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[AHA2008]《国际循环》顾问委员Steven Nissen教授专访:冠心病患者代谢异常的治疗进展

作者:StevenE.Nissen 编辑:国际循环网 时间:2008/11/25 21:56:00 关键字:糖尿病 他汀 REVERSAL研究 利莫那班 肥胖症 

nissenSteven E. Nissen教授

International Circulation: The mechanisms that underlie adverse cardiovascular outcomes in diabetic patients have not been well characterized. I have read some of your articles on this issue. Would you like to tell us the characteristics of diabetic patient’s coronary artery?

Prof. Steven Nissen: We know that diabetics have a significant increase in the risk of major adverse cardiovascular outcomes, including death, heart attack, stroke, and revascularization. We have done some studies using intravascular ultrasound (IVUS) that have demonstrated that they also have a substantially greater rate of the development of atherosclerosis. The rate of progression of their disease, once it is present in the coronary arteries, is much greater than non-diabetics. This we think probably plays an important role in the high risk for adverse cardiovascular outcomes. Surprisingly, the mechanisms by which having a high blood sugar increases the risk of adverse cardiovascular events is not entirely understood. Certainly there are abnormalities in lipid metabolism. Although LDL cholesterol is often not particularly elevated, HDL cholesterol is often low in these patients, and triglycerides are often high. Therefore, the combination of high triglycerides and low HDL may play a role. There is a higher incidence of hypertension in diabetics, and so with more hypertension, and lower HDLs, and higher triglycerides, diabetics are much more likely to have the metabolic syndrome than non-diabetics. Finally, there are advanced glycation end products (AGEs) that may be produced by high blood sugar that are involved in abnormalities in the vessel wall that may also lead to accelerated atherosclerosis.
Steven Nissen教授: 我们知道糖尿病患者发生不良心血管事件的风险显著增加,包括死亡、心脏病发作、卒中以及血运重建。我们利用血管内超声(IVUS)做了一些研究,证实他们发生动脉粥样硬化的比例更高。糖尿病患者一旦出现冠状动脉粥样硬化会比非糖尿病患者进展更快。 我们认为这是导致不良心血管事件高发的主要原因。然而,高血糖增加不良心血管事件风险的机制仍不明确。当然脂质代谢异常是其中一项原因。虽然LDL胆固醇通常不是显著升高,但这些患者通常HDL胆固醇降低,甘油三脂升高。因此,高甘油三脂和低HDL也在其中发挥作用。糖尿病患者高血压发病率更高。高血压、低HDL和高甘油三脂使得糖尿病患者较非糖尿病患者更易患代谢综合征。最后,高血糖产生的糖基化终产物会导致血管壁异常,也可能加速动脉粥样硬化进展。

International Circulation: The REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume. Statin therapy resulted in significant increases in OxPL/apoB, MDA/apoB, and lipoprotein (a) levels and decreases in apoB immune complexes and OxLDL autoantibodies. However, these measures did not correlate with changes in QCA parameters or atheroma volume. Could you explain these results for us?
Prof. Steven Nissen: We do not know the answers. This was a sub-study based upon banked blood of the REVERSAL trial. The main result of the REVERSAL trial, which was published in 2004 in JAMA, was really very striking. What we found was that patients who got an intensive statin regimen with atorvastatin had a slower rate of progression of coronary atherosclerosis than patients who got a more moderate statin regimen based on pravastatin. The attempt of this sub-study was to find out whether measures of oxidized LDL and some more sophisticated measures would be a better predictor of who progressed and who did not, but we really did not see very striking findings. So, we are really back to the original findings of the trial, namely that more LDL lowering produced a better outcome than less LDL lowering. We have also reported that greater reductions in CRP produced better outcomes than lesser reductions in CRP. Beyond that, everything else is really just exploratory.
Steven Nissen教授: 我们不知道答案。这是一个源于REVERSAL试验库存血的分支研究。在2004年JAMA上发表的 REVERSAL试验的主要结果相当惊人。我们发现服用阿托伐他汀进行他汀强化治疗的患者相比服用普伐他汀进行他汀常规治疗的患者,冠状动脉粥样硬化的进展会延缓。这一分支研究尝试了解是否OxLDL和一些更高级的检测手段可以更好地预测动脉粥样硬化的发展,但我们没有特别的发现。因此,我们回到这一实验的最初发现,就是LDL降低的越多,临床效果越好。我们还发现C反应蛋白降得越低,患者的临床转归越好。除此之外,其他的检测指标还有待探索。
International Circulation: Do you have any plans on looking at this further and following up on it?
Prof. Nissen: We don’t because we only had a limited amount of blood saved for the trial and we used the samples that we have. I think the REVERSAL trial has probably taught us as much as it can teach us. It doesn’t mean we won’t look at this in other trials, but that is where we stand with REVERSAL.
Steven Nissen教授: 我们没有,因为我们现有的样本有限。我想我们已经从REVERSAL试验得到了我们想要的。这不代表我们不会在其他试验中进一步研究,但我们会以REVERSAL实验为基础。
International Circulation: The STRADIVARIUS trial failed to show an effect of rimonabant on disease progression for the primary end point. Up to this point, there is still no obesity management strategy that has demonstrated the ability to slow progression of coronary disease. What do you think about the current situation?

 Prof. Steven Nissen: I think it is extremely challenging. We do not have good drugs for obesity. It is a growing problem, particularly in developed countries, although not all developed countries have the problem. For example, in Japan and China there is certainly less obesity than there is in the United States, but they are catching up with us. It has been very difficult to find drugs that work and work well enough to produce major and sustained weight loss. To date, the only therapies that really produce a large effect are therapies like bariatric surgery. It would be interesting to test disease progression in people who undergo bariatric surgery, but it has not been possible so far to do that kind of study. We were disappointed in the rimonabant results and in fact this drug will not be developed any further and has been withdrawn in Europe, primarily because of adverse psychiatric effects. So looking for the magic bullet for obesity is still an unfulfilled dream.
Steven Nissen教授:

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