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ORLANDO, Fla. -- After an analysis of data collected from
two large multi-center clinical trials, Duke University Medical
Center researchers have found that patients with diabetes have
an almost twofold increase in dying or suffering severe
outcomes from heart disease compared to non-diabetics.

Furthermore, the particular strategy taken in controlling
the diabetes may have an adverse effect on the course of
cardiovascular consequences of the disease, leading the
researchers to question the prevailing wisdom behind current
diabetes treatment. This is an important health policy issue,
they said, because there are currently more than 150 million
people with Type 2 diabetes in the world, a number that is
expected to double by 2025.

After determining that patients with diabetes have
significantly worse cardiovascular outcomes than those without
the disease, Duke cardiologist Dr. Darren McGuire wanted to
find out if there were any differences in outcomes associated
with the strategy used to manage the diabetes. In general
terms, current medication-based strategies are divided into two
approaches: "insulin-providing," in which injected insulin or
other agents make up for the body's inability to produce
sufficient insulin, or "insulin-sensitizing," in which
different agents are taken to stimulate the body's tissues to
better utilize the existing supply of insulin.

"Our unadjusted analysis indicates that patients who are
being treated with insulin-sensitizing agents have better
outcomes than those being treated with insulin-providing
agents," McGuire said. He prepared the results of his analysis
for presentation Wednesday at the 50th annual scientific
sessions of the American College of Cardiology. "Substantial
uncertainty exists regarding the clinical strategies used to
treat the

diabetes and their effects on cardiovascular outcomes.

"Given the high cardiovascular risks faced by diabetic
patients, this situation constitutes a clinical trial
emergency," McGuire continued. "The bottom line is that in the
past we've relied on changes over time in intermediate
biomarkers -- the state of the retina, protein in the urine --
to guide the treatment of diabetes. We target treatment on
maintaining glucose control without regard to the treatment's
specific influence on a major clinical outcome, in this case
cardiovascular disease. Very little scientific information
exists on how diabetes treatments influence heart attack,
stroke and death."

McGuire combined the data from two related trials, SYMPHONY
and Second SYMPHONY (Sibrafiban vs. Aspirin to Yield Maximum
Protection from Ischemic Heart Events Post-Acute Coronary
Syndromes). Both trials, which compared the effectiveness of
aspirin to a new class of "super aspirin" to prevent recurrent
heart attacks, enrolled a total of 15,904 patients at 716
hospitals in 35 countries. Of those enrolled, 3,101, or 19.5
percent, were patients with diabetes.

The trial also collected data on how each patient's diabetes
was being managed. Patients on insulin-providing therapy took
insulin alone or in combination with drugs known as
sulfonylureas, which stimulates the pancreas to produce more
insulin. Patients on insulin-sensitizing drugs take a class of
drugs known as biguanides (of which the commonly-used metformin
is a member) alone or in combination with
thiazolidinediones.

Overall, the researchers found that when compared to
non-diabetics, diabetic patients had a significant increase --
11.4 percent vs. 9 percent -- in the number of severe cardiac
events, including death, after a heart attack. After one year,
6 percent of patients with diabetes had died, compared to 3.5
percent of nondiabetic patients.

"Digging deeper into the data we also found that those
patients taking insulin-providing therapies did worse than
those on insulin-sensitizing therapies," McGuire said. For
example, at 90 days, about 12 percent of insulin-providing
patients had a major cardiac event, compared to only 5 percent
of insulin-sensitizing patients. "It may be that the
insulin-providing approach may actually exacerbate
cardiovascular risk," McGuire noted.

The major problem, according to McGuire, is that there
haven't been any large-scale clinical trials to determine the
effects of diabetes treatments on the cardiovascular
system.

"Up until now, the prevailing medical message for diabetic
patients was that control of blood sugar is the most important
goal," McGuire said. "Although that is an important objective,
it may not be the most important therapeutic goal, especially
when we don't have a clear idea what existing therapies
actually do."

McGuire said he is hopeful that an answer is on the horizon.
The National Heart, Lung and Blood Institute, part of the
National Institutes of Health, has earmarked more than $100
million for two separate but related large-scale trials.
Enrolling more than 12,000 patients with diabetes, these trials
should finally answer some of these questions.

"The fact that the NHLBI is investing more than $100 million
to address these questions is a clear testament to clinical
uncertainty involving diabetes treatment," McGuire said. "The
best thing for diabetes

treatment will be to back it up with more scientific data.
It is amazing to me that we are treating such an important
disease with a paucity of data and a lack of evidence-based
medicine."

McGuire's data is in line the recent United Kingdom
Prospective Diabetes Study which appeared to support the
benefits of metformin alone. The trial also found, however,
that when metformin was combined with a sulfonylurea, the risk
of death due to cardiovascular causes doubled. McGuire
emphasizes these data are preliminary and need to be confirmed
by randomized clinical trials.

Dr. Kristin Newby of the Duke Clinical Research Institute
was the principal investigator for the coordinating center for
both the SYMPHONY and Second SYMPHONY trials.