High Risk for Intensified Glucose Lowering in High Risk Patients with Type 2 Diabetes- Accord Study

For the first time a previously unrecognized harm due to a strategy of intensified glucose lowering in high risk patients with type 2 diabetes has been identified, according to a report at the American Diabetes Association’s 68th Annual Scientific Sessions.

The news came in a report on the Action to Control Cardiovascular Risk in Diabetes trial, known as ACCORD, sponsored by the National Heart, Lung, and Blood Institute. The trial had been studying whether a strategy of intensive control of blood glucose in type 2 diabetes could reduce the risk of cardiovascular disease. A safety review terminated its intensive treatment arm in February due to an increased death rate in the intensive treatment group.

All-cause mortality reported today indicated that the intensive group had a 22% higher relative risk of death compared to the standard group, which translates into an absolute mortality increase of about 1% during the average 3.5 years of treatment and follow-up.
The goal of the intensive group was to reach an A1C level of less than 6%, while the standard group goal was between 7 and 7.9%. In fact, at the time of termination, the median A1C was 6.4% in the intensive group vs. 7.5% in the standard group. A1C is a measure of blood glucose over the prior two to three months.

“The major clinical implication is that there is some risk associated with this level of intensification of glycemic control in high risk cardiovascular patients with type 2 diabetes similar to ACCORD patients and that has to be considered by clinicians in the management of the disease,” said Robert Byington, PhD, head of the ACCORD coordinating center and Professor of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston Salem, NC, in a recent interview. He noted that all ACCORD patients were at high risk: 35% had had a CVD event such as a heart attack or stroke prior to entering the trial; the balance had subclinical cardiovascular disease or major cardiovascular risk factors.

“Despite the fact that we achieved a good 1.1% difference in A1C levels between the two treatment groups, the intensive group patients only had a non-significant 10% lower risk of our primary outcome measure, the first occurrence of a major fatal or non-fatal cardiovascular event during follow-up. In ACCORD, we defined this as having a nonfatal heart attack, a nonfatal stroke, or dying from a cardiovascular cause,” said Dr. Byington. “Specifically, 6.9% of intensives vs. 7.2% of the standard patients had one of these events during the 3.5 years of treatment and follow-up.”

The following secondary outcomes were also assessed in ACCORD. The rate of cardiovascular death due to events such as heart attacks, heart failure, and arrhythmias was 35% higher in the intensive group, a significant finding. In contrast, there was good news in another secondary outcome. Those in the intensive group had a 24% lower risk of nonfatal heart attacks, which was also a significant finding. However, there was no difference between the two groups in the rate of nonfatal strokes and heart failure.

The 22% higher total mortality in the intensive group – the reason for trial cessation – was also a secondary outcome. Dr. Byington reported that 5% of intensive participants compared to 4% of standard participants died during the 3.5 years of follow-up. This reflected the deaths of 257 intensive patients compared to 203 standard patients who died, a difference of 54 people. Patients in both groups died of a variety of causes.
A significant question remains in that the researchers were unable to date to identify any subgroup among the intensive patients as more likely to die in response to intensive therapy, despite analyses by age, gender, ethnicity, comorbidities, glycemic control, current or severe hypoglycemia, drugs used (including rosiglitazone), or combinations of these factors.

“All we can say at this time is that it appears that a strategy of intensive glycemic lowering itself, compared to a standard approach, in a population of people with type 2 diabetes at high risk for cardiovascular disease, increases mortality over the course of three and a half years of treatment,” said Dr. Byington.  “We will be continuing to follow all of the patients who have been in the study for at least another 18 months, when the study was scheduled to end in 2009, and we will reanalyze the results at that time,” he said.

ACCORD, sponsored by the National Heart, Lung, and Blood Institute, enrolled 10,251 adults at 77 clinics in the U.S. and Canada.  “The treating physicians were told to use any drugs they wanted to get to the target, enabling them to use their clinical judgment to determine the order and types of medication to be used,” said Dr. Gerstein. “Because all intensive and standard patients had the same drugs but those in the intensive therapy group had more of them, we must say that it is the intensive strategy that was associated with the higher mortality.”

Publishers Comment:  I believe that it is too early to change the way we treat patients from the results of this study.  If you look at the study, you can see that those in the intensive control group were patients that already had cardiovascular problems, most were obese or overweight and they were given industrial doses of medications for high blood pressure, cholesterol, diabetes and other medical problems.    And the intensive control patients never even got to an A1c of 6%.  

Presented at the American Diabetes Association’s 68th Annual Scientific Sessions.
Martínez-González MA, et al "Adherence to Mediterranean diet and risk of developing diabetes: A prospective cohort study" BMJ 2008:
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FACT:
The world’s largest diabetes trial, The Advance Trial, has shown intensive blood glucose can reduce the risk of kidney disease by 21% with no evidence of any increased risk of death when blood glucose was intensively controlled.  See This Weeks’ Item #2

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