SOURCE: American Diabetes Association

June 08, 2008 19:15 ET

Intense Blood Glucose Control Yields No Significant Effect on CVD Reduction in VA Diabetes Trial

7.5 Year Trial Surpasses Goals in Blood Glucose, Lipids, Blood Pressure

SAN FRANCISCO, CA--(Marketwire - June 8, 2008) - A major long-term U.S. clinical trial to study whether intense control of blood glucose in type 2 diabetes would reduce the risk of cardiovascular disease found a reduction in cardiovascular events, but it was not statistically significant, according to a report presented here today at the American Diabetes Association's 68th Annual Scientific Sessions.

"This was a complicated study in which all of the patients had multiple health problems, including 40% with prior cardiovascular events. Our first goal was to reduce all other cardiovascular risk factors in order to compare outcomes between standard and intensive blood glucose treatment groups -- and we achieved that goal superbly," said Carlos Abraira, MD, Professor of Medicine at the Miami VA Medical Center, University of Miami Miller School of Medicine, and Co-Chair of The VA Diabetes Trial. On average, participants in both groups were at or below targets for lipids and blood pressure within the first two years, and maintained them for the six years of their participation.

While the average A1C, a measure of blood glucose control over the prior two to three months, was 9.5% upon entry into the trial, the standard group reached 8.4% and the intensive group reached 6.9% within six months. These A1C levels were maintained throughout the trial, assuring a sufficient separation between groups to discern a difference.

"While we found that intensive treatment of patients with type 2 diabetes suggested some benefits from glucose control, it did not reach significance for a reduction in the primary endpoint -- a composite of specified cardiovascular disease events -- in this population," said William C. Duckworth, MD, Director of Diabetes Research, Carl T. Hayden VA Medical Center in Phoenix, Professor of Clinical Medicine, University of Arizona, and Co-Chair of the trial.

"The aim of this study was to examine a typical older VA population, mostly male, and around 60 years of age at the outset of the 7.5 year study," he said. "Our results may not be applicable to earlier treatment of younger patients with less advanced diabetes."

Trial Strategy and Findings

Dr. Duckworth explained that the VA Diabetes Trial specifically included only patients who had already failed what he called "simple therapy."

"They had unacceptable A1Cs on maximal doses of at least one oral antidiabetes drug and/or insulin, meaning they averaged 9.5% when a normal A1C is 6%," he said. "So, among the current crop of outcome studies, we had the highest risk population from the point of view of A1Cs, as well as in terms of cardiovascular disease because, in addition to the 40.4% with prior events at the outset, 80% had hypertension, over 50% had lipid abnormalities, and the vast majority were obese."

"We had significantly fewer CVD events in both groups than predicted," he said. The predicted CVD event total was between 650 and 700 events, whereas the actual in the standard group was 263, and the intensive group was 231 events. "Based on historical studies, we believe this was largely due to the excellent blood pressure control, lipid control, improved diet and exercise, and treatment with aspirin. Both our intensive and control groups reduced their blood pressure levels to a mean of 127/70 mm/Hg, and both improved lipid control to near or at ADA guidelines."

Having taken out the effects of all of these CVD risk factors so they could focus entirely on blood glucose control, and having achieved an A1C difference of 1.5% between the intensive and control groups (although there was the possibility of benefit for intensive glucose control), there was no significant difference in number of deaths between the two groups.

"We think that if you reduce all the other CVD risk factors, A1C is a stronger marker for microvascular complications, such as retinopathy, nephropathy, and neuropathy, than for macrovascular complications such as heart attacks and strokes," said Dr. Duckworth.

"For intensive glucose control to yield a significant benefit on cardiovascular risk reduction, you may have to do it early. If you go into a population that already has multiple risk factors -- or prior CVD -- and longstanding poor glucose control, you cannot expect benefits from glucose control in the short term," he emphasized. "You can't expect miracles."

The composite primary endpoint included: myocardial infarction, stroke, or death from cardiovascular disease; severe congestive heart failure; surgical intervention for revascularization surgery (such as bypass) for the brain, heart, and legs; amputations for vascular insufficiency proven by pathology; and inoperable vascular disease.

"While we did not find a significant benefit of glucose control on any of the individual components, all endpoints favor good glucose control except cardiovascular death, where there was a very slight, insignificant increase in the intensive group," said Dr. Duckworth.

The group has not begun to analyze the secondary endpoint results, which include microvascular events such as retinopathy, neuropathy, nephropathy, as well as lesser cardiovascular conditions (such as angina, claudication, and transient ischemic attacks), quality of life and cost effectiveness. They will be presented at the European Association for the Study of Diabetes meeting in Rome in September.

