BOSTON (EGMN) – Pitavastatin lowers LDL cholesterol at lower doses than other statins do, while raising HDL cholesterol, investigators reported at a symposium sponsored by the International Atherosclerosis Society.

In clinical trials in Japan, where the HMG CoA-reductase inhibitor was approved in 2003, pitavastatin at 2- to 4-mg doses resulted in lowering of LDL cholesterol by 38%-45%, a reduction in atherosclerotic plaque volume of about 17%, and a rise in HDL cholesterol of about 8%, reported Dr. Jun Sasaki of the International University of Health and Welfare in Otawara City, Tochigi Prefecture, Japan.

“Pitavastatin is characterized by having a cyclopropyl group in its core structure, and this function is one of the reasons pitavastatin shows increased HMG CoA-reductase inhibition and therefore has potent LDL-cholesterol–lowering activity at a lower dose [than that of other marketed agents],” said Dr. Sasaki.

In addition, laboratory studies comparing pitavastatin with simvastatin or atorvastatin in hepatocytes shows that pitavastatin induces a more rapid release of apolipoprotein A1 (ApoA-1), a key precursor of HDL cholesterol.

In a postmarketing Japanese study (Japan-ACS) pitting pitavastatin 4 mg against atorvastatin 20 mg, there were no significant differences in the change in LDL cholesterol (about a 36% decrease for both drugs) or in plaque volume (about a 17.5% decrease for both drugs). Other studies in Europe and in the United States have shown that pitavastatin is comparable to atorvastatin in its effects on LDL cholesterol, Dr. Sasaki said.

Where pitavastatin may have an edge over atorvastatin, however, is in its effect on HDL cholesterol. In a European study, pitavastatin at doses of 2 mg and 4 mg improved HDL-cholesterol levels by 4% and 5%, respectively over 12 weeks, compared with a 3% increase for atorvastatin 10 mg and a 2.5% increase for atorvastatin 20 mg. These differences were not statistically significant.

But in the PIAT study, which looked at the effects of pitavastatin and atorvastatin on HDL levels in patients with hyper-LDL-cholesterolemia and glucose intolerance in 173 patients, pitavastatin 2 mg/day resulted in a 8.2% climb in HDL, compared with 2.9% for atorvastatin 10 mg/day. Similarly, pitavastatin was associated with a 5.1% increase in ApoA-1, vs. 0.6% for atorvastatin. Both differences were statistically significant.

Pitavastatin has also been shown to be similar in efficacy to simvastatin in clinical trials, Dr. Sasaki said.

Safety data from a phase III European trial show a similar incidence of treatment-emergent adverse events with pitavastatin at both the 2 mg and 4 mg dose levels compared with atorvastatin at 10 mg and 20 mg. Five patients on pitavastatin 2 mg and six on the 4-mg dose had to discontinue therapy because of adverse events, compared with none on either dose of atorvastatin, but this difference was not statistically significant. In all drug and dose groups, musculoskeletal or connective tissue disorders were seen in about 3%-5% of patients, and myalgia was seen in about 1%-2%.

Whether the increase in HDL seen with pitavastatin and other HMG CoA-reductase inhibitors has any clinical meaning, however, is another story, said Dr. Antonio M. Gotto Jr., dean of the Weill Cornell Medical College in New York.

“I don’t know whether we can tease out this benefit from pitavastatin, but I believe that eventually we will find that there are benefits in raising HDL, and I think the most likely way of doing this would be through stimulating the production of Apo-A1. And there were some suggestions that possibly pitavastatin might stimulate ApoA-1. Also, increasingly, HDL turnover, although it doesn’t raise HDL, has been shown to have a powerful antiatherosclerotic effect in animals,” said Dr. Gotto, who moderated the session in which Dr. Sasaki presented the data.

Dr. John J.P. Kastelein, professor of medicine and chairman of vascular medicine at the Academic Medical Center in Amsterdam, said that he also believes that a strategy of raising HDL may eventually be shown to be beneficial for preventing cardiovascular complications, but that clinical studies to date have failed to demonstrate that effect. Dr. Kastelein was the lead investigator in a study of torcetrapib, the failed HDL-raising agent whose development was halted in 2006 when studies showed excessively high levels of all-cause mortality among patients who received it in combination with atorvastatin.

