烟酸的真相: 最安全、最廉价、最有效的降脂物质

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The Truth About Niacin: The Safest, Cheapest, Most Effective Lipid-Lowering Substance Available

By 作者 NutritionReview.org -July 23, 2020 2020年7月23日0769

Ward Dean, MD

沃德 · 迪安医学博士

A 2014 study in the New England Journal of Medicine disparaged the lipid-lowering benefits of niacin and implied that it was actually toxic. The study in question was not a study of niacin, per se. It was actually a study comparing the addition of extended-release niacinplus laropiprant (an antihistamine which purportedly reduced niacin-induced flushing) to patients who were already taking simvastatin 40 mg per day, or simvastatin plus ezetimibe10 mg per day (ezetimibe is a drug that is designed to increase HDL).1

《新英格兰医学杂志》2014年的一项研究贬低了烟酸的降脂作用,并暗示它实际上是有毒的。这项研究本身并不是烟酸的研究。这实际上是一项研究,比较那些每天服用40毫克辛伐他汀或10毫克辛伐他汀加依折麦布(依折麦布是一种旨在增加高密度脂蛋白的药物)的病人是否增加烟酸加拉罗普兰缓释片(据称减少了烟酸引起的脸红)

I was really surprised to note that it wasn’t just a single article warning against niacin. The same issue of the New England Journal coincidentally had a Letter to the Editor, questioning the “Safety Profile of Extended-Release Niacin in the AIM-HIGH Trial,”2 and an Editorial, “Niacin and HDL Cholesterol – Time to Face Facts”— i.e., a triple take-out piece!

我真的很惊讶地注意到,它不仅仅是一篇文章警告烟酸。同一期的《新英格兰杂志》恰好有一封致编辑的信,质疑“高度戒断试验中延长释放烟酸的安全性” ,2和一篇社论,“烟酸和高密度脂蛋白胆固醇——面对事实的时间”3ー也就是说,一份三次外卖!

The study involved 25,637 high-risk patients from 245 test sites in the UK, Scandinavia, and China. The “placebo” group received Simvastatin 40 mg or Simvastatin 40 mg plus Ezetimibe 10 mg, plus a 50 mg low-dose niacin-containing “placebo.” The “Niacin” group received 2,000 mg of extended-release niacin and 40 mg of Laropiprant, in addition to the Simvastatin or Simvastatin plus Ezetimibe, as was given to the placebo group. The participants in the study were followed for a median of nearly four years. The study was stopped prematurely after three years because of an apparent lack of benefit with extended-release niacin (plus laropiprant).

这项研究涉及来自英国、斯堪的纳维亚和中国245个测试点的25,637名高风险患者。“安慰剂”组接受辛伐他汀40毫克或辛伐他汀40毫克加依折替米布10毫克,加上50毫克低剂量含烟酸的“安慰剂”“烟酸”组除了辛伐他汀或辛伐他汀加依折替米布外,还接受了2000毫克烟酸缓释片和40毫克 Laropiprant,与安慰剂组相同。这项研究的参与者被跟踪调查了近四年。该研究三年后过早停止,因为延长释放烟酸(加拉罗普兰)明显缺乏益处。

The authors concluded that the Niacin-Laropiprant combination “did not significantly reduce the risk of major vascular events, but did significantly increase the risk of serious adverse harm,” and alleged that, “the study identified significant hazards, some of which had not been reported previously with niacin.”

作者得出结论,烟酸-拉罗普兰联合用药“并没有显著降低重大血管事件的风险,但确实显著增加了严重不利伤害的风险” ,并声称,“该研究确定了重大危害,其中一些以前没有报道过烟酸。”

Lipid-Lowering Effects of Niacin

烟酸的降脂作用

Let’s digress. The cholesterol-lowering effects of nicotinic acid were first reported in 1955.4The clinical benefits of immediate-release nicotinic acid were best demonstrated in the Coronary Drug Project (CDP), which compared immediate-release niacin with other cholesterol-lowering regimens on cardiovascular end points.5 In the CDP, immediate-release niacin reduced the total cholesterol level by 26 mg/dl (from a high baseline level of 253 mg/dl), and after six years, reduced the incidence of non-fatal MI (heart attacks) by 26% and cerebrovascular events (strokes) by 24%. Moreover, 9 years after trial termination, the group treated with niacin had 11% fewer deaths than the placebo group (Fig 1).5 Although lipid fractions were not measured in the CDP, subsequent studies with immediate-release niacin showed that it reduces LDL up to 25%, triglycerides up to 50% and Lp(a) up to 35%; and increases HDL up to 35%.6-8

