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MedScape对DeFronzo的专家访谈：关于双重PPAR激动剂muraglitazar [精华]

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一种全新的TZD类药物，muraglitazar已经在美国完成三期临床试验，即将上市并对2型糖尿病伴随的糖代谢和脂代谢紊乱同时有明显的治疗效果。muraglitazar同时激动PPAR-α和γ，具有明显降低甘油三酯、升高HDL-C，增大sd-LDL颗粒直径和减少其密度、改善脂蛋白谱；并显著改善机体胰岛素敏感性，有效控制血糖达标等作用。相关报道在前一段结束的EASD年会上成为最大的焦点，我们期待着这样一种双重激动剂的面世，相信会对2型糖尿病和MS综合征的治疗带来新的推动。

Medscape 10月12日就此双重PPAR激动剂muraglitazar的目前临床试验进展和未来治疗趋向等问题采访了Ralph A. DeFronzo(:)Big guy，不用介绍了吧)。DeFronzo除了谈到这个即将面世的双重PPAR激动剂外，更谈了一些关于药物临床试验的对待态度、TZD副作用的客观评价、对代谢综合征的看法等等。其中一些观点让我很吃惊，毕竟是大师，出言不凡！全文如下，各位都是高手，就不翻译了。

From Medscape Diabetes & Endocrinology
Expert Interview

New Options for Treating Dysglycemia and Dyslipidemia in Type 2 Diabetes: An Expert Interview With Ralph A. DeFronzo, MD
Posted 10/12/2005

Editor's Note:
A new generation of peroxisome proliferator-activated receptor (PPAR) agonists that interacts with both PPAR alpha and gamma receptors -- the dual PPAR agonists -- demonstrates lipid effects and insulin-sensitizing effects. These drugs have the potential to treat the dual defects of type 2 diabetes -- hyperglycemia and dyslipidemia -- with one medication. Medscape talked to Ralph A. DeFronzo, MD, Professor of Medicine, The University of Texas Health Science Center at San Antonio, about muraglitazar, one of the dual PPARs, at the European Association for the Study of Diabetes 41st Annual Meeting in Athens, Greece.

Medscape: A lot of exciting data were presented at EASD [European Association for the Study of Diabetes] this year, but in this interview I would like to focus on muraglitazar. Physicians are certainly familiar with the PPARs, but they may not be familiar with the dual PPARs. Can you give us a brief overview of the mechanism of action of the dual alpha-gamma PPAR activators?

Dr. DeFronzo: The dual PPARs, of which muraglitazar is the most advanced in terms of development, are very powerful in terms of lowering the blood sugar level as well as improving the dyslipidemia that occurs in type 2 diabetes. Working through the PPAR gamma receptor, muraglitazar has very potent insulin-sensitizing effects on liver and muscle to lower the blood sugar levels. It probably will also have beneficial effects on the beta cell, although that remains to be determined. Then, working through the PPAR alpha receptor, muraglitazar is very potent in terms of lowering the triglycerides and raising the HDL [high-density lipoprotein] cholesterol and converting small dense LDL [low-density lipoprotein] particles to larger, more buoyant particles, so it promotes a very good lipid profile from the standpoint of prevention of atherosclerosis.

Medscape: Phase 3 pivotal clinical trials of muraglitazar have been completed. Can you give us an overview of the results of those trials?

Dr. DeFronzo: The results of the phase 3 trials, which have been presented to the FDA [US Food and Drug Administration] Advisory Board, clearly demonstrate quite good efficacy in lowering hemoglobin A1C. In the studies, A1C fell about 1.2% to 1.4% -- from a starting point in the 8% to 8.5% range -- so this would be equivalent to the more potent drugs that are available now, including metformin, the sulfonylureas, and the thiazolidinediones, in particular, pioglitazone and rosiglitazone.

Medscape: You were also involved in a comparator trial with pioglitazone. What were the results of that study?

Dr. DeFronzo: Yes, there was a head-to-head trial with muraglitazar and pioglitazone. It's a bit difficult to interpret because the dose of pioglitazone used in the trial was 30 mg/day, which is not the maximum dose of pioglitazone, whereas the dose of muraglitazar was 5 mg, which is the maximum dose that has been recommended for approval by the FDA Advisory Committee. So it's a bit difficult to compare the doses. But I would say that if you were to extrapolate the pioglitazone data from 30 mg to 45 mg, you would have equivalent efficacy in dropping the A1C and better efficacy on the plasma lipid profile with muraglitazar. One of the benefits of muraglitazar is that 5 mg/day is not the top dose, and there are ongoing trials looking at a higher dose of 10 mg. Based upon early phase 2, dose-response studies, one would expect that the 10-mg dose would be superior to the 45-mg dose of pioglitazone. But, as I said, those trials are ongoing, and we'll have to wait for results before we can make a definite statement about the potency of pioglitazone vs muraglitazar.

