Phase II Data Show Alagebrium Reduces Arterial Stiffness in Elderly With Isolated Systolic Hypertension

Martha Kerr

November 23, 2005

Nov. 23, 2005 (Dallas) — Advancing age results in the formation of glycation cross-links in the arterial walls, creating vascular stiffness. A new drug, alagebrium, effectively breaks those cross-links and in effect reverses the aging process. The result: improved vessel elasticity, researchers told attendees at the American Heart Association 2005 Scientific Sessions.

Phase 2 data on alagebrium, an advanced glycation endproduct (cross-link) breaker, were presented by Susan J. Zieman, MD, assistant professor of medicine at Johns Hopkins Medical Institution in Baltimore, Maryland. She and her colleagues evaluated 13 adults (9 men, mean age 65 years) with isolated systolic hypertension on stable antihypertensive therapy. None of the subjects had a history of coronary artery disease, Dr. Zieman stressed. Patients had systolic blood pressure greater than 140 mmHg and diastolic pressure less than 90 mmHg and/or a mean pulse pressure greater than 60 mmHg.

The study design involved a two-week placebo run-in phase, followed by eight weeks of oral alagebrium (210 mg bid). Subjects were blinded to active drug or placebo. Carotid artery augmentation, aortic pulse wave velocity, brachial artery distensibility and echocardiography were measured to determine arterial stiffness. Endothelial function was assessed by brachial artery flow-mediated dilation. Data analyses were performed blinded during the placebo run-in phase and after eight weeks of active treatment.

Dr. Zieman reported that alagebrium reduced carotid augmentation index 37% (P = .007) and carotid augmented pressure from 16.4 mmHg to 9.6 mmHg (P < .001). Pulse wave velocity, heart rate, arterial pressures and brachial artery distensibility were unchanged, while flow-mediated dilation improved from 4.6% to 7.1% (P < .05), she said.

These changes are "very much clinically significant, especially the flow-mediated dilation – those results are remarkable. That's a 102% improvement," Dr. Zieman told Medscape.

"These are very exciting findings, because this single drug seems to have two important mechanisms of action," she commented. "First, alagebrium improves endothelial dysfunction and it also reduces stiffness, probably by affecting the nitric oxide pathway in some way."

"Advanced glycation endproducts are primarily known in food chemistry," she explained, "when proteins exposed to sugars form irreversible bonds, as in caramelization of crème brûlée…The more exposure over time, the more cross-links develop."

"Until now, there weren't really any medications to break the cross-links. The usual drugs given for diastolic hypertension didn't really apply to the elderly with systolic hypertension, but there wasn't anything else available," Dr. Zieman pointed out.

In a related study presented at the AHA, investigators at Methodist Debakey Heart Institute and Baylor College of Medicine in Houston, Texas, reported that alagebrium in fact improved diastolic function.

In the study, led by Vinay Thohan, MD, Medical Director of the Multi-Organ Transplant Unit at Methodist DeBakey Heart Institute, 20 patients with systolic heart failure and severe diastolic abnormalities were treated with alagebrium in an open-label two-dose (35 mg and 420 mg) design. Doppler echocardiography was performed at six-month intervals to assess changes. Mean ejection fraction at baseline was 20%.

Doppler showed improved diastolic function, left atrial pressure dropped 32%, there was a 10% reduction in left ventricular mass and end diastolic volume fell approximately 5% with alagebrium. "Future investigation aimed at improving diastole among patients with heart failure is needed," Dr. Thohan and colleagues concluded.

AHA Scientific Sessions 2005: Abstracts 2647, 2875. Presented Nov 15, 2005.

Reviewed by Ariana Del Negro

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