Milano Apolipoprotein Targets Atherosclerosis: A Newsmaker Interview With Steven E. Nissen, MD

Laurie Barclay, MD

November 11, 2003

Nov. 11, 2003 -- Editor's Note: Intravenous infusion of Milano apolipoprotein A targets atherosclerotic plaques in patients with acute coronary syndromes (ACS), according to the results of a preliminary randomized trial published in the Nov. 5 issue of The Journal of the American Medical Association . Absolute reduction in atheroma volume on serial intravascular ultrasound was 4.2% within weeks, suggesting new therapeutic avenues with the potential to rapidly reverse the vascular complications of atherosclerosis.

The rationale motivating development of this drug, which targets high-density lipoprotein (HDL) cholesterol, was the discovery that carriers of ApoA-I Milano, a naturally occurring variant of apolipoprotein A-I, have very low levels of HDL cholesterol, longer life span, and much less atherosclerosis than expected for their HDL cholesterol levels.

Because the results of this trial were so unexpected, the authors as well as the editorialist warn that additional research is mandated, and that the findings should be interpreted in light of various study limitations. Nonetheless, the therapy is being hailed as a potentially revolutionary approach to therapy for atherosclerosis.

To learn more about the clinical implications of these findings, Medscape's Laurie Barclay interviewed lead author Steven E. Nissen, MD, FACC, medical director of the Cleveland Clinic Cardiovascular Coordinating Center of the Cleveland Clinic Foundation in Ohio.

Medscape: What led your group to test Milano apolipoprotein A as a treatment for atherosclerosis accompanying ACS?

Dr. Nissen: We knew that individuals that carried this gene had low HDL levels but no vascular disease. Therefore, we hypothesized that administering this variant HDL would regress coronary disease in patients following myocardial infarction.

Medscape: What were the main findings of this study?

Dr. Nissen: After five intravenous doses given at weekly intervals for five weeks, a significant amount of plaque was removed from the coronary artery as measured by intravascular ultrasound, a precise technique for assessing the volume of plaque in the coronary arteries.

Medscape: Were you surprised by these findings, especially in terms of the rapidity of plaque reversal?

Dr. Nissen: Not surprised -- shocked and stunned!

Medscape: How significant were any study limitations in terms of affecting the results? Why were only 57 patients randomized of 123 who were screened?

Dr. Nissen: The small size is a definite limitation, but it is counterbalanced by a statistically compelling result.

Medscape: How well characterized is the relationship between intravascular ultrasound (IVUS) findings and clinical benefit?

Dr. Nissen: IVUS has not yet been shown to correlate with morbidy and mortality, but for other imaging methods, the relationship between plaque growth and outcome has proven reliable.

Medscape: Do you attribute the findings to the effects of Milano apolipoprotein A specifically, as opposed to a general effect of any apolipoprotein A?

Dr. Nissen: Nobody knows. We didn't test "normal" A1.

Medscape: What is known about potential short-term and long-term adverse effects?

Dr. Nissen: We are unlikely to see adverse effects. The Milano apolipoprotein A is nearly identical to natural HDL. There is only one amino acid different, so it is not antigenic.

Medscape: Is there any danger that rapidly removing plaque from an atherosclerotic vessel could weaken it, leading to aneurysm formation, or could it dislodge emboli?

Dr. Nissen: There's no reason to worry about this. Plaque does not support normal vessel structure.

Medscape: What are the implications of these findings in terms of treatment?

Dr. Nissen: A paradigm shift. We now know that HDL is a critically important target for therapy.

Medscape: Is additional research planned?

Dr. Nissen: We will need to perform a large morbidity and mortality study.

Editor's Note: Esperion Therapeutics funded this study and has financial arrangements with two of its authors. Dr. Nissen has received research support from Pfizer, Merck, Schering-Plough, Takeda, Sankyo, Esperion, AstraZeneca, and Novartis.

JAMA. 2003;290:2292-2300

Reviewed by Gary D. Vogin, MD

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