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Text sizeDallas, TX - A new class of lipid drug is in development that works mainly by raising HDL cholesterol. By inhibiting the cholesteryl ester transfer protein (CETP) enzyme, which plays a key role in HDL metabolism, these agents should reduce event rates at least as well as statins, and could have additive effects when combined with statins, according to Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), a leading researcher in this field.
One of the first of these CETP inhibitors is the subject of a paper by Kastelein's group, which appears as a rapid access publication in Circulation online.1 JTT-705 is made by the Japanese company Akros Pharma, which is the pharmaceutical arm of Japan Tobacco. The study reported in this paper shows a 34% increase in HDL cholesterol and a 7% reduction in LDL cholesterol with the drug. Kastelein says this agent is the most advanced CETP inhibitor in development - it is currently in Phase IIb clinical trials, and could reach the market in about 4 years time. Pfizer also has one of these compounds, which Kastelein says is "slightly behind" JTT-705 in development.
In an interview with heartwire, Kastelein noted that most of the current drugs that address cholesterol such as the statins target LDL cholesterol, but low HDL cholesterol is actually a greater problem and HDL has a stronger relationship to heart disease than LDL. "If you look at the typical western male with heart disease, the most prevalent problem is low HDL. And for every percentage increase in HDL you get more benefit than for each percentage lowering of LDL. Raising HDL should give us a better return on our investment than lowering LDL."
Raising HDL should give us a better return on our investment than lowering LDL.
Epidemiological studies show that a 34% increase in HDL should translate into a 30-40% reduction in clinical events, Kastelein explained. "This compares favorably even to the statins, which are the best cholesterol drugs we have at present. For example, in the Heart Protection Study, a 34% reduction in LDL with a statin produced a 27% reduction in events. We should be able to achieve at least the same and probably more by raising HDL to a similar degree," he added.
Kastelein cautioned, however, that the results need to be confirmed in prospective studies.
So why has HDL not been the main focus of drug development? Kastelein says that LDL is much easier to understand and use as a target for drugs than HDL. "HDL is much more complicated and is involved in so many different mechanisms." The fibrate drugs such as gemfibrozil do raise HDL cholesterol, but Kastelein says this is only a relatively modest effect - producing about an 11% rise. He adds that nicotinic acid produces a greater rise in HDL but its use is limited by side effects.
The beginning of the HDL era
"The CETP inhibitors raise HDL cholesterol to a far greater extent with few side effects - this is the beginning of the HDL era," Kastelein commented. He explained that the CETP enzyme transfers cholesterol from HDL to LDL. "This enzyme effectively makes good cholesterol into bad cholesterol, so if we inhibit it we should see an increase in HDL and a reduction in LDL and that is exactly what we do see."
Another potential advantage of these agents is that they should give additive effects when combined with statins. "In theory, we should be able to add the beneficial effects of raising HDL with CETP inhibitors to those of lowering LDL with statins. This could give us a reduction in event rates of a staggering 70% with the combination. Just imagine that!" Kastelein commented.
Phase II studies of JTT-705 in combination with pravastatin are now about to begin. These studies will look at changes in lipid profiles with the combination.
Kastelein believes, however, that as the exact role of CETP in humans is unknown some sort of endpoint studies will be needed before these new drugs will be approved for marketing.
We could add the beneficial effects of raising HDL with CETP inhibitors to those of lowering LDL with statins. This could give us a reduction in event rates of 70%.
The current study was a randomized, double-blind, placebo-controlled trial, in which 198 healthy subjects with mild hyperlipidemia were randomized to 300, 600, and 900 mg JTT-705 per day or placebo. After 4 weeks of treatment with 900 mg JTT-705, there was a 37% decrease in CETP activity (p=0.0001), a 34% increase in HDL cholesterol (p=0.0001), and a 7% decrease in LDL cholesterol (p=0.017). Triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase levels were unaffected. In line with the increase of total HDL, a rise of HDL2, HDL3, and apolipoprotein A1 was also observed.
JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests, but was associated with minor gastrointestinal side effects (diarrhea, flatulence, nausea). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk, the authors comment.
The researchers note that studies in rabbits, which develop high CETP plasma levels on a high-cholesterol diet, have shown that CETP inhibition by JTT-705 can protect against atherosclerosis. However, studies in mice, which are CETP deficient by nature, showed that expression of human CETP can be either atherogenic or antiatherogenic. "The precise role of CETP in human atherogenesis and how its activity relates to coronary artery disease risk is still unclear" and so "endpoint or surrogate coronary artery disease marker trials have to clarify whether JTT-705 can reduce or prevent cardiovascular disease," they conclude.
