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【medical-news】AHA:升高HDL的新型药物并不能带来获
January 20, 2011 (Cleveland, Ohio) — Larger long-term studies may be able to show that that RVX-208, the first oral agent for raising high-density-lipoprotein cholesterol (HDL-C) through apolipoprotein A1 (apoA-1) synthesis, can increase those levels, according to investigators of the ASSERT trial, now published, which missed the primary end point of apoA-1 increase [1]. An accompanying editorial, however, called the lipid benefits "modest" and the liver side effects "unacceptable."
The ASSERT data were first presented by Dr Stephen Nicholls (Cleveland Clinic, OH) at the American Heart Association 2010 Scientific Sessions.
The study randomized 299 statin-treated patients with coronary artery disease to two daily doses of placebo, 50 mg of RVX-208, 100 mg of RVX-208, or 150 mg of RVX-208 for 12 weeks. Twelve-week results from ASSERT, published online January 19, 2011 in the Journal of the American College of Cardiology, show that treatment with RVX-208 is associated with a dose-dependent increase in apoA-1 levels of up to 5.6% (p=0.035 for the trend), but none of the individual pairwise comparisons of apoA-I change--the primary end point--achieved statistical significance.
Compared with placebo, the 50-mg, 100-mg, and 150-mg doses of RVX-208 significantly increased the levels of HDL-C 3.2%, 6.3%, and 8.3%, respectively (p=0.02), and the number of large HDL particles increased by 11.1%, 20.2%, and 21.1%, respectively (p=0.003). Also, the apoA-I levels increased rapidly from weeks eight to 12, suggesting that the peak pharmacological effect was not achieved by the end of the study and that a longer study will show a much greater increase in apoA-1, according to the authors.
Eighteen patients taking RVX-208 in the study showed a transient and reversible elevation in liver transaminases over three times the upper limit of normal but did not have an associated increase in bilirubin levels.
"Although the observed changes in lipid parameters in statin-treated patients were modest, increases of a similar magnitude in HDL-related parameters for other therapies, such as statins and fibrates, have reduced adverse clinical outcomes and exerted a beneficial effect on the progression of atherosclerosis," Nicholls et al explain. "The most striking effect of RVX-208 was elevation of the concentration of larger HDL particles," which has been shown to be a strong predictor of cardiovascular protection in population studies. Since there was no observed plateau of efficacy, "further incremental benefit may be observed during longer duration of treatment. This would be consistent with the experience of many other agents that raise HDL-C," the authors predict.
"Ultimately, the ability to bring this strategy to clinical practice would represent a significant paradigm change, in which the focus is predominantly on specifically targeting the functional quality, rather than the quantity, of HDL," they conclude.
In an accompanying editorial, Dr Michael Davidson (University of Chicago, IL) is less optimistic about the prospects for RVX-208 [2].
The increases in HDL-C and apoA-1 at the highest dose of RVX-208 were only modest and were also associated with an "unacceptable" 10% rate of transaminase elevation, Davidson argues. The increase in large HDL particles with RVX-208 is "encouraging" and "suggests an improvement in reverse cholesterol transport due to enhanced maturation to more lipid-rich HDL, [but] these modest changes in large HDL particles with RVX-208 are less than can be achieved with niacin therapy.
"Based on the disappointing efficacy of RVX-208, safety issues due to transaminase elevations, and significant regulatory hurdles, major challenges lie ahead for the future clinical development of this nuclear transcription factor for increasing apoA levels," Davidson predicts. "Hopefully, therapeutic approaches to modulating apoA-1 production will continue to progress, because the potential clinical benefits represent a major unmet need in the treatment and prevention of cardiovascular disease." [标签:content2]
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作者:admin@医学,生命科学 2011-01-26 00:19
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