The studies reported by Dr. Sasaki were funded by Kowa Pharmaceuticals, maker of pitavastatin. Dr. Sasaki disclosed receiving research support from Daiichi Sankyo, Mochida, and Bayer. Dr. Gotto has served as a consultant to Kowa, Aegerion, Arisaph, DuPont, Genentech, Martek, Merck, Merck/Schering-Plough, and Novartis. Dr. Kastelein has received fees and grant support from Pfizer, Merck/Schering Plough, Bristol-Myers Squibb, and Sankyo.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

波士顿(EGMN) —— 一种正在研究之中的他汀pitavastatin，可以以比其他他汀更低的剂量降低LDL胆固醇，同时升高HDL胆固醇，研究者于6月15日在国际动脉粥样硬化学会发起的研讨会上报告。

在日本的临床试验中(HMG CoA还原酶抑制剂于2003年在日本获准使用)， 2~4 mg的pitavastatin可降低LDL38%~45%，减少动脉粥样硬化斑块体积约17%，同时使HDL胆固醇升高约8%，日本枥木县小田园市国际医疗福祉大学的Jun Sasaki医生报告。

“Pitavastatin的特征为在其核心结构中含有一个环丙基基团，这一结构是pitavastatin增强HMG CoA还原酶抑制并因此在较低剂量水平(较其他市售他汀类药物)具有很强的降低LDL胆固醇活性的原因之一，”Sasaki医生说。

此外，在实验室研究中，pitavastatin与辛伐他汀或阿托伐他汀在肝细胞中的比较显示，pitavastatin可诱导载脂蛋白A1 (Apo A1)更快释放，而Apo A1是HDL胆固醇的重要前体。

在日本的一项上市后研究(Japan-ACS)中，将蚀刻pitavastatin 4 mg与阿托伐他汀20 mg相比较，结果发现两种治疗对LDL胆固醇(均为降低约36%)或斑块体积(均为减少约17.5%)的改变无统计学差异。欧洲和美国的其他研究也显示pitavastatin降低LDL胆固醇的疗效与阿托伐他汀相当，Sasaki医生说。

Pitavastatin较阿托伐他汀的优越之处可能在于其升高HDL的疗效。在欧洲的一项研究中，2 mg和4 mg的pitavastatin治疗12周后，分别使HDL胆固醇水平提高了4% 和 5%，而阿托伐他汀10 mg和20 mg仅分别使HDL胆固醇水平提高了3% 和 2.5%。这些差异无统计学意义。

PIAT研究则评估了pitavastatin 和阿托伐他汀对173例高LDL胆固醇血症和葡萄糖耐量受损患者HDL水平的影响，pitavastatin 2 mg/d治疗使HDL升高了8.2%，而阿托伐他汀10 mg/d治疗仅使HDL升高了2.9%。相似的，pitavastatin治疗者Apo A1升高了5.1%，阿托伐他汀治疗者仅升高了0.6%。这些差异具有统计学意义。

“临床试验也显示Pitavastatin的疗效与辛伐他汀相似，”Sasaki医生说。

欧洲的一项III期试验的安全性数据显示，pitavastatin 2 mg及 4 mg剂量水平与阿托伐他汀10 mg和20mg的治疗不良事件发生率相似。pitavastatin 2 mg组中的5例患者和4 mg组中的6例患者因不良事件而停止治疗，阿托伐他汀的任何剂量组中均无患者因不良事件停止治疗，但这种差异无统计学意义。在所有药物的所有剂量组中，3%~5%的患者发生肌肉骨骼或结缔组织疾病，1%~2%发生肌痛症状。

 “而pitavastatin及其他HMG CoA还原酶抑制剂治疗引起的HDL升高是否具有临床意义则又是另外一回事了。”纽约Weill Cornell 医学院院长Antonio M. Gotto Jr医生说。

 “我不知道是否可以从pitavastatin治疗中得到这种益处，但我相信最终将发现升高HDL是有益的，并且我认为最可能是通过刺激Apo A1的产生而获益。有人提出pitavastatin可能会刺激Apo A1。同时也增加HDL的转化，在动物试验中，尽管pitavastatin未能升高HDL，却显示具有很强的抗动脉粥样硬化效应，”Sasaki医生报告所属会议的主持人Gotto医生说。

阿姆斯特丹医学中心医学教授及血管医学系主任John J.P. Kastelein医生说，他也认为升高HDL的策略最终将显示对预防心血管并发症有利，但迄今为止的临床研究均未能显示这种效应。Kastelein医生是一项关于torcetrapib研究的首要研究者，在那项研究中，torcetrapib未能升高HDL，并且在2006年因为接受torcetrapib与阿托伐他汀联合治疗患者的全因死亡率水平过高而致该研究中途停止。

Sasaki医生报告的研究由pitavastatin的生产商Kowa制药公司资助。Sasaki医生披露接受了Daiichi Sankyo、Mochida和拜耳公司的研究支持。Gotto医生曾担任Kowa、Aegerion、Arisaph、杜邦、基因泰克、Martek、默克/先灵葆雅和诺华公司的顾问。Kastelein医生曾接受辉瑞、默克/先灵葆雅、百时美施贵宝和 Sankyo公司的酬金及资助。