The Truth About Niacin: The Safest, Cheapest, Most Effective Lipid-Lowering Substance Available
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
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”3 — i.e., a triple take-out piece!
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).
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.”
Lipid-Lowering Effects of Niacin
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).
Statin plus Niacin – Adverse Effects
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.
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
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:
“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.”
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
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.
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.