The other is in Nature.com assessing whether the problem with torcetrapib is rooted in the way the drug itself elevates LDL or the fact that as Moti Kashyap, who directs atherosclerosis research at the VA Medical Center in Long Beach, California points out "When HDLs excrete cholesterol in the liver, they actually rely on LDLs for part of this process. So inhibiting CETP, which prevents the transfer of cholesterol from HDL to LDL, might actually cause an abnormal and irreversible accumulation of cholesterol in the body. "You're blocking a physiologic mechanism to eliminate cholesterol and effectively constipating the pathway," says Kashyap.
These articles are well-written, well-researched, balanced and thoughtful. Taken together it raises an important question: wouldn't drug development be helped by developing models that incorporate the off-target effects of medicines earlier in the clinical testing process? And that raises another question. Given the small difference in mortality is it possible to target the drug to people based on genotype variation? Can torcetrapib be retooled?