Diabetes doubles heart disease death risk; diabetes control approach may effect outcomes

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 two-fold 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 non-diabetic 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.