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【drug-news】微粒体甘油三酯转运蛋白抑制剂可降
January 10, 2007 (Philadelphia, PA) - A new study examining the use of a microsomal triglyceride transfer protein (MTP) inhibitor suggests that this class of drugs may effectively slash LDL-cholesterol levels in patients with familial hypercholesterolemia, but at the price of GI side effects and significant hepatic fat accumulation [1]. Authors of the study say the potential risk to the liver may be offset by the LDL-lowering effects in rare cases of homozygous familial hypercholesterolemia; whether the risks can be justified in lower-risk patients is unclear.
Others, however, say that while MTP inhibitors may not have a future in therapeutics, the research into these agents paves the way for future therapies that act on LDL secretion by the liver.
As Dr Marina Cuchel (University of Pennsylvania Medical School, Philadelphia) and colleagues write in the January 11, 2007 issue of the New England Journal of Medicine, people with homozygous familial hypercholesterolemia carry loss-of-function mutations in both alleles of the LDL-receptor gene, leaving them with plasma cholesterol levels of more than 500 mg/dL (12.9 mmol/L). Carriers typically develop cardiovascular disease before age 20 and are dead by age 30.
By contrast, carriers of a mutation in the MTP gene are known to have very low levels of cholesterol, leading to the development of MTP inhibitors with the aim of blocking LDL production and reducing LDL. Cuchel et al's study tested an MTP inhibitor--BMS-201038, developed by Bristol-Myers Squibb and since licensed to Aegerion Pharmaceuticals for further development as AEGR-733--in six patients with homozygous familial hypercholesterolemia.
"In these patients, the risk/benefit strongly favors treatment," senior author on the study, Dr Daniel Rader (University of Pennsylvania Medical School), told heartwire. "If you're going to die of heart disease in 10 years, you're not too worried about the risk of chronic liver disease in 20 or 30 years. It's very easy to argue that people with severe hypercholesterolemia--and I would say not just the most extreme patients, but even the heterozygous familial hypercholesterolemia people we see, who despite statins and [ezetimibe] still have LDLs in the 200 range. These are people in whom I think the risk is so high that the benefit to them may exceed the theoretical long-term liver risk. Where that becomes more tenuous, or where we are really going to need to figure things out, is where do we draw that line and at what point does the liver issue exceed the benefit in terms of cholesterol lowering? That's where the fascinating debate is going to occur: the cardiovascular benefit vs the theoretical but real possibility of some risk to the liver in the long run."
A niche for MTP inhibition
Cuchel et al's study is the first published paper examining the use of an MTP inhibitor in patients with familial hypercholesterolemia; only one other small study of this class of drugs for lipid-lowering--in healthy volunteers--has been published, Rader told heartwire.
In the current study, the authors tested four doses (0.03, 0.1, 0.3, and 1.0 mg/kg body weight per day) over four weeks in six patients with homozygous familial hypercholesterolemia, followed by a four-week washout period. Cuchel and colleagues report that all patients tolerated the highest dose and experienced a mean reduction of 58.4% in total cholesterol levels at this dose. Mean LDL reduction at the highest dose was 50.9%. Despite having different baseline LDL levels (ranging from 480 mg/dL to 789 mg/dL), percent reductions were similar across the six patients. Where the authors saw a difference, however, was in the side effects. While no patients withdrew from the study due to side effects, five of the six patients reported one or more episodes of stool frequency, four out of six had elevated liver aminotransferase levels, four patients had substantial increases in hepatic fat during drug treatment, and two had minimal increases in hepatic fat. In five patients, the hepatic fat and aminotransferase levels returned to baseline levels four weeks after therapy was stopped, while in one patient, return to normal took 14 weeks.
Hepatic fat: Implications and debate
Asked about the clinical significance of the hepatic fat, Rader called it a "fascinating issue around which there has been so much disagreement."
Many people are concerned that a fatty liver could lead ultimately to hepatitis and possibly fibrosis. Increased hepatic fat is associated with insulin resistance in diabetes, Rader noted. But evidence is also emerging to suggest that a fatty liver is much more common than previously thought, with only a minority of people with hepatic fat actually going on to develop any kind of chronic liver problems, he said.
"There's no doubt that some patients who take this drug at a certain dose have an increase in hepatic fat, short term. The questions are, does that maintain long term, or does the liver adapt and does the hepatic fat go down over time with continued dosing? Even if it stays modestly elevated, does it create any long-term problems? Obviously those are hard questions to answer, but clearly they will need to be looked at. And then, finally, are the people who are going to have real problems with the liver, do they declare themselves with a liver function test such that you can pick that up, stop the drug, have the liver fat go back to normal and then basically conclude that they are people who shouldn't take this drug, but not have done any harm to them?"
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作者:admin@医学,生命科学 2011-03-27 11:48
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