新药Evacetrapib可以降低坏的胆固醇（LDL)和升高好的胆固醇（HDL)

An experimental new drug may someday offer people struggling with cholesterol problems a treatment option that raises good cholesterol and lowers bad cholesterol in the blood, potentially reducing the risk of suffering a heart attack or other cardiac problems.

Researchers from the Cleveland Clinic, Georgetown University's MedStar Research Institute, Academic Medical Center in the Netherlands and Eli Lilly examined the effects of a drug called evacetrapib on cholesterol levels in nearly 400 patients with either low HDL, the "good" cholesterol, or high LDL, the "bad" cholesterol.

The study, presented at this year's American Heart Association meeting and published in this week's Journal of the American Medical Association, found that evacetrapib, either alone or in combination with cholesterol-lowering statins, increased HDL cholesterol and lowered LDL cholesterol.

"The drug more than doubled HDL and lowered LDL by 36 percent," said Stephen Nicholls, the study's lead author and clinical director of the Cleveland Clinic Center for Cardiovascular Diagnostics and Prevention. "There was a profound effect on the protective aspect of HDL and lowered LDL in a way we see with statins. If the drug was added to statins, we saw better lowering than with statins alone."

While the results are promising, Nicholls and experts not involved in the research say they are very preliminary. Without additional long-term studies, it's unclear whether the drug will be successful in decreasing the number of deaths from heart disease or the number of cardiac "events."

"We've known from epidemiological studies that low HDL levels are associated with an increased likelihood of heart disease and heart attack, and high levels are protective," said Dr. Cam Patterson, chief of the division of cardiology at the University of North Carolina School of Medicine in Chapel Hill. Patterson was not involved in the evacetrapib research.

"The average HDL level is about 45 mg/dl, and for every one point that goes up, the risk of heart disease goes down three percent," said Dr. Philip Ragno, director of cardiovascular health and wellness at Winthrop University Hospital in Mineola, N.Y.

But it's still unclear what actual effect raising HDL levels using this drug will have on heart disease.

"We don't know what will be the effect on clinical events," said Nicholls. "That will be the major determinant of whether these drugs come into clinical practice."

Limited Options for Raising HDL

Evacetrapib belongs to the class of drugs known as cholesteryl ester transfer protein inhibitors. The first drug in this class, torcetrapib, raised HDL levels, but its clinical trial was stopped because of deaths caused by side effects of the drug.

One of the challenges with developing drugs that can raise HDL, according to Nicholls, is that HDL is very complex.

"HDL is really complicated. It comes in all shapes and sizes, and we don't know if all are equally as protective," he said. "All forms of LDL are bad and we know that if we lower all forms, good things happen to patients." "The only other drug that we have that raises HDL is niacin. Many cardiologists have used it to raise HDL levels, and it's shown a modest increase of up to 30 percent in some individuals," said Dr. Philip Ragno, director of cardiovascular health and wellness at Winthrop University Hospital in Mineola, N.Y.

But data from the recent AIM-HIGH study, which tried to determine whether adding niacin to statin treatment regimens would raise HDL levels in people who successfully lowered their LDL with statins, showed the drug combination did not reduce the chances of having a heart attack. As a result, the AIM-HIGH trial ended a year and a half early.

- From ABC Health News.

新药可增加HDL胆固醇并降低LDL胆固醇浓度

芝加哥 – 据11月16日刊《美国医学会杂志》上的一则研究披露，在低密度脂蛋白胆固醇（LDL-C）或高密度脂蛋白胆固醇（HDL-C）处于次佳状态的病人中单独使用药物evacetrapib或evacetrapib与他汀类药物联合使用与HDL-C浓度的明显增加及LDL-C浓度的下降有关；这一期杂志是有关心血管疾病的专刊。这项研究将在互联网上提前发布，以使其与它在《美国心脏协会》科学会议上的报告时间相吻合。

研发可增加HDL-C浓度的药物一直具有挑战性，并充斥着失败的经历，其中包括提前终止一项研究胆固醇酯转移蛋白（CETP）抑制剂torcetrapib的大型的结果试验。根据文章的背景资料，尽管该类药物中的第一个药物失败了，但人们对抑制CETP作为一种治疗策略仍然有着相当大的兴趣，因为这些药物具有大幅升高HDL-C浓度以及在某些情况下可降低LDL-C浓度的能力。 “很少有研究记录了CETP抑制剂在与常用的他汀类合用时的功效和安全性。”

克利夫兰诊所的Stephen J. Nicholls, M.B.B.S., Ph.D.及其同事对CETP抑制剂evacetrapib在单用时及与在临床实践中在血脂异常病人中常用的他汀类药物合用时的生物化学功效、安全性和耐受性进行了评估。这一包括了398名LDL浓度增加或HDL-C浓度低下的患者的随机对照试验是在2010年4月至2011年1月间在美国和欧洲的社区及学术中心中进行的。患者被随机指派服用安慰剂（n=38）；evacetrapib 单药疗法每日30毫克（n=40）、每日100毫克（n=39）、或每日500毫克（n=42）；或他汀疗法（n=239）（辛伐他汀, 每日40毫克; 阿托伐他汀, 每日20毫克; 或瑞舒伐他汀, 每日10毫克），这些他汀类药物或是与每日100毫克evacetrapib合用，或是单用，时间为12周。

患者在本研究开始的时候的血脂平均浓度为HDL-C每分升55.1毫克及LDL-C每分升144.3毫克。研究人员发现，在单药疗法中， evacetrapib可剂量依赖性地增加HDL-C：每分升30.0毫克至每分升66.0毫克（增加53.6% 至128.8%），而安慰剂则使HDL-C每分升下降0.7毫克（降低 3.0%）；evacetrapib可降低LDL-C：每分升20.5 毫克至 51.4毫克（降低13.6%至35.9%），而安慰剂则使LDL-C每分升增加7.2毫克（增加3.9%）。

与他汀类单药疗法所观察到的疗效相比，每日服用100毫克evacetrapib加上他汀疗法可使HDL-C浓度增加：每分升42.1毫克至50.5毫克（78.5%至88.5%）并导致更大幅度的LDL-C的下降（降低67.1至75.8毫克/分升[降低11.2%至13.9%]）和非HDL-C的下降。

文章的作者写道：“这些初步的发现提示，evacetrapib可与他汀类合并使用，并可对脂蛋白产生潜在的临床重要的增量功效。目前的研究结果为一个旨在评估evacetrapib功效和安全性的大型第三期的临床试验提供了基础。”

(JAMA. 2011;306[19]:2099-2109)