新藥Evacetrapib可以降低壞的膽固醇（LDL)和升高好的膽固醇（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.

新藥可增加HDL膽固醇並降低LDL膽固醇濃度

芝加哥 – 據11月16日刊《美國醫學會雜誌》上的一則研究披露，在低密度脂蛋白膽固醇（LDL-C）或高密度脂蛋白膽固醇（HDL-C）處於次佳狀態的病人中單獨使用藥物evacetrapib或evacetrapib與他汀類藥物聯合使用與HDL-C濃度的明顯增加及LDL-C濃度的下降有關；這一期雜誌是有關心血管疾病的專刊。這項研究將在互聯網上提前發布，以使其與它在《美國心髒協會》科學會議上的報告時間相吻合。

研發可增加HDL-C濃度的藥物一直具有挑戰性，並充斥著失敗的經曆，其中包括提前終止一項研究膽固醇酯轉移蛋白（CETP）抑製劑torcetrapib的大型的結果試驗。根據文章的背景資料，盡管該類藥物中的第一個藥物失敗了，但人們對抑製CETP作為一種治療策略仍然有著相當大的興趣，因為這些藥物具有大幅升高HDL-C濃度以及在某些情況下可降低LDL-C濃度的能力。 “很少有研究記錄了CETP抑製劑在與常用的他汀類合用時的功效和安全性。”

克利夫蘭診所的Stephen J. Nicholls, M.B.B.S., Ph.D.及其同事對CETP抑製劑evacetrapib在單用時及與在臨床實踐中在血脂異常病人中常用的他汀類藥物合用時的生物化學功效、安全性和耐受性進行了評估。這一包括了398名LDL濃度增加或HDL-C濃度低下的患者的隨機對照試驗是在2010年4月至2011年1月間在美國和歐洲的社區及學術中心中進行的。患者被隨機指派服用安慰劑（n=38）；evacetrapib 單藥療法每日30毫克（n=40）、每日100毫克（n=39）、或每日500毫克（n=42）；或他汀療法（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），這些他汀類藥物或是與每日100毫克evacetrapib合用，或是單用，時間為12周。

患者在本研究開始的時候的血脂平均濃度為HDL-C每分升55.1毫克及LDL-C每分升144.3毫克。研究人員發現，在單藥療法中， evacetrapib可劑量依賴性地增加HDL-C：每分升30.0毫克至每分升66.0毫克（增加53.6% 至128.8%），而安慰劑則使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%），而安慰劑則使LDL-C每分升增加7.2毫克（增加3.9%）。

與他汀類單藥療法所觀察到的療效相比，每日服用100毫克evacetrapib加上他汀療法可使HDL-C濃度增加：每分升42.1毫克至50.5毫克（78.5%至88.5%）並導致更大幅度的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。

文章的作者寫道：“這些初步的發現提示，evacetrapib可與他汀類合並使用，並可對脂蛋白產生潛在的臨床重要的增量功效。目前的研究結果為一個旨在評估evacetrapib功效和安全性的大型第三期的臨床試驗提供了基礎。”

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