Medscape: As you mentioned, on September 8, an advisory panel voted to recommend to the FDA that muraglitazar be approved as monotherapy and in combination with metformin for the treatment of type 2 diabetes. The panel voted against approval in combination with sulfonylureas. You were at that meeting. Could you describe the highlights and what the concerns were that led the panel to vote against combination treatment with sulfonylureas?

Dr. DeFronzo: I think the important thing is that the advisory panel recognized that muraglitazar would provide a nice addition to the therapeutic armamentarium for type 2 diabetes, and particularly that the panel recognized its potency and its ability to improve the lipid profile. There was close to unanimous approval of monotherapy and also in combination with metformin. There were some concerns raised by one of the statisticians about adverse cardiovascular events in the sulfonylurea group. It was somewhat strange that he introduced his discussion of this topic by noting that you need a minimum of 5000 people studied for 5 years to say anything about cardiovascular disease, so that the data, from the cardiovascular standpoint, were quite meaningless because the number of subjects in these trials (which were designed to look at glucose-lowering not cardiovascular problems) was really quite small -- in the realm of several hundred. Nonetheless, he voted against approval in combination with sulfonylureas, raising an issue about potential cardiac concerns because the 4 or 5 events that were observed in the trials all occurred in the sulfonylurea-muraglitazar group. There was some considerable debate amongst the panel about this issue, but I think that this particular statistician had a heavy influence on how the rest of the panel voted. We'll have to wait and see what the FDA decides, because they are not bound by the advisory board vote. My guess is that there will be approval for use with sulfonylureas. There may be some kind of warning, as there is with all of these TZD [thiazolidinedione]-type drugs.

Medscape: Am I right that the adverse reactions associated with muraglitazar are consistent with the PPAR class as a whole? Could you describe those adverse reactions in more detail?

Dr. DeFronzo: What most people call adverse reactions I wouldn't necessarily call adverse reactions, but what was noted was weight gain with muraglitazar. That's fat weight gain, and we know now that the more weight you gain the better the improvement in insulin sensitivity, the better the effects on beta-cell function, the better the drop in A1C, and the better the effect on cardiovascular risk factors. This has to do with the mechanism of action of muraglitazar, which causes a redistribution of fat out of all tissues in the body except subcutaneous fat. When you mobilize fat out of muscle, liver, beta cells, and arteries, you improve insulin sensitivity, preserve beta-cell function, and presumably get protection against atherosclerosis.

The other issue is edema. I think that when these drugs work on the blood vessels -- and that's largely where PPAR gamma receptors are -- they cause vasodilation. There are a number of compensatory mechanisms that come into play when you vasodilate that lead to the development of edema, and, unfortunately, people have confused edema with congestive heart failure. Now there's no doubt that very rarely patients do retain fluid, and if they have a bad myocardium they can develop congestive heart failure. But I believe this is a quite uncommon event and that the drug itself has no deleterious effect on cardiac function.

Medscape: At sessions I attended on PPARs at EASD, and specifically on muraglitazar, a common question from the floor was, "Why a single drug that treats dysglycemia and dyslipidemia? Why not just use 2 drugs?" Could you address that question?

Dr. DeFronzo: First, the drugs that are currently available are somewhat limited in terms of potency -- at least with regards to lowering lipids and raising the HDL. The dual PPARs, and particularly muraglitazar, appear to be more potent in correcting the dyslipidemia. But, as I mentioned earlier, there are no head-to-head studies. A second issue, of course, is that our diabetic patients have the dual defects of hyperglycemia and dyslipidemia, and it would be very nice to have 1 drug that attacks both of them rather than patients having to take 2 drugs. From the standpoint of the patient, it's always nice in terms of compliance and in terms of copays to have both of these problems attacked by 1 drug, and 1 drug alone.

Medscape: What is the profile of a patient who would be a candidate for treatment with muraglitazar once the drug is in the clinic?

Dr. DeFronzo: I think basically any diabetic patient would be a candidate for treatment with muraglitazar. The dual PPARs as well as the thiazolidinediones have the potential to save beta cells, so you would want to start early. We also now know from the PROactive [Prospective PioglitAzone Clinical Trial in MacroVascular Events] study that the thiazolidinedione class of drugs -- and I would presume when the studies are done, also the dual PPARs and muraglitazar, specifically -- will give you protection against cardiovascular disease. So that is another reason for starting earlier. But, in fact, muraglitazar could be added to people who are on any of the currently available oral agents. It could be added to metformin. It could be added to a sulfonylurea. So I think you'll see it being used in all stages of the natural history of type 2 diabetes.

Medscape: In closing, muraglitazar has been discussed as a treatment for metabolic syndrome. Of course, there has been lots of controversy recently about whether the metabolic syndrome is a useful clinical diagnosis. Would you like to weigh in on that question?

