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[ADA2012]TZD类药物治疗糖尿病的安全性问题
——Ralph A. DeFronzo教授专访
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作者:R.A.DeFronzo 2012/6/12 11:00:00    加入收藏
内容概要:DeFronzo教授:从2000年吡格列酮上市以来,我一直把它作为T2DM的一线治疗药物。吡格列酮是唯一真正的胰岛素增敏剂。吡格列酮能够保存胰岛β细胞功能。目前TZD类药物只有吡格列酮了,这是相当明确的。吡格列酮能够持久控制血糖;HbA1c降低且能够得到维持。

  Ralph A.DeFronzo  美国德克萨斯大学附属Audie L. Murphy Memorial VA 医院保健中心糖尿病科主任,2008年ADA Banting奖获得者

  <International Diabetes>: You made a provocative statement in the PPAR agonist debate that you would use pioglitazone as a first-line therapy. Can you explain that?
  Prof. DeFronzo: I have been using pioglitazone as first-line therapy since 2000 when it came out. It is the only true insulin sensitizer that we have. It also preserves beta cell function. It is now, I think well-established, as are TZDs in general, but the only one left standing is pioglitazone. It provides durability of glycemic control; the A1C comes down and it stays down. We have the PROactive study which shows that there is a decrease in the MACE endpoint (myocardial infarction, stroke and death) of 16%.

        We have actually done one of the very first studies into NASH syndrome published in the New England Journal of Medicine, showing that it reverses NASH, not only mobilizing fat out of the liver but decreasing inflammation and even lessening fibrosis in the liver. So it has many attributes that are favorable in diabetic patients.

        The salt and water retention is very simple to handle. Every patient who comes in, you should have them take their shoes and socks off. For our interns and residents, we have a very simple dogma. One finger. One place. One minute. If they have edema they need to be treated with a diuretic or the dose of pioglitazone is lowered. I haven’t seen a case of heart failure since I have been using the drug. If you cannot get rid of the edema you should stop the drug. If you know the side effects, you can avoid them. Weight gain? I also use triple therapy in all of my patients, so its metformin, pioglitazone (the Actoplus MET tablet) and a GLP-1 analogue. All of my patients on pioglitazone lose weight and they lose the amount of weight you expect them to lose with the GLP-1 analogue. The GLP-1 analogues also promote sodium excretion by the kidney so that is another reason why you don’t see sodium retention.

        The only issue that is a little bit more difficult to handle is the fracture issue. It has primarily been described in post-menopausal women; you don’t see it in pre-menopausal women and you don’t see it in men. We know the high risk category are the post-menopausal women so all post-menopausal women should have a bone mineral density scan as part of their post-menopausal estrogen status because we know they will tend to become osteoporotic. If their bone mineral density is reduced, I just don’t use it in those people. If the bone mineral density is normal, I use it but I will follow the bone mineral density anyway. There is no perfect drug; they all have side effects. If you are a good physician and you know what the side effects are, you can minimize them and pioglitazone has many attributes as I said so the benefits far outweigh the risks of using the drug.

