主页 > 医学讨论 >
【社会人文】恶性胆固醇再现
Pharmaceuticals
Bad Cholesterol's Comeback
Matthew Herper and Robert Langreth 03.26.07, 12:30 PM ET
Cardiologist Evan Stein remembers the moment he decided what he was going to do with his life. When he was just beginning his medical career, a patient in his 20s died of a heart attack under his care.
The man had a genetic disease that causes levels of bad cholesterol, so-called LDL, to skyrocket. These patients have defective versions of the gene that processes cholesterol in the body. They often die young. Even modern cholesterol drugs such as Lipitor can't get cholesterol fully under control in these patients. The problem is so bad that some have their cholesterol laboriously filtered from the blood, at a cost of $70,000 a year.
On Monday, at the American College of Cardiology's annual meeting, Stein presented data from a new drug that had "more dramatic lipid-lowering effects in these patients than we have ever seen." The new drug, 301012 from Isis Pharmaceuticals (nasdaq: ISIS - news - people ), works directly on DNA to prevent production of the protein that is the main component of LDL. The trial contained only three patients, but it provides new hope for a difficult to treat group. One concern: The drug has elevated liver enzymes.
"It's definitely worth keeping an eye on," says Daniel Rader, a cholesterol researcher at the University of Pennsylvania. "Safety is still going to be a big question; they need to treat a lot more people to know that." Willis Maddrey, of a hepatologist at the University of Texas Southwestern Medical Center who is consulting for Isis on safety, says he is not overly concerned. "There is nothing so far that gives me undue concern about the liver, but we have to watch it."
The Isis results present a stark contrast to reports that drugs to treat the so-called "good cholesterol" are delivering dramatic disappointments. Drug companies have been focusing on new drugs to boost good cholesterol. But the terrible trial results of the first drugs to raise good cholesterol may force doctors to reconsider how important HDL really is. It will likely cause them to focus once again on doing a better job lowering bad cholesterol in their patients.
"LDL is a pretty easy molecule to understand," says Stein. "It's consistent no matter how we've looked at it for 50 years. Genetically, it always makes sense. No matter how you lower LDL, you reduce risk."
Researchers promoting HDL-boosting drugs presented a simple picture based on population research: The higher your HDL, the less your chance of a heart attack. But this straightforward finding masks a far more complex reality. Unlike bad cholesterol, HDL isn't a single type of particle but a chemical chameleon whose precise composition fluctuates, like a flatbed truck that is constantly taking on different types of cargo. HDL may be different in healthy people (the kind in the population studies) compared with those sick with heart disease.
But the results of Pfizer's (nyse: PFE - news - people ) big experimental drug to raise HDL have been negative. It hurt patients in a large trial and didn't clear plaque from the arteries. John Kastelein of the University of Amsterdam, who presented data on the drug, said it reminded him of "a Dutch pancake. You can't get any flatter."
"We were naive about HDL, because nothing in nature is all good or all bad," says UCLA cardiologist Alan Fogelman. His lab studies hint that HDL may be helpful in healthy people but sometimes turns harmful in heart patients with inflamed arteries. Fogelman says researchers need to develop blood tests that measure the efficiency of HDL at removing cholesterol from blood vessels, rather than just measuring the amount.
Further complicating matters, HDL doesn't act independently, but it usually is inversely correlated with levels of blood fats called triglycerides. Patients with high triglycerides usually also have low HDL.
In any case, drug researchers have relatively few good ideas about how to raise HDL, besides the mechanism that yielded such bad results for Pfizer. "One of the discouraging facts is there are not a lot of other drugs in the pipeline that are good candidates for raising HDL," says Bryan Brewer of the MedStar Research Institute in Washington, D.C.
Many doctors argue for a renewed focus on LDL, given that many patients still have high levels. James O'Keefe Jr. of Mid America Heart Institute in Kansas City argued that LDL is the prime mover in causing heart disease; doctors should pay more attention to getting it as low as possible rather than worrying about HDL. "It is too soon to be relying on drugs to raise HDL," he said. But, he added, "LDL is an essential element for atherosclerosis."
In a debate at the meeting, he argued that the natural levels of LDL throughout most of human history were far below typical levels today in the Western world. Studies of remote tribes that eat leafy, nutty diets have found that they often have total cholesterol levels of around 100, he said.
阅读本文的人还阅读：
作者:admin@医学,生命科学 2011-01-08 05:14
医学,生命科学网