Dr. DeFronzo: Well, personally, I don't want to weigh in on it. I think there's enough controversy. I have never called it the metabolic syndrome. I think the metabolic syndrome is a grab-bag term for a number of quite distinct disorders that end up with the same phenotype. I've always preferred to call it the insulin resistance syndrome. Clearly, we can define a large group of people who have a specific molecular defect at the cellular level that leads to insulin resistance, which in turn leads to a host of cardiovascular/metabolic abnormalities that predispose to accelerated atherosclerosis. So, I think that if we had called this the insulin resistance syndrome, it would have been much more acceptable. I think eventually that the best thing that will come from this controversy is there'll be a lot more research aimed at defining what really causes the metabolic syndrome. I think what we'll find is a dozen or so different disorders that lead to this phenotype, and then, as we define these disorders, we'll come up with therapies that are more specific. So maybe the controversy is helpful, in that it will generate more research about the basic pathophysiologic mechanisms responsible for the disease.

Medscape: Thank you, Dr. DeFronzo. You've been very gracious.

Dr. DeFronzo: No problem.

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2005-10-20 22:18 浏览 : 1676 回复 : 5

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ranjm 编辑于 2005-10-20 22:20

• 教育部：今年国家定向培养免费医学生，你会报考吗？——回帖

小小东方

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看完了，不错。
比较有收获的是Dr. DeFronzo对于PPAR类药物的体重增加和水肿的“副作用”的解释。他的观点还是比较让我信服的，不过对于PPAR类药物改变了脂肪的分布以前曾经有过相关文章。
对于Dr. DeFronzo对于代谢综合征的一段其实也是一种代表观点。但是偶还是认为，胰岛素抵抗作为代谢综合征（或者是胰岛素抵抗综合征）的病理发生基础的证据不足，至少目前还不能这么说。
Clearly, we can define a large group of people who have a specific molecular defect at the cellular level that leads to insulin resistance, which in turn leads to a host of cardiovascular/metabolic abnormalities that predispose to accelerated atherosclerosis.
这句话说的没有错，但是这与代谢综合征的定义是两回事。如果根据这条线：胰岛素抵抗——代谢异常——心血管疾病的发展顺序，那就用胰岛素抵抗综合征这个名称更合适。但是目前的研究是一种回溯性的：心血管疾病——代谢异常——？？？。所以目前能够观察到的是一群代谢异常，也就是第二部分，至于？？？，就是其发生机制是不明确的，在没有足够证据说明一种发生机制是所有代谢异常的基础前，都不能得到肯定的答案。
这次去北京听了糖尿病防治论坛，其间在讨论的时候美国疾病控制中心一级预防代理副理事 Michael Engelgau对于代谢综合征还谈到了一点，这也是我以前还没有注意过的一点。他主要从代谢综合征的机制研究方面说的，代谢综合征目前争议确实比较大，他还是比较倾向于代谢综合征是具有存在的意义的，至少可以有利于人们研究在心血管疾病中这么多代谢异常聚集的原因。

代谢综合征目前的争议很大，其实这个问题不光涉及到心血管疾病，还涉及到糖尿病的预防。改天咱们论坛可以开一个专贴好好讨论讨论。

2005-10-22 00:30

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• 胸闷伴出汗1小时，帮忙诊断一下心电图

sxl1977

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学习完毕

早就关注双重PPAR激动剂，终于露出庐山真面目啦

从机理上讲肯定是一种非常有效的药物

DeFronzo对于PPAR类药物的体重增加的解释也非常有说服力，另一种解释是脂肪细胞本身体积的变化。对水肿的解释有待进一步证实，毕竟那么多扩血管药物，也没有看见个个会引起水肿。

是否联合用药，就像DeFronzo所猜，机理不同，应该有协同作用。

代谢综合征发生机制，目前为止最好的解释还是胰岛素抵抗，因为它的定义覆盖面很广，所以肯定存在不足的方面。目前已有很多关于MS与糖尿病和心血管疾病的前瞻性研究，证实MS对DM和CVD具有很强的预测能力，只是MS对DM和CVD的预测力不及已有的预测模型强。

2005-10-22 11:16

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• 【交流】你遇见过哪些令人遗憾的患儿？

h797

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　　衷心感谢ranjm朋友为我们带来的精华贴！也感谢小小东方、sxl1977的精彩论述，内分泌版需要这样的好文章！
　　因为：报道前沿动态＋自己的观点＋原文，所以该贴给予：精华＋置顶＋推荐热门话题＋2分
　　曾经反复强调：内分泌版不是资料库，所以单纯机械地提供一些文章、讲义等资源，我们没有给分，请大家能够谅解，这也是内分泌版为成为有自己特色的、高专业水平论坛而坚持不懈的做法，另外，已经开展并将继续执行下去的就是：禁止非专业人员的求助，因为本版既非科普性质，也无远程医疗的资质

2005-10-25 09:46

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h797 编辑于 2005-10-25 09:58

• 普放病例分享31：X线虽有不足但有用，请各位上眼（1楼43楼已更新图像）

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