Tight glucose control is widely known to lower cardiovascular disease (CVD) risk in Type 2 diabetics. Now, the same can be said for Type 1 diabetics, those who require daily intake of insulin via injection, inhalation or pumps. Results of a follow-up study to the landmark Diabetes Control and Complications Trial (DCCT), reported during a "Late-Breaking Clinical Trials" session at the 65th scientific sessions of the American Diabetes Association (ADA; Alexandria, Virginia) last month, were characterized by the ADA's top scientific official as "the biggest news story of this meeting."

At a press conference prior to the results unveiled for the Epidemiology of Diabetes Interventions and Complications (EPIC) study, Richard Kahn, PhD, the ADA's chief scientific and medical officer, said it was "remarkable to see this kind of substantial reduction [in CVD rates] after just six years of intensive therapy." The EDIC research was a follow-up to the epic DCCT study, which compared intensive management of blood glucose to conventional control in 1,441 persons with Type 1 diabetes. DCCT and EDIC were funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (NIH; both Bethesda, Maryland).

David Nathan, MD, of Massachusetts General Hospital (Boston), who co-chaired the DCCT/EDIC research group, noted that the original DCCT study focused on eye, nerve and kidney damage of Type 1 diabetes, finding that intensive glucose control "greatly reduced" such effects. That study, which ran from 1983 to 1993, involved intensive treatment through at least three insulin injections a day, or via an insulin pump. "Intensive" meant keeping hemoglobin A1c (HbA1c) as close as possible to what is considered "normal" 6% or less. The HbA1c blood test reflects a person's average blood sugar over a two- to three-month period and is a key diagnostic used in determining both control and compliance by both Type 1 and Type 2 diabetics.

The EDIC study focused on such cardiovascular events as angina, heart attack and stroke, with the most remarkable finding being the long-lasting benefit of such control. In a statement, EDIC chair Saul Geneth, MS, of Case Western Reserve University, said, "The longer we follow patients, the more we're impressed by the lasting benefits of tight glucose control." He said that the earlier such therapy begins and the longer it is maintained, "the better the chances of reducing the debilitating complications of diabetes."

The results indicate that the intensively treated patients, among the roughly 1,375 persons who volunteered to continue in the study while continuing intensive therapy on their own, had less than half the number of CVD events 46 vs. 98 than the conventionally treated group. Noting that the risk of heart disease is "about 10 times higher in people with Type 1 diabetes than in people without diabetes," a proportion he termed "much higher than in the Type 2 population." Nathan added that tight control "is difficult to achieve and maintain, but its advantages are huge."

The "major message" of the EDIC study after some 6-1/2 years of follow-up, he said, is that "intensive therapy should be implemented in as many Type 1 patients as possible and as early as possible."

Cardiovascular breaks 'ethnic' drug ground

Cardiovascular technology often breaks new ground for the medical device arena, and a recent FDA panel recommendation demonstrates that it can pave the way for pharmaceutical development as well. In mid-June the agency's Cardiovascular and Renal Drugs Advisory Committee voted 9-0 to recommend approval of BiDil, a cardiovascular drug made by NitroMed (Lexington, Massachusetts), with that approval specifically targeting its use in African-Americans.

While FDA panels focus on the clinical benefits of therapeutics, the question of labeling and thus marketing to a specific ethnic group persisted throughout the day-long panel gathering to consider the recommendation for the drug. The application for the drug, combining the generic drugs isosorbide dinitrate and hydralazine hydrochloride, was based primarily on data from a single study developed by a hypothesis that arose from two previous trials, those earlier trials failing to convince the FDA of BiDil's value for use in the general population.

However, the pilot African-American Heart Failure Trial (HeFT) demonstrated that BiDil provides significant cardiovascular benefit among that subgroup population, improving all components of a composite primary endpoint. "Race was the strongest predictor of survival," said Michael Sabolinski, NitroMed's senior vice president of clinical development and regulatory affairs. Specifically, BiDil patients had a 43% lower risk of death, compared to those on placebo, a 39% lower risk of hospitalization for heart failure and a better quality of life.

Publicity concerning the targeting of a specific racial group has raised the issue to the level of controversy in the general media, and during the meeting critics expressed their opposition to race-specific labeling. Additionally some panelists noted a lack of genomic evidence available to define race, with A-HeFT patients identifying themselves as African-American, unsupported by measurable evidence.

But there was not much arguing the benefit seen in the HeFT trial results. "I have to approve a drug when I think there's evidence you can reduce mortality by 43%," said Steven Nissen, medical director of the cardiovascular coordinating center of the Cleveland Clinic and the committee's chairman. "As a clinician, I find the evidence more than adequate to vote for approval."

"BiDil represents a new heart failure treatment for African-Americans," said Clyde Yancy, a professor at the University of Texas Southwestern Medical School (Dallas). Noting the disease's disproportionate effect on that subgroup, he added that when BiDil improves outcomes for African Americans, "this opportunity should not be missed."

The drug is thought to enhance nitric oxide, which among African Americans has reduced bioactivity. That led Rep. Donna Christensen (D -Virgin Islands), a member of the Congressional Black Caucus who spoke during the committee hearing, to call the drug's approval "an unprecedented opportunity to significantly reduce" a leading health problem for that subpopulation.

NitroMed indicated that it was looking to expand the product's target population through further studies of genetic markers and other physiological factors.

Stem cell therapy improves heart function

Patients with advanced heart failure significantly improved after receiving stem cell therapy, according to results of a small clinical trial presented as late-breaking news at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS; Beverly, Massachusetts) in June. Researchers called the study the first to use human fetal-derived stem cell therapy in patients with heart failure. The surgical procedure was performed by physicians at Luis Vernaza Hospital (Guayaquil, Ecuador).

Study data showed that 30 days after receiving the stem cells, by injection into their hearts, study patients' hearts improved an average of 41% in pumping efficiency and the distance they could walk nonstop increased by 72%. After 90 days, the heart-pumping improvements were sustained and patients further improved their walking distance by an additional 16% compared to 30 days, and doubled compared to baseline.

The study showed the eight analyzed study patients demonstrated significant improvements at 30 and 90 days vs. baseline measures: An increase of 72.5% at 30 days and an additional 16.8% at 90 days in the distance completed while performing the six-minute walk test (275.0m to 553.8m); treadmill exercise tolerance test increase from 2.5 METs at baseline to 5.6 METs at 90 days (no 30-day follow-up was performed); 42.9% improvement in NYHA class (32.1% at 30 days and further 15.8% at 90 days, from 3.5 to 2.0); 41% increase in ejection fraction (26.6% to 37.5% at 30 days and sustained at 90 days).

"This is the first-ever study to use human fetal-derived stem cell therapy in patients with heart failure and, though from a small group of patients, the results are very compelling and demand additional research," said Valavanur Subramanian, MD, chairman of the department of cardiothoracic surgery at Lenox Hill Hospital (New York), the study's senior investigator. "It was especially gratifying to see these patients, many of whom couldn't walk more than a short distance without losing their breath, improve their ability to perform physical activities that are a part of everyday living."

"These results suggest a potential for changing the trajectory of heart failure," said Barnett Suskind, CEO of the Institute for Regenerative Medicine (IRM; Barbados), which provided the unrestricted grant for the study. "We will follow these patients to obtain additional, longer-term data, as well as perform variations of the procedure in new patients as part of an extension of this study."

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