New York, NY - Reassurance that the cholesterol-ester-transfer-protein (CETP) inhibitors—a new class of HDL-boosting drugs in development—should produce beneficial effects has come from a new study [1].

The study, conducted by a group from Columbia University, New York, NY led by Dr Fumihiko Matsuura, is published in the May 2006 issue of the Journal of Clinical Investigation. It addresses the issue of whether the HDL cholesterol formed by inhibiting the CETP enzyme is actually functional in reverse cholesterol transport, the transfer of cholesterol from peripheral tissues back to the liver for excretion. And the results suggest that it is.

CETP mediates the transfer of cholesterol from HDL to LDL. CETP inhibition therefore leads to higher HDL concentrations and as such represents an attractive therapeutic strategy. Two CETP inhibitors are in late-stage clinical development—Pfizer's torcetrapib and Japan Tobacco's JJT-705. Phase 2 results suggest that these agents significantly increase HDL, but it is not known whether the type of HDL formed by inhibition of CETP is as effective as the HDL that predominates in normal subjects, and animal models have shown conflicting results.

Senior author of the current study, Dr Alan Tall (Columbia University, New York, NY), explained to heartwire that the HDL formed when CETP is inhibited is predominantly HDL2—a larger and more cholesterol-laden molecule than the regular HDL that dominates in normal individuals, and it has not been known whether this molecule can take up more cholesterol. To investigate this issue, his team compared HDL from normal individuals and from CETP-deficient individuals for its ability to promote cholesterol removal from macrophages, a key step in removing cholesterol from the artery wall. While there have been concerns that the HDL formed from inhibiting CETP may not be as effective as normal HDL in this regard, results of this study actually showed that the HDL from the CETP-deficient individuals was two-to-threefold more effective.

"We found that the people lacking CETP appeared to have superfunctional HDL," Tall commented. He admitted that this was quite a surprise: "I thought maybe it would be the same as the HDL from normal individuals, or maybe perhaps a little less effective, but it appears to be much better."

But Tall cautioned that although very encouraging, this is still not definitive proof that the CETP inhibitors will work in reducing clinical events. "This is another piece of evidence on the plus side, and I would say it was an important piece of evidence. But we will not have proof until we see results from clinical outcome studies." One such trial—with torcetrapib—is currently under way, with results expected in 2009.

Matsuura et al also report that the enhanced ability of HDL particles from CETP-deficient subjects to accept cholesterol appears to be related to their very high content of lecithin cholesterol acyltransferase (LCAT) and apolipoprotein E (apoE), which drives cholesterol efflux by promoting cholesterol esterification in the HDL particles. In addition, they found that the efflux of cholesterol from foam cells to the HDL2 molecule was mediated by a transporter known as ABCG1, present on macrophages.

The paper is accompanied by an editorial by Drs Robert Mahley, Yadong Huang, and Karl Weisgraber (University of California, San Francisco). Mahley commented to heartwire: "The HDL formed by CETP inhibition is already heavily loaded with cholesterol, and it was not known if it could take on any more. This study suggests that it can, and that apoE and LCAT play a major role in this process. It seems that apoE allows the HDL2 particle to expand and accept more cholesterol."

The editorialists write: "These findings, coupled with the previous in vitro studies and demonstration of effective reverse cholesterol transport in CETP-deficient animal models, suggest that CETP inhibitors are likely to be effective in generating an antiatherogenic HDL profile in humans. However, as pointed out by Matsuura et al, the answer awaits completion of ongoing clinical trials."