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Dr. Stephen Davis, Vanderbilt University Medical Center Chief of the Division of Diabetes, Endocrinology and Metabolism

For nearly a decade now, researchers and physicians have realized that angiotensin converting enzyme (ACE) inhibitors impact more than just high blood pressure. As reported in the January 20, 2000 issue of the New England Journal of Medicine, results from the HOPE (Heart Outcomes Prevention Evaluation) study showed that ramipril could serve as a tool to not only lessen the risk of heart attack and stroke but also prevent or delay the onset of type 2 diabetes.

The HOPE study, made up of 9,000 high-risk patients from 19 countries studied over five years, looked at participants deemed at increased risk of atherosclerotic disease events or death due to the presence of atherosclerosis or diabetes plus one other cardiovascular risk factor such as high blood pressure, smoking or elevated cholesterol. Those on the ramipril arm reduced their risk of death from cardiovascular disease by 25 percent, heart attack by 20 percent, stroke by more than 30 percent, and developing diabetes by 30 percent.

Since then, the DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) study has found rosiglitazone to be more effective in reducing the incidence rate of diabetes. However, the ramipril arm also showed a significant regression to normoglycemia compared to placebo. Researchers did conclude that both drugs helped reduce hyperglycemia and noted that a longer or larger trial might have yielded more significant results for ramipril.

While both studies indicate ramipril impacts blood glucose, the mechanisms behind the outcome are unclear –– enter Stephen N. Davis, MD, FRCP, and his team of Vanderbilt researchers.

Davis, who is chief of the Division of Diabetes, Endocrinology and Metabolism for Vanderbilt University Medical Center, said, "The metabolic effects of ramipril haven't really been studied before." He added other researchers and institutions have looked at the mechanisms of rosiglitazone's metabolic actions.

"We want to look at the in vivo physiologic metabolic mechanisms of ramipril," he continued. "We are going to be studying insulin sensitivity at the level of the liver and peripheral target tissues. We're also going to look at effects of ramipril on glucose-stimulated insulin secretion; ramipril's effects on modulating the autonomic nervous system; and we'll also be looking at the effects on endothelial function and atherogenic risk factors and inflammation."

Davis said it isn't enough to know that something seems to work. For both scientific and scholarly purposes, he continued, it's imperative to understand the "how" and "why" behind the action. In the case of type 2 diabetes, he pointed out patients typically progress along a spectrum beginning with having cardiometabolic risk factors and moving to true metabolic syndrome and then on to type 2 diabetes and ultimately, in many cases, to stroke or heart attack.

"If we can identify how new agents … or new indications for existing agents … work, then maybe we can block this deadly progression," he theorized.

In the current double blind trial, "Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes," Davis and his team have three arms. Patients are randomized to receive ramipril, the diuretic HCTZ-hydrochlorothiazide or both for a period of six months.

The goal is to enroll 48 patients (half male and half female) with impaired glucose tolerance, between the ages of 20-65 and with a BMI greater than 25 kg/m2. The subjects' fasting plasma glucose should fall between 100 and 126 mg/dl, or their post prandial glucose should be between 140-200 mg/dl. Exclusion criteria include smoking, pregnancy or the intent to become pregnant during the study, and any patients receiving agents designed to increase or lower blood glucose levels such as metformin. The trial is a collaboration between Vanderbilt University and King Pharmaceuticals (manufacturer of Altace®).

For those that meet the criteria, Davis said, "We believe that ramipril would be beneficial for these individuals who have pre-diabetes and that it will have a protective effect in preventing these individuals from progressing to overt diabetes and also return them to normal blood glucose."

Prior to being placed in one of the trial arms, participants come to VUMC for two days of comprehensive metabolic physiologic studies. Then, they are randomized to one or both drugs for six months. At the end of that time, the participant returns to the hospital for another two days of the same metabolic studies.

Although identifying participants for this study has been challenging –– to date about half-a-dozen patients have completed the six-month trial –– Davis and his colleagues are hopeful they will be able to test four dozen patients by late summer/early fall of 2009.

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