  《国际糖尿病》:在年会的PPAR激动剂辩论中,你提到自己把吡格列酮作为T2DM的一线治疗。对这个说法有些争议,你能否解释一下?
  DeFronzo教授:从2000年吡格列酮上市以来,我一直把它作为T2DM的一线治疗药物。吡格列酮是唯一真正的胰岛素增敏剂。吡格列酮能够保存胰岛β细胞功能。目前TZD类药物只有吡格列酮了,这是相当明确的。吡格列酮能够持久控制血糖;HbA1c降低且能够得到维持。PROactive试验显示,吡格列酮使主要心脏不良事件(MACE,即卒中、心梗和死亡)的发生率降低16%。
  实际上,我们开展了首个在非酒精性脂肪性肝炎(NASH)患者观察吡格列酮的研究,该研究发表于《新英格兰医学杂志》,显示吡格列酮能够逆转NASH。吡格列酮不但能够使脂肪从肝脏中转移出来,还能够减轻炎症反应,甚至能够改善肝纤维化。因此说,吡格列酮具有很多对糖尿病患者有益的特点。
  水钠潴留的问题是非常容易解决的。每一位高血压患者就诊时,都得让他脱鞋子和袜子。对实习医生和住院医师来讲,有一个非常简单的方法,就是一次用一根手指按压一个部位一分钟。如果患者有水肿的话,要给予利尿剂或小剂量吡格列酮治疗。应用吡格列酮以来,我从未遇到患者发生心衰。如果水肿不缓解,应停用吡格列酮。如果我们知道药物的不良反应,就可以避免它。对于所有体重增加的患者,我应用三联治疗,即二甲双胍、吡格列酮(Actoplus MET)加上一种GLP-1类似物。所有应用吡格列酮的患者都有体重减轻,减轻程度与应用GLP-1类似物时的预期相似。另外,GLP-1类似物促进尿钠排出,患者不会有钠潴留。
  唯一有些难处理的是骨折。研究者首先在绝经后女性描述了骨折的问题,绝经前女性不会发生骨折,男性也不会发生骨折。我们知道,绝经后女性是发生骨折的高危人群,因此所有绝经后女性都应当接受骨密度扫描,以便从某种程度上判断绝经后的雌激素状况,因为我们知道绝经后女性易发生骨质疏松。如果患者骨密度降低的话,我就不会应用吡格列酮。如果骨密度正常的话,我会应用吡格列酮,但是会观察骨密度。没有药物是完美的,每一种药物都有不良反应。如果你是一位优秀的临床医生,就会知道药物都有哪些不良反应,可以尽量避免它。吡格列酮有很多特点,正如我刚才所讲的,吡格列酮带来的益处远远超过了风险。

  <International Diabetes>: You had a very strong opinion about the bladder cancer issue. Could you explain your position?
  Prof. DeFronzo:  It is even clearer now that we have the final follow-up from the Kaiser Permanente data which were published today, that the bladder cancer risk has a hazard ratio of 0.98. It is not significantly less than 1.0 but it is not over 1.0 and even if you look at the previous analysis from the four or five year data, there was maybe an increase of 3 per 10000 cases. That is really pretty small. If you look at PROactive, the risk reduction for MI, stroke and death was 16% which is relative risk. Absolute risk is about 2.5% to 3%. So 3% extrapolates to 300 fewer people dying, having an MI or stroke per 10000 compared to maybe 3 more cases of bladder cancer per 10000. I have actually never really been concerned about this because the benefit so far outweighs and risk, 300 to 3, and we have just found out today that it is really not even an increase of 3 per 10000 whereby the hazard ratio was less than 1.0 for bladder cancer. Plus, I think it is unfair. There are many cancers you can get. Why is it that you pick on one cancer that occurs very infrequently? Looking at other cancers like breast cancer, liver cancer and so on, many of these are decreased on pioglitazone with genuinely significant reductions and hazard ratios less than 1.0. Why do you ignore these and choose to pick on the cancer that is very uncommon and which we now know is not even increased at all?

  《国际糖尿病》:你对吡格列酮与膀胱癌的问题有很明确的看法。能否解释一下你的看法?
  DeFronzo教授:目前这个问题更明确了,因为我们现在有来自美国凯泽医疗机构(Kaiser Permanente)的最终随访结果。今天这一刚刚发表的结果显示,应用吡格列酮时发生膀胱癌的风险比是0.98。这一数值不比1.0小很多,但是并没有超过1.0。即便是看以往针对4、5年数据的分析结果,会发现在每10,000例糖尿病患者中,吡格列酮可能只增加了3例膀胱癌发生。例数相当少。如果我们观察PROactive研究,就会吡格列酮使发现心梗、卒中和死亡的相对风险降低了16%。绝对风险降低了2.5%~3%。绝对风险降低3%相当于每10,000例患者中死亡、发生心梗或卒中的人数减少了300例,相比之下每10,000例中增加3例膀胱癌发生。事实上,我从未担心过膀胱癌的问题,因为其获益远远超过了风险(300比3的比例)。今天,我们通过最新数据了解到膀胱癌的风险比小于1.0,这相当于实际上每10,000例患者中膀胱癌发生风险增加的还不到3例。另外,我认为针对膀胱癌是不公平的。除了膀胱癌,患者可能患上的癌症还有很多种。为什么单单挑选出膀胱癌这一非常不常见的癌症?当我们观察乳腺癌和肝癌等癌症时,吡格列酮确实可以减少其中很多种癌症的发生,风险比低于1.0。为什么我们要忽略这些而只是针对膀胱癌这一非常不常见的癌症?现在我们知道,吡格列酮甚至根本不增加膀胱癌的风险。 



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