Correspondence

ACAT Inhibition and the Progression of Coronary Atherosclerosis

N Engl J Med 2006; 354:2616-2617June 15, 2006

Article

To the Editor:

Nissen et al. (March 23 issue)1 report on the ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) study, in which patients with coronary disease were treated with an enzyme acyl–coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, pactimibe, to evaluate the potential for beneficial effects on coronary-artery atherosclerosis. We believe the authors' sweeping conclusion that ACAT inhibition is not an effective strategy for limiting atherosclerosis and that such treatment may promote atherogenesis is premature.

As the article pointed out, there are two types of ACATs (ACAT1 and ACAT2), which have distinct physiologic roles. Studies in animals show that the inhibition of ACAT1 (in macrophages) may be detrimental,2,3 whereas the inhibition of ACAT2 (in the small intestine and liver) is atheroprotective through the lowering of levels of plasma cholesterol esters.4,5 Pactimibe is reportedly a nonselective agent, and the authors present no evidence that the 100-mg daily dose inhibited ACAT2. In fact, this treatment had no effect on plasma cholesterol levels, which suggests that ACAT2 inhibition was insufficient.

We believe the jury is still out with respect to the specific inhibition of ACAT2. Studies that are designed to test ACAT2 inhibition in humans are needed to determine whether this strategy reduces atherosclerosis.

Lawrence L. Rudel, Ph.D.
Wake Forest University Health Sciences, Winston-Salem, NC 27157

Robert V. Farese, Jr., M.D.
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158
bfarese@gladstone.ucsf.edu

5 References

1. 1

   Nissen SE, Tuzcu EM, Brewer HB, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2006;354:1253-1263
   Full Text | Web of Science | Medline

2. 2

   Accad M, Smith SJ, Newland DL, et al. Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J Clin Invest 2000;105:711-719
   CrossRef | Web of Science | Medline

3. 3

   Fazio S, Major AS, Swift LL, et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest 2001;107:163-171
   CrossRef | Web of Science | Medline

4. 4

   Willner EL, Tow B, Buhman KK, et al. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A 2003;100:1262-1267
   CrossRef | Web of Science | Medline

5. 5

   Lee RG, Kelley KL, Sawyer JK, Farese RV Jr, Parks JS, Rudel LL. Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme a:cholesterol acyltransferase 2 have opposite atherosclerotic potential. Circ Res 2004;95:998-1004
   CrossRef | Web of Science | Medline

Author/Editor Response

My colleagues and I were very careful to point out that other ACAT inhibitors might be successfully developed but warned that “if other agents in this class are studied in patients with coronary disease, there should be reasonable evidence that their biologic effects differ from those of pactimibe. Clinical trials of other ACAT inhibitors will require warnings in the informed-consent form and close monitoring by an independent data and safety monitoring board.”

We deliberately did not suggest that further study was inappropriate. With close monitoring, we believe that additional trials of ACAT2 inhibitors could be conducted ethically. However, we are very doubtful that a successful agent can be developed. To our knowledge, no ACAT inhibitor, administered at any dose, has been associated with a reduction in cholesterol levels in humans. In fact, pactimibe inhibited ACAT2 at the 100-mg dose used in the ACTIVATE trial, and avasimibe inhibited ACAT2 in the Avasimibe and Progression of Lesions on Ultrasound (A-PLUS) trial, but neither agent reduced cholesterol.1 Accordingly, we think that developers of therapies to treat atherosclerosis are best served by looking elsewhere for successful approaches.

Steven E. Nissen, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195
nissens@ccf.org

1 References

1. 1

   Tardif JC, Gregoire J, L'Allier PL, et al. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004;110:3372-3377
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Taichi Ohshiro, Hiroshi Tomoda. (2011) Isoform-specific inhibitors of ACATs: recent advances and promising developments. Future Medicinal Chemistry 3:16, 2039-2061
   CrossRef