NEWS - Animal tests and statins

Have animal studies misled for years on cholesterol and statins?

Decades of animal studies and epidemiological data had suggested that raising blood levels of high-density lipoprotein — HDL, or 'good' cholesterol — might have a stronger protective effect against heart disease than statins, drugs that lower levels of low-density lipoprotein ('bad' cholesterol or LDL).

But in 2006, a US$1-billion trial of torcetrapib, an HDL-raising drug, found it seemed to increase patients' risk of death, casting a pall of doubt over the entire field. In November 2010, the first study since to focus on the class of drugs that boosts HDL levels may offer good news for the approach.

The study, published in The New England Journal of Medicine, was a 1,623-patient trial investigating the safety of anacetrapib, a drug functionally similar to torcetrapib, developed by pharmaceuticals giant Merck, based in Whitehouse Station, New Jersey. The drug inhibits a protein called CETP, which raises HDL. The trial found with 94% confidence that anacetrapib does not harm patients — in contrast to the 15,000-patient trial of torcetrapib, also a CETP inhibitor. When Pfizer halted that trial early, many companies stopped working on CETP blockers. Researchers were left wondering whether torcetrapib's failure was down to unexpectedly high toxicity in that compound, whether the inhibition of CETP itself is harmful, or whether the idea that raising HDL levels lowers risk is flawed.

The anacetrapib trial also tracked the drug's effects on LDL and HDL levels, which, according to Christopher Cannon, a cardiovascular researcher at Brigham and Women's Hospital in Boston, Massachusetts, and the study's principal investigator, are "jawdropping". After 24 weeks on the drug, patients experienced a 138% increase in HDL levels. In contrast, exercising and changing diet might only raise HDL by 10%, says Cannon. The participants, all of whom were also on statins, experienced a further 40% reduction in LDL levels.

Although the study wasn't large enough to look at the effect of anacetrapib on heart disease, the researchers noted some positive trends: 3.3% of patients taking the drug experienced heart attacks, stroke or other kinds of cardiovascular events, compared with 5.3% of patients in the placebo group.

The drug's apparent safety is encouraging, says Prediman Shah, director of cardiology and atherosclerosis research at Cedars-Sinai Medical Center in Los Angeles, California, "but there are some interesting red flags". One, he says, has to do with c-reactive protein (CRP), a marker of inflammation in blood that tends to drop as patients regulate their cholesterol with statins or lifestyle changes. Despite the huge changes in LDL and HDL levels, CRP levels actually increased slightly.

Shah also says he is surprised that such enormous shifts in HDL levels yielded such small clinical benefits. "In all fairness, the study wasn't powered to test that," says Shah, but if epidemiological predictions on HDL's benefits are correct, the drug should virtually "confer immortality".

Whether raising HDL really works won't become clear until data from larger studies begin to emerge, Shah says. An international, 30,000-patient trial testing anacetrapib's efficacy will begin next year, but results won't come in until at least 2014 (see
Table 1). Meanwhile, results on another CETP inhibitor called dalcetrapib, developed by Roche, are expected in 2013.  

From Nature