SOURCE: American Diabetes Association

June 06, 2008 17:00 ET

Previously Unrecognized Harm of Intensified Glucose Lowering Reported in High Risk Patients With Type 2 Diabetes

SAN FRANCISCO, CA--(Marketwire - June 6, 2008) - 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 here today 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.

Other Trial Findings

"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.

Trial Design and Strategy

ACCORD, sponsored by the National Heart, Lung, and Blood Institute, enrolled 10,251 adults at 77 clinics in the U.S. and Canada. Among the participants, 61% were men; 19% were African-Americans; 7% were Hispanic; and the rest were Caucasian. The average age at study entry was 62 years. The 35% who had prior CVD events (heart attacks and strokes) were the secondary prevention group, while the balance who were at high risk for such events had problems such as left ventricular hypertrophy, microalbuminuria, or at least two of the following risk factors: high LDL (the "bad" cholesterol), low HDL (the "good" cholesterol), high blood pressure, an elevated BMI (an indicator of overweight or obesity), or were smokers.

"ACCORD was designed to address the high rates of CVD in type 2 diabetes by testing three complementary strategies for treating the disease," said Hertzel Gerstein, MD, MSc, Chair of ACCORD's Glycemia Group and Principal Investigator of its Canadian Network, in a recent interview. He is a Professor of Medicine and the Population Health Institute Chair in Diabetes Research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

"We were testing an intensive strategy of glycemic control versus a standard strategy, so intensive group patients had more frequent clinic visits and were required to do more frequent self-monitoring of blood glucose, because they modified certain medications themselves in response to self-monitoring results," explained Dr. Gerstein. Intensive patients were seen every two months and standard patients every four months. Intensives were required to self-monitor their blood glucose levels two to four times per day if their A1C was above the target, while the standard group was required to self-test only once a day.

"The same menu of medications was available to physicians treating both groups, but patients in the intensive group tended to be prescribed more of them," said Dr. Gerstein. A broader comparison is that 52% of intensive patients were likely to be on insulin plus three oral agents versus 16% of those in the standard group. However, he also gave examples of particular medications.

"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."

Although the arm of the study under discussion at the American Diabetes Association's Scientific Sessions is the glycemia trial, embedded within it are two other studies. Approximately 45% of each of the intensive and standard glycemic control group patients were given either intensive or standard blood pressure control. Similarly, approximately 55% of each of the intensive and standard glycemic control group patients were given (in addition to background simvastatin to lower LDL cholesterol) a placebo or fenofibrate to raise HDL and lower triglycerides. The blood pressure and lipid trials will close in June 2009.

Nearly 21 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputations. It is the fifth leading cause of death by disease in the U.S. Type 2 diabetes involves insulin resistance ---the body's inability to properly use its own insulin. Type 2 occurs mainly in adults who are overweight and ages 40 and older.

The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities. For more information, please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit www.diabetes.org. Information from both these sources is available in English and Spanish.

Symposium Tuesday, 7:30 am PDT

NOTE TO EDITOR:

Visit http://www.diabetes.org/adablog to read blog posts from the Association's Scientific Sessions from former USA Today reporter, Anita Manning.

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