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HDL as Therapeutic Target After ACS?

A synthetic HDL formulation might reduce atheroma burden.

Although low HDL cholesterol is linked with risk for heart disease, there are about 40 residents of a small Italian village who have very low HDL levels (10 to 30 mg/dL [0.25-0.78 mmol/L]) but very low documented rates of atherosclerosis. This apparent paradox is attributable to a genetic variant of apolipoprotein A-I (called apoA-I Milano), which these people have, that makes their HDL particles highly efficient at lipid removal. In animal models, a formulation of recombinant apoA-I Milano/phospholipid complex (ETC-216) has yielded rapid regression of atherosclerosis. Is there such potential for humans?

In a manufacturer-funded, multicenter, double-blind, placebo-controlled, phase 2 trial, U.S. researchers enrolled 57 patients (mean age, 57) who required coronary angiography within 2 weeks after an acute coronary syndrome (ACS) episode. Subjects were randomized to 1 of 3 regimens in a 1:2:2 ratio: placebo, low-dose (15 mg/kg) weekly infusions of ETC-216 for 5 weeks, or a high-dose (45 mg/kg) version of the ETC-216 regimen. Atheroma burden was assessed by intravascular ultrasound (IVUS) soon after angiography and again after the 5-week treatment.

Among 47 study completers, mean percent atheroma volume declined significantly from baseline to follow-up (by –1.06%) in the two ETC-216 groups combined (though, interestingly, not in the high-dose group alone) and increased slightly in the placebo group (by 0.14%). The two ETC-216 groups also saw significant overall declines in mean total atheroma volume (by –14.1 mm³) and in mean maximum atheroma thickness (by –0.042 mm); declines in the placebo group were not significant.

Comment: In this study, an intravenous recombinant apoA-I Milano/phospholipid complex (ETC-216) yielded significant regression of IVUS-assessed coronary atherosclerosis in ACS patients. However, as an editorialist notes, the phospholipid -- rather than its apoA-I component -- might have produced the regression. He also notes the curious lack of a dose response to ETC-216. HDL-targeted interventions are promising, but larger trials of such interventions must overcome this study's limitations and must assess effects on atherosclerosis progression and clinical cardiac outcomes.

— JoAnne M. Foody, MD

Published in Journal Watch Cardiology December 26, 2003

Citation(s):

Nissen SE et al. Effect of recombinant apoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA 2003 Nov 5; 290:2292-300.

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Rader DJ. High-density lipoproteins as an emerging therapeutic target for atherosclerosis. JAMA 2003 Nov 5; 290:2322-4.

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• Medline abstract (Free)