Diabetes Dateline
Fall 2009

Research News

Optimal Medical Therapy As Beneficial As Elective Revascularization Procedures in Patients with Type 2 Diabetes and Stable Coronary Artery Disease
Landmark Study Also Finds No Difference between Insulin-providing and Insulin-sensitizing Drugs

Optimal medical therapy for patients with diabetes and stable coronary artery disease (CAD) is equally effective at lowering the risk of death, heart attack, and stroke as prompt revascularization procedures, either coronary bypass surgery or angioplasty, according to results from an international multicenter clinical trial supported by the National Institutes of Health. Optimal medical therapy includes intensive drug therapy and lifestyle interventions, such as dietary changes and smoking cessation.

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study simultaneously compared two cardiovascular treatment approaches and two diabetes control strategies to improve survival and to lower the risk of heart attacks and strokes. The findings were published June 11, 2009, in The New England Journal of Medicine in conjunction with the researchers’ presentation at the American Diabetes Association’s 69th Annual Scientific Sessions in New Orleans.

BARI 2D also found that patients who had prompt coronary bypass surgery in addition to optimal medical therapy had significantly fewer nonfatal heart attacks or strokes compared with similar patients who initially received optimal medical therapy alone. No such benefit was seen in patients who received both optimal medical therapy and prompt angioplasty, most of whom also received a stent—a wire mesh scaffold to keep the affected artery open—versus similar patients who initially received optimal medical therapy alone. However, participants in the bypass surgery group were more likely to have more extensive CAD than those in the angioplasty group. Both angioplasty and bypass surgery are revascularization procedures to relieve or bypass blockages in the coronary arteries.

Researchers also discovered that, overall, strategies using newer drugs that aim to make insulin work better by lowering the body’s resistance to insulin, known as insulin-sensitizing drugs, are as effective as insulin provision strategies, which emphasize drugs that provide insulin or stimulate insulin production.

“By comparing different strategies for both blood sugar control and prevention of cardiovascular events such as heart attack and stroke, we aim to provide physicians with evidence-based guidance to help them identify the safest and most effective therapies for their patients,” said Elizabeth G. Nabel, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary funder of the study.

Adults with type 2 diabetes, a condition that hampers the body’s ability to control blood glucose—also called blood sugar—levels, are two to four times more likely to develop heart disease than those without diabetes. In addition, heart attack and stroke often occur earlier than in people without diabetes and are more likely to be fatal. Sixty-five percent of people with diabetes die from cardiovascular disease (CVD).

Forty-nine Clinical Sites

BARI 2D was conducted in 49 clinical sites in the United States, Canada, Brazil, Mexico, the Czech Republic, and Austria. The study was coordinated by the Epidemiology Data Center at the University of Pittsburgh Graduate School of Public Health.

When the study began, the 2,368 adult participants had stable CAD and, on average, were 62 years old with a 10-year history of type 2 diabetes. One component of the study compared optimal drug treatment alone with coronary revascularization—either bypass surgery or angioplasty—in addition to optimal drug treatment. Optimal drug treatment included drugs to control blood glucose levels, cholesterol, and blood pressure. In angioplasty, blocked arteries are opened by inflating a small balloon inside a narrow vessel and often followed by the placement of a stent. Of the 798 BARI 2D participants selected to receive prompt angioplasty, 91 percent had a stent inserted, of whom about one-third received a drug-eluting stent.

At enrollment, all participants’ CAD had to be stable enough so that the patients could be safely managed with optimal medical therapy without immediate revascularization. Participants were selected to be in either the bypass or the angioplasty group based on whether the extent and severity of their coronary artery blockages would be best treated by coronary bypass surgery or angioplasty, according to their physician. As reflective of standard medical practice, patients with more extensive and severe CAD were more likely to be candidates for bypass surgery than angioplasty. When they were screened to enter the trial, approximately two-thirds of BARI 2D participants were considered suitable candidates for elective angioplasty, while the remaining one-third were considered candidates for elective bypass surgery.

Within the bypass surgery and angioplasty groups, participants were randomly assigned to either promptly receive the designated revascularization procedure or to receive optimal medical therapy alone. Thus, the two coronary revascularization procedures were not compared with each other. Rather, patients receiving either revascularization procedure were independently compared with their own control groups receiving optimal medical therapy alone.

Participants randomized to receive prompt revascularization underwent the designated procedure within 4 weeks from the start of the study while also receiving optimal medical therapy. Participants in the medical therapy alone group could undergo revascularization during the study if needed, and about 40 percent of participants in the medical therapy groups did so.

Five-year Follow-up

Overall, researchers found that after an average follow up of 5 years, there were no differences in mortality rates, the primary endpoint of the study, which were about 12 percent in both the prompt revascularization and optimal medical therapy groups. In addition, deaths combined with nonfatal cardiovascular events—a principal secondary outcome—between the combined revascularization groups who received early coronary procedures compared with those in the medical therapy alone groups were similar (23 percent vs. 24 percent, respectively). However, among the subgroup of participants who were pre-identified as candidates for coronary bypass surgery, those who had bypass surgery within the first month of being in the study had significantly fewer subsequent major cardiovascular events—death or nonfatal heart attacks or strokes—compared with those who initially received optimal medical therapy alone (22 percent vs. 30 percent, respectively).

Insulin Strategies

In the diabetes control component of the study, researchers randomly divided the same participants into two blood glucose control strategy groups. One strategy emphasized insulin-sensitizing drugs including biguanides, such as metformin, and thiazolidinediones, primarily rosiglitazone. The other strategy group emphasized insulin-providing drugs including sulfonylureas, such as glipizide, and meglitinides, such as repaglinide.

Participants in both groups were treated to targeted levels of glycated hemoglobin (A1C) levels of less than 7 percent, which is consistent with current diabetes care guidelines. A1C is a measure of average blood glucose levels from the previous 2 to 3 months. On average, participants in the insulin-sensitizing group had an A1C level of 7 percent, and participants in the insulin-providing group had an A1C level of 7.5 percent.

“Other studies have suggested that insulin resistance contributes directly to the development of coronary artery disease,” noted Suzanne Goldberg, R.N., M.S.N., NHLBI project officer of the study and program director in the Atherothrombosis and Coronary and Artery Disease Branch in the Division of Cardiovascular Diseases. “Our study was an opportunity to directly compare the effects of drugs that enhance the body’s ability to use insulin to the more traditional drugs that increase the amount of insulin.”

Overall, the numbers of deaths and cardiovascular events were about the same in both diabetes treatment strategy groups. In addition, because of safety concerns raised in other studies, BARI 2D researchers conducted an in-depth analysis of CVD rates in patients receiving rosiglitazone versus other diabetes drugs and found no evidence of increased risk of heart attack in participants receiving rosiglitazone.

“We found some indications that insulin-sensitizing drugs might be beneficial for certain patients with diabetes, especially those with more extensive coronary artery disease who undergo bypass surgery, but more research is needed,” noted Sheryl F. Kelsey, Ph.D., professor of epidemiology at the University of Pittsburgh Graduate School of Public Health, and a principal investigator and co-author of the study.

In addition to the NHLBI, BARI 2D received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and others.

For more information about the BARI 2D study, visit www.bari2d.org.

The NIDDK has fact sheets and easy-to-read booklets about diabetes. For more information or to obtain copies, visit www.diabetes.niddk.nih.gov.

NIH Publication No. 10–4562
November 2009

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