduction in the 5-year incidence of ischemic events. Reductions for MI, coronary revascularization, and unstable angina were, on their own, also significant in the analysis, which had not been prespecified.

"At best, you could say that this analysis certainly supports the hypothesis, and it's consistent with other data, showing that more vs less glycemic control seems to have an effect on ischemic heart disease," lead investigator Dr Hertzel Gerstein (McMaster University, Hamilton, ON) told heartwire . "It doesn't explain the [original] ACCORD mortality signal, and it doesn't try to say anything more than that."

The analysis is published in the November 29, 2014 issue of the Lancet.

ACCORD Stopped Early: Mortality Signal

As reported previously, ACCORD was a National Heart, Lung, and Blood Institute (NHLBI) study of 10 251 adults aged 40 to 79 years of age with type 2 diabetes and heart disease (or risk factors for heart disease). In the glycemic-control part of the trial, investigators tested whether an intensive strategy that targets an HbA1c level <6.0% reduces the rate of cardiovascular events more than a standard strategy that targets an HbA1c between 7.0% and 7.9%. The study ran for 3.7 years until it was stopped early because of an increased risk of death in the intensive-therapy arm.

Speaking with heartwire , Gerstein said the primary end point in ACCORD was a composite end point of major adverse cardiac events (MACE), which included nonfatal MI, nonfatal stroke, and death from cardiovascular causes. Death from cardiovascular causes was increased significantly by 35% in the intensive-therapy group, and all-cause mortality went up 22%. Nonfatal MI was reduced by 24%.

While the mortality signal in ACCORD remains unexplained—multiple analyses looking at the speed of glucose lowering, hypoglycemia, the drugs used, weight changes, and glucose levels achieved were all unable to explain it—meta-analyses of other glucose-lowering trials appeared to suggest a benefit in terms of reducing the risk of MI with intensive therapy. For example, a 2009 analysis of ACCORD, ADVANCE, VADT, and UKPDS showed that intensive glucose lowering reduced cardiovascular outcomes by 9%[2]. In this analysis, there was a 15% reduction in the risk of MI and no effect on stroke or cardiovascular death.

"All of the studies consistently show that ischemic heart disease indices seem to benefit over a period of 3 to 4 years with intensive glucose control," said Gerstein. "So, we said let's look in the ACCORD data at the effect of more vs less glucose control on all of the indices of ischemic heart disease that we measured."

During active treatment, the ACCORD regimen focused on intensively reducing glucose concentrations, which significantly reduced the risk of MI by 20% and reduced the composite end point of MI, coronary revascularization, and unstable angina by 11%. Nonfatal MI was reduced 22%. Fatal MIs appeared to increase, but the number of events were small and the increase was not statistically significant.

When investigators included an additional 1.2 years of follow-up after patients were switched to standard glycemic control because of the mortality signal, there was a 16% reduction in the risk of MI and a 13% reduction in the composite end point of MI, coronary revascularization, and unstable angina. During the 5-year follow-up, nonfatal MI was reduced 19%, coronary revascularization by 16%, and unstable angina by 19%.

The investigators also adjusted for HbA1c levels during active treatment, and when they did the reduction in risk of ischemic cardiac events with intensive treatment disappeared.

"This suggests that the reason for the reduction in ischemic heart disease can be explained, at least statistically, by the difference in HbA1c that was achieved during the active part of treatment," said Gerstein. "It's consistent with the hypothesis that glucose lowering does appear to have an effect on ischemic heart disease. But as I said, because it wasn't predefined up front, this can be only hypothesis generating. It does tell us that the story is not over at this point in time."

Making Sense of the Results

In an editorial[3], Drs Jean-Louis Chiasson and Jacques Le Lorier (Université de Montréal, QC) also highlight the 2009 meta-analysis of ACCORD, ADVANCE, VADT, and UKPDS. Along with the latest ACCORD report, they say the findings suggest that early intensive glucose lowering—to a target less than 7.0%—in patients with diabetes, combined with aggressive treatment of other risk factors, is likely to result in a long-term reduction in cardiovascular risk.

"These potential benefits, however, do not totally negate the potential harmful effect of intensive glycemic treatment on cardiovascular mortality in selected patients under specific conditions," they write. At this stage, it is "probably wise to aim for a target HbA1c concentration of less than 64 mmol/mol (8.0%) in patients older than 65 years with comorbidities."

Gerstein doesn't disagree.

"There is no question that intensive glucose lowering has clear benefits on retinal disease, nerve disease, and on renal disease," he told heartwire . "Most people accept that. And it probably has a benefit on some indices of heart disease, but because of the mortality signal that we saw, we can't be applying this indiscriminately to every patient with diabetes. It's more complicated than that."

Gerstein said the clinical guidelines all emphasize individualizing care and to use clinical judgment, noting there might be some benefit from tighter glucose control in selected patients. He personally believes that reducing glucose concentrations intensively has a benefit on clinical outcomes, but it takes longer than 3 or 4 years for such benefits to become evident. He points out that tight glucose control in young type 1 diabetics reduces cardiovascular risk, but these are patients without other comorbidities treated for longer periods of time.

"Some treatments, you plant a seed and they work right away. For others, the seed has to germinate longer," said Gerstein.

ACCORD is primarily sponsored by the National Heart, Lung, and Blood Institute, with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention. Gerstein has received grants from the National Heart, Lung, and Blood Institute, Sanofi, and Lilly and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman LaRoche, Novo Nordisk, and Sanofi. Disclosures for the coauthors are listed in the article. The editorialists declare they have no relevant financial relationships.

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