Study Background and Design

"Many epidemiological studies across various populations have shown a direct relationship between glucose levels and cardiovascular disease, but prior clinical studies have failed to demonstrate a significant cardiovascular event reduction from good glycemic control. Thus, well-designed clinical trials were needed to determine if the relationship between cardiovascular disease and glucose levels was more than a simple association," said Dr. Abraira explaining why the trial was launched. That is why the researchers sought to eliminate as many variables as possible other than glycemia.

The VA Diabetes Trial of Glycemic Control and Complications in Diabetes Mellitus Type 2, also known as the VA Diabetes Trial (VADT), enrolled 1,791 U.S. veterans at 20 Veterans' Affairs Medical Centers around the country. Among the participants: 97% were men; 16% were African-Americans; 16% were Hispanic whites; 62% were non-Hispanic whites; and 5% other races. The average age at study entry was 60 years. Of the 40% who had prior CVD events, those events were mostly heart attacks and strokes, bypass surgery of the carotid or coronary artery or legs, and lesser conditions such as angina, or transient ischemic attacks.

By the time the trial closed at the end of May 2008, it had been ongoing for 7.5 years, but the average follow-up time for individual participants had been 6.25 years.

Goals Achieved

"Everyone in both groups was treated with maximum lipid, blood pressure, diet and lifestyle control, which included education and counseling on exercise, diet and smoking," said Dr. Abraira. "Throughout the trial, each patient had a visit with a nurse every three months, and we believe adherence and achievement records are impressive, especially for this older population."

--  The greatest success was in blood pressure, in which the group entered
    at 131/77 mm/Hg and reached 127/70 mm/Hg within six months, and stayed
    there throughout the trial.
--  While 57% exercised regularly at the end of the first year, adherence
    leveled off to 40% by year 6.
--  Diet adherence, measured by the nurse by means of a questionnaire
    every 3 months, was 68% at the end of the first year, and reached 60% by
    year 6.
--  All were at -- or better than goal -- for the cholesterol fractions at
    year 5, with LDL declining from 106 mg/dL at entry to 78 mg/dL. HDL rose
    from 34 mg/dL at the outset to 40 mg/dL in the standard group and 39 mg/dL
    in the intensive group. Triglycerides fell from 157 mg/dL at the outset to
    135 mg/dL in the standard group and 128 mg/dL in the intensive group.
--  At study entry, 16% were smoking, which dropped to 12% at one year and
    10% by year 6.
--  The glycemic goal for the intensive group as near normal as possible
    for the intensive group and between 8 and 9% for the standard group, in
    order to maintain a 1.5% separation, which was achieved. In A1C, the
    intensive arm reached a median of 6.9% and the standard arm 8.4%.
    

Drug Therapy

"Most people received two to three oral agents plus insulin," reported Dr. Abraira. By the end of the first year and thereafter throughout the trial, 90% in the intensive group were on insulin, whereas only 74% in the standard group were taking insulin throughout the trial after the first year. Ninety-four percent of all participants were taking oral antidiabetes drugs throughout the duration of the trial, albeit more so in the intensive group than the standard group, but the difference was minimal.

Rosiglitazone was the drug most commonly prescribed in the first year -- 85% of intensives and 78% of those in the standard group. However, because some people gained too much weight or developed edema by the third year, drug patterns changed despite the original intention that investigators were supposed to use the same drugs in both arms. Thus, by the third year, 72% of the intensives but only 62% of the standard group were on rosiglitazone.

"The investigators were more aggressive with rosiglitazone and practically everything else in the intensive arm in order to maintain the desired A1C goals," said Dr. Abraira.

Metformin was the most common drug used in obese people, and was consistently used in the first year in 75% of the intensives and 71% of the standard group. This level dropped off throughout the trial, reaching 60% in intensives and 55% in the standard group by the fifth year.

Use of glimepiride, initially used only in lean patients (85% of participants were obese) increased over the course of the trial. By year five, it was used by 55% of intensives and 45% of the standard group.

Use of oral drugs dropped off over the years as use of insulin and glymepiride increased.

There were no increased deaths associated with any of the drugs used, including rosiglitazone.

Hypoglycemia

Always a concern in those taking insulin, especially older adults, are episodes of hypoglycemia (low blood glucose) in which symptoms can range from lightheadedness to loss of consciousness. If someone is not around to help the individual, coma and death could occur. "The rate of hypoglycemia was a little bit higher than we expected, although we took great caution to prevent it," said Dr. Abraira.

"When an episode of impaired consciousness occurred, it usually was not repeated, probably because the nurse or doctor adjusted the medication regimen," explained Dr. Abraira. He reported that 21% of those in the intensive group vs. 10% of those in the standard group had severe hypoglycemia requiring medical assistance, which was statistically significant.

Observation to Continue

The plan is to continue the VA Diabetes Trial as an observational study for another 9 years. The researchers will obtain data on their patients from the VA's central electronic database.

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. African Americans, Hispanic/Latino Americans, American Indians, and some other ethnic groups are at particularly high risk for type 2 diabetes and its complications.

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, Sunday, 4:15 pm 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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