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Jul 03, 2008

Tight Control and Cardiovascular Disease (Part 3): VADT

Tara Dairman

The VA Diabetes Trial, or VADT, was the third large study of tight blood glucose control and cardiovascular disease (CVD) risk in Type 2 diabetes that was presented at the June 2008 ADA Scientific Sessions. You can read about the results of the other two major studies in this vein, ADVANCE and ACCORD, in "Tight Control and Cardiovascular Disease (Part 1): ADVANCE" and "Tight Control and Cardiovascular Disease (Part 2): ACCORD."

While the VADT's results have not been published yet, preliminary findings from the trial were presented at the ADA Scientific Sessions on June 8, and further results will be presented at the European Association for the Study of Diabetes (EASD) meeting in September.

The VADT
The VADT enrolled 1,791 people, all veterans, at 20 Veterans' Affairs Medical Centers around the United States. It was designed see whether intensive control of blood glucose levels—aiming for HbA1c levels below 7%—would reduce the number of cardiovascular "events" in people with Type 2 diabetes at high risk of CVD. Cardiovascular events measured included heart attack, stroke, death from CVD, severe congestive heart failure, and bypass surgery, among other vascular problems.

Participants had an average age of 60, body-mass index (BMI) of 31 (meaning that they were, on average, obese), and HbA1c of 9.5% at the start of the trial. The vast majority of participants (97%) were men, and about 62% were white. Participants were considered to be at high cardiovascular risk; in addition to having high HbA1c levels, 80% had high blood pressure, 50% had abnormal blood lipid (cholesterol and triglyceride) levels, and 40% had had a prior cardiovascular event (mostly heart attacks, strokes, bypass surgery, angina, or transient ischemic attacks ["ministrokes"]). They had also all been unable to control their blood glucose levels with "simple therapy," or maximum doses of at least one oral diabetes drug or insulin, before the start of the study.

Once the study began, all of the participants were treated intensively with drugs and lifestyle therapies to control their blood pressure and blood lipid levels. Meanwhile, half the participants were randomly assigned to be in the intensive blood glucose control group and the other half were assigned to the standard control group; all were followed for an average of 6.25 years. Members of both groups were prescribed oral drugs and insulin as needed—90% of the intensive group ended up using insulin compared to 74% of the standard group, and slightly more people in the intensive group took oral drugs. Within six months, the intensive group achieved an average HbA1c level of 6.9% and the standard group reached a level of 8.4%. These levels were maintained for the rest of the trial, resulting in an average difference of 1.5 percentage points between the groups.

Results
At the end of the study, the researchers found the following:

• No significant difference in cardiovascular events or death between the two groups
• A drop in average blood pressure in both groups from 131/77 mm/Hg to 127/70 mm/HG
• A drop in average LDL ("bad") cholesterol in both groups from 106 mg/dl to 78 mg/dl
• A rise in average HDL ("good") cholesterol from 34 mg/dl to 40 mg/dl in the standard group and from 34 mg/dl to 39 mg/dl in the intensive group
• A drop in average triglycerides from 157 mg/dl to 135 mg/dl in the standard group and from 157 mg/dl to 128 mg/dl in the intensive group
• Incidences of severe hypoglycemia (very low blood glucose levels, resulting in a change in consciousness) in 21% of participants in the intensive group and 10% of those in the standard group

Although tight blood glucose control did not seem to make a difference in people's risk of cardiovascular events in this study, there was a trend toward fewer events with intensive blood glucose control, with 231 events occurring in the intensive group and 263 in the standard group. However, this difference was not large enough to be considered statistically significant. (A similarly nonsignificant trend was found in the ADVANCE trial.) There was a very slight increase in cardiovascular death in the intensive group (seven additional deaths), but it was also not large enough to be considered significant.

The researchers did point out that fewer cardiovascular events occurred overall than they had predicted at the beginning of the study. This result was likely due to the improvements in cardiovascular risk factors other than blood glucose levels—namely, blood pressure and blood lipid levels—that were seen in both groups in the study, as well as improvements in diet, exercise, and treatment with aspirin.

William C. Duckworth, M.D., Co-Chair of the VADT, commented that "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." (The study's findings on microvascular complications will be presented at the EASD in September.)

Rosiglitazone
The oral diabetes drug rosiglitazone (brand name Avandia) was the most commonly used drug in the first year of the VADT, when it was prescribed to 85% of people in the intensive group and 78% of people in the standard group. By the third year, it was being used by 72% of the intensive group and 62% of the standard group. The researchers found no association between use of rosiglitazone and risk of cardiovascular events or death in this study; in fact, they stated that, if anything, it appeared to provide a protective effect.

These findings contrast with the highly publicized meta-analysis study that linked rosiglitazone to heart attacks and death last year (see "Type 2 Drug Avandia Linked to Increased Risk of Heart Attacks").

Hypoglycemia
In their analysis of the data, the VADT researchers uncovered a link between severe hypoglycemia and cardiovascular risk. They found that people who had experienced severe hypoglycemia within the last three months had a significantly higher risk of having a cardiovascular event. (A possible link between hypoglycemia and cardiovascular events was also proposed to help explain the increase in risk found in the intensive group of the ACCORD study.)

The Take-Home Message
The VADT researchers suggest that intensive blood glucose control early on—closer to a person's diagnosis of diabetes—may be more helpful in preventing cardiovascular problems than intensifying control later. In fact, a substudy of the VADT showed that people who had less advanced atherosclerosis (narrowing of the arteries, a risk factor for CVD) benefited more from intensive blood glucose control in terms of lowering their CVD risk than people with more advanced atherosclerosis.

The researchers also believe that reducing people's risk of severe hypoglycemia is important, since such episodes strongly predicted cardiovascular events in the study.

And the VADT researchers agree with the ACCORD and ADVANCE researchers that controlling blood pressure and cholesterol levels is likely more useful than tightly controlling blood glucose levels when it comes to protecting people with Type 2 diabetes and high CVD risk from cardiovascular events.

Data from the VADT will continue to be analyzed as the researchers prepare for the presentation and publication of further results from the trial. They also plan to continue observing the trial's participants for another nine years.

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