我们离题吧。4烟酸立即释放的临床效果在冠状动脉药物项目(CDP)中得到了最好的证明,该项目比烟酸立即释放和其他降低胆固醇的方案在心血管终点上的效果更好。5在 CDP 中,烟酸立即释放降低了总胆固醇水平26毫克/分升(从高基线水平253毫克/分升) ,六年后,非致命性心肌梗死(心脏病发作)的发生率降低了26% ,脑血管事件(中风)降低了24% 。此外,在试验终止9年后,使用烟酸治疗组的死亡率比使用安慰剂组低11% (图1)。5虽然在 CDP 中没有测量脂质组分,随后使用烟酸立即释放的研究表明,它降低低密度脂蛋白高达25% ,甘油三酯高达50% ,脂蛋白(a)高达35% ,高密度脂蛋白高达35% 。6-8

The most commonly reported side effect of immediate-release niacin is the well-known flushing and itching of the skin (cutaneous vasodilation) that can be so uncomfortable that it may cause some people to discontinue taking it. Although the flushing can be overcome by taking niacin at the end of a meal, or by taking an aspirin 30 minutes prior to taking niacin, it is also self-limited, and tolerance to flushing develops with continued use. Nevertheless, pharmaceutical companies developed timed-release preparations to minimize or eliminate this effect.   Unfortunately, timed-release niacin is less effective (and more toxic) than immediate release, cheap, over-the-counter niacin (Fig. 2).

最常见的报道的立即释放烟酸的副作用是众所周知的潮红和皮肤瘙痒(皮肤血管扩张) ,可以是如此不舒服,它可能导致一些人停止服用。虽然在饭后服用烟酸或在服用烟酸前30分钟服用阿司匹林可以克服脸红,但它也是有自我限制的,而且随着持续服用而产生脸红的耐受性。然而,制药公司开发了定时释放制剂,以尽量减少或消除这种影响。不幸的是,定时释放的烟酸比立即释放的便宜的非处方烟酸有效(且毒性更大)。

Statin plus Niacin – Adverse Effects

他汀类药物加烟酸-不良反应

Back to the New England Journal study. The “serious adverse harm” included “diabetes-related, gastrointestinal, musculoskeletal and skin-related disorders,” which the authors stated were previously known to be caused by niacin. Additionally, the authors stated that most of the serious musculoskeletal adverse events with niacin-laropiprant were due to myopathy (muscle weakness, pain and atrophy); and there was an unexpected finding of excess serious infection, and serious bleeding events. The authors further claimed that “niacin alone” was also associated with a significant increase in the risk of serious infection in a previous study as well (AIM-HIGH10).1

回到《新英格兰杂志》的研究。“严重的不良危害”包括“糖尿病相关、胃肠道、肌肉骨骼和皮肤相关的疾病” ,作者声称这些疾病以前已知是由烟酸引起的。此外,作者指出,大多数严重的肌肉骨骼不良事件是由于肌病(肌无力,疼痛和萎缩) ,并有一个意外的发现过度严重感染,严重出血事件。作者进一步声称,在以前的研究中,”仅烟酸”也与严重感染风险的显著增加有关(AIM-HIGH10)

The AIM-HIGH study, 高等教育研究,10 however, was not a study of “niacin alone”—it was a study that also combined extended-release niacin with intensive statin therapy. 然而,这并不是一项单独使用烟酸的研究,而是一项将烟酸缓释剂与强化他汀类药物联合使用的研究

With regard to the excess bleeding, the authors conceded that it may not have been due to niacin—but may have been due to laropiprant – as several potential mechanisms for bleeding have been previously proposed for laropiprant,11,12 and niacin has not previously been reported to cause bleeding problems.

关于过量出血,作者承认,这可能不是由于烟碱酸引起的,而是由于拉罗普兰引起的,因为以前曾提出过几种可能的出血机制,11、12和烟碱酸以前没有报道过会引起出血问题。

The authors of the New England Journal study curiously overlooked the fact that the FDA in 2012 required that labels on statin drugs be changed to include information concerning statin-induced glycemic effects, diabetes, and increases in hemoglobin A1C or fasting plasma glucose.13 This label change was based on several meta-analyses that demonstrated the relationship between statin use and diabetes. One meta-analysis examined the effect of statins on the risk of diabetes in 91,140 patients from 13 trials, which showed that statins were associated with a 9% increased risk of diabetes.14 Another meta-analysis of 32,752 patients, in five trials, found that higher potency statins were associated with a 12% increased risk of diabetes, compared to low potency statins.15Simvastatin, at a dose of 40 mg (as used in the New England Journal study), was considered to be a high potency statin.16

