ACE inhibitor: Screen of protection for diabetes

Ramipril protects against heart disease

The news was so good for diabetics and other heart patients that even the New England Journal of Medicine couldn’t wait to release the results. The angiotensin-converting enzyme (ACE) inhibitor ramipril offers broad protection against cardiovascular disease in diabetics, prevents complications, and may even prevent the onset of the disease.

Results from the Heart Outcomes Prevention Evaluation (HOPE) study was to be published in the Jan. 20 issue of the journal, but editors thought the news was too important. They released the article more than two months early on the publication’s Web site at www.NEJM. org.

The multinational HOPE study shows ramipril has a vast impact on the overall incidence of cardiovascular disease in the general population. More importantly, for diabetic patients, a full dose of 10 mg per day reduced cardiovascular events by 50% and offered a bonus: strong protection against diabetic complications and new cases of diabetes.

The study’s authors say the benefits are so marked that clinicians should consider adding ramipril to the pharmaceutical regimen for diabetics and heart patients.

"Our findings show that ramipril, an [ACE] inhibitor, is beneficial in a broad range of patients without evidence of left ventricular systolic dysfunction or heart failure who are at risk for cardiovascular events," wrote the research team based at McMaster University in Hamilton, Ontario, Canada.

In addition, the researchers concluded, "Treat-ment with ramipril reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and heart failure, as well as the risk of complications related to diabetes and of diabetes itself."

Tissue-binding properties

Ramipril’s power lies in its tissue-binding effects, speculates lead researcher Salim Yusuf, MD, PhD, director of cardiology at McMaster University. "The results would likely be similar for other long-acting ACE inhibitors if you can calculate the appropriate dosage."

"This shows ACE inhibitors should be first link in the treatment chain for diabetics, particularly those who have already manifested signs of cardiovascular disease," says William Castelli, MD. Castelli is a cardiovascular epidemiologist who spent more than 20 years working on the Framingham Heart Study and is now director of the Framingham (MA) Cardiovascular Institute. He agrees that ACE inhibitors like ramipril, quinapril, and captopril seem to have particularly beneficial effects.

Castelli theorizes ramipril may be somewhat unique "because of its ability to localize in the cells, where other ACE inhibitors don’t get taken up as well."

Part of the beneficial effect, says Yusuf, is the direct protection of vessel walls and its indirect effect on insulin resistance through improved blood flow to skeletal muscles, causing better glucose uptake.

Yusuf’s team said there was a "marked" reduction in complications related to diabetes as well as in anticipated new cases of diabetes. Team members suggest ramipril increases insulin sensitivity, decreases hepatic clearance of insulin, has an anti-inflammatory effect, improves blood flow to the pancreas, or has an effect on abdominal fat. In addition, treatment with an ACE inhibitor such as ramipril or the similar captopril, slows the progression of nephropathy in patients with Type 2 diabetes.

The benefits of ramipril held even in patients who were already taking several effective treatments, including aspirin, beta-blockers, and lipid-lowering agents, says Yusuf. "That means the inhibition of angiotensin-converting enzyme offers an additional way to prevent atherothrombotic complications," he says.

The study showed only a small blood pressure reduction of 3 mm Hg systolic and 2 mm Hg diastolic. Yusuf and his fellow researchers believe that small reduction means there are other important effects. The majority of the 9,541 patients who participated in the HOPE study did not have hypertension at the beginning of the study. The mean blood pressure of the patients in the HOPE study was 139/79.

Yusuf thinks the high level of benefit from a relatively low reduction in blood pressure validates the Hypertension Optimal Treatment Study, which suggested that high-risk patients, especially those with diabetes, might benefit from reducing blood pressure even if they are normotensives.

The HOPE researchers determined that treating 1,000 patients with ramipril for four years prevents about 150 cardiovascular events in approximately 70 patients. HOPE study patients were recruited at 129 centers in Canada, 27 in the United States, 76 centers in 14 western European countries, 30 in Argentina and Brazil, and five in Mexico.