《新英格兰杂志》研究报告的作者奇怪地忽略了一个事实,即美国食品药品监督管理局在2012年要求他汀类药物的标签必须改变,包括他汀类药物引起的血糖效应、糖尿病、血红蛋白 A1C 或空腹血糖增加等信息。13这种标签的改变是基于一些荟萃分析,这些荟萃分析证明了他汀类药物的使用与糖尿病之间的关系。一项荟萃分析研究了他汀类药物对13个试验中91,140名患者糖尿病风险的影响,结果显示他汀类药物与糖尿病风险增加9% 有关。另一项荟萃分析在5个试验中对32,752名患者进行了分析,发现较高效力的他汀类药物与低效力的他汀类药物相比,糖尿病风险增加12% 。15辛伐他汀在40毫克的剂量下(在《新英格兰杂志》的研究中使用)被认为效力较高

Although immediate-release niacin may cause reductions in glucose tolerance when treatment is initially begun, studies show that glucose generally returns to pre-treatment levels with continued use17,18 (Fig. 3). On the other hand, the package insert for extended-release niacin (as used in the New England Journal study) cautions that “NIASPAN can cause an increase in blood sugar levels.” It is thus likely that the combination of simvastatin and extended-release niacin in the New England Journal study caused the increased incidence of diabetic changes.

虽然立即释放的烟酸在治疗初期可能导致葡萄糖耐量减少,研究表明,葡萄糖一般恢复到治疗前的水平,继续使用17,18(图3)。另一方面,延长释放烟酸的说明书(新英格兰杂志研究中使用)警告说“ NIASPAN 可能导致血糖水平升高。”因此,在新英格兰杂志的研究中发现,辛伐他汀和烟酸缓释片联合使用可能导致糖尿病发病率的增加。

Timed-release niacin also tends to be more hepatotoxic than immediate-release niacin, causing significant increases in liver enzymes, and multiple reports of hepatic failure.19,20One report, which illustrated the comparative safety of immediate-release niacin involved three patients who incurred hepatitis from timed-release niacin, who were later rechallenged with immediate-release niacin with no evidence of hepato-cellular injury due to the immediate release niacin.21

19,20其中一份报告说明了立即释放烟酸引起的肝炎的相对安全性,这三名患者因立即释放烟酸而导致肝细胞损伤,后来再次接受立即释放烟酸的挑战,没有证据表明立即释放烟酸导致肝细胞损伤

Statins are known to cause myalgias, fatigue, and rhabdomyolysis. These effects may be worsened by combining statins with niacin. Most of the excess musculoskeletal adverse events in the New England Journal report were due to myopathy, and the absolute excess of myopathy associated with adding niacin-laropiprant to the statin-ezetimibe therapy was more than 10 times as great among participants in China as those in Europe.1 This should not have been surprising. The Zocor/Simvastatin package insert warns:

众所周知,他汀类药物会导致肌痛、疲劳和横纹肌溶解。他汀类药物与烟酸联合使用可能会加重这些影响。《新英格兰杂志》报道的大多数肌肉骨骼不良事件是由肌病引起的,在他汀-依折咪贝治疗中加入烟酸-赖诺普兰引起的肌病绝对过量,中国参与者是欧洲参与者的10倍以上。舒降之/辛伐他汀产品说明书警告:

“Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (more than 1 g/day) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products.”

“辛伐他汀与含有烟酸的产品调脂剂量(每天超过1克)联合应用,观察到肌病/横纹肌溶解症的病例。特别是,在治疗辛伐他汀剂量超过20毫克/天的中国患者与调脂剂量的烟酸含量产品共同使用时,应当谨慎使用

The New England Journal study concluded that “treatment with extended-release niacin-laropiprant did not significantly reduce the risk of major vascular events but did significantly increase the risk of serious adverse events.”1

《新英格兰杂志》的研究得出结论: “延长释放烟酸-拉罗普兰治疗并不能显著降低主要血管事件的风险,但确实显著增加了严重不良事件的风险。”1

The highly-publicized New England Journal article was thus not a true study of the clinical efficacy of over-the-counter immediate-release niacin. It was, instead, a testament that it’s probably not a good idea to combine extended-release niacin with a pharmaceutical hodge-podge of a high potency statins, ezetimibe, and latanoprost.

因此,《新英格兰杂志》高度报道的文章并不是非处方即时释放烟酸临床疗效的真实研究。相反,这是一个证明,它可能不是一个好主意结合延长释放烟酸与一个高效力他汀类药物,依折替米布,拉坦前列素大杂烩。

I’d like to see a head-to-head 3-arm study comparing the efficacy and side-effects of (1) immediate release niacin, (2) a statin, and (3) a statin plus niacin. Until such a study is conducted, I will continue to use (and recommend to my patients) immediate-release niacin—which I believe to be the safest, cheapest, most effective lipid-lowering substance available.

我希望看到一个头对头的三臂研究,比较(1)立即释放烟酸,(2)他汀,(3)他汀加烟酸的疗效和副作用。在进行这项研究之前,我将继续使用(并向我的病人推荐)立即释放烟酸——我认为这是目前可用的最安全、最廉价、最有效的降脂物质。

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