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最新研究结果给钠的争议火上浇油

Sodium controversy: More fuel for the fire

发布者:爱思唯尔 发布时间:2014-8-19

《新英格兰医学杂志》8月14日在线版发表的3项有关钠摄入对血压、心血管和死亡率影响的大型国际研究,似乎并不能平息围绕该问题的争论。不仅如此,其中1项研究的结果与另外2项研究的结果截然相反,反而给争论火上浇油。

钠与血压:PURE研究

第一项研究是对前瞻性城乡流行病学(PURE)研究数据的亚研究。PURE研究从全球18个低、中和高收入国家的667个社区纳入了102,216名年龄35~70岁的成年人。麦克马斯特大学人口健康研究所(安大略省)的Andrew Mente博士介绍,尿钠和尿钾水平被当作这些元素膳食摄入量的替代指标,而且这些排泄水平与受试者的血压水平相关。

现行指南建议的钠摄入量为1.5~2.4 g/d,具体取决于所在国家。仅有0.6 %的研究受试者达到了1.5 g/d的最低水平(适用于美国),仅有10%达到了3 g/d以下。46 %的受试者的钠排泄量介于3~5 g/d,其次是钠排泄量超过5 g/d的受试者(占44 %)。

研究者指出:“这一结果提示,目前,只有很少的人长时间保持极低的钠摄入量。”

研究者发现,校正多重因素后,在全球范围内,钠排泄量每增加1 g,收缩压和舒张压分别增加2.11 mmHg和0.78 mmHg(P<0.001)。然而,这种相关性是非线性的。钠和血压之间的相关性在钠排泄量介于3~5 g/d的受试者中较弱,在钠排泄量低于3 g/d的受试者中不具有显著性,在钠排泄量超过5 g/d的受试者和基线时已患有高血压的受试者中较强。

综上所述,钠对血压的影响是不均匀的,取决于人群饮食背景和个人年龄、高血压状态(N. Engl. J. Med. 2014 Aug. 14;371:601-11 [doi:10.1056/NEJMoa1311989])。

钠与心血管死亡率:PURE研究

第二项研究也是PURE研究的亚研究,是由麦克马斯特大学人口健康研究所的Martin O’Donnell博士主导的。研究者开展了一项纳入101,945例受试者的前瞻性队列研究,以评估基线尿钠和尿钾排泄水平(仍然作为摄入量的替代指标)与3.7年随访期间散发性心血管(CV)事件和死亡之间的关联(N. Engl. J. Med. 2014 Aug. 14;371:612-23 [doi:10.1056/NEJMoa131889])。

主要复合终点包括死亡和主要CV事件,结果有3317例患者(3.3%)发生主要复合终点。平均24小时尿钠排泄量为4.9 g。

令人惊讶的是,死亡率和CV事件发生率最低的,不是钠排泄量达到推荐水平的受试者,而是钠排泄量高得多(3~6 g/d)的受试者。实际上,当钠排泄量低于3 g/d时和高于6 g/d时,风险均增加。而且,高钠排泄量与高CV、死亡风险之间的关联,仅在基线时已患有高血压的患者中具有显著性。

“低钠摄入量的预期获益……是从模型中衍生的……假定钠摄入量与血压之间、血压与心血管事件之间存在线性关系。这些指南中隐含的假设是,钠摄入量并不存在安全下限。”

这两项PURE亚研究的结果对上述假设提出了质疑。

钠与心血管死亡率:NUTRICODE研究

第三项研究是对有关全球钠摄入量的CV死亡率影响的文献综述。研究者以汇集的数据为基础构建了一个复杂的统计模型,以估算有多少例死亡可以归因于钠摄入量超出推荐量2 g/d。这项研究是由全球疾病负担、营养和慢性疾病专家组(NUTRICODE)开展的,主要研究者为塔夫斯大学和哈佛公共卫生学院的流行病学家DariushMozaffarian博士(N. Engl. J. Med. 2014 Aug. 14;371:624-34 [doi:10.1056/NEJMoa1304127])。

研究者对66个国家的居民(约占全球成年人的74%)的钠摄入量进行了量化分析,首先将这些数据与对107项限制钠摄入量的随机试验的荟萃分析结果相关联,然后将这些数据与2项有关不同水平血压CV死亡率影响的大型国际临床试验的结果相关联。

研究者估计,全球的钠摄入量平均水平是3.95 g/d,平均水平因地区而异,介于2.18~5.51 g/d。“总体而言,在187个国家中有181个(约占全球成年人的99.2%)的估计钠摄入量平均值超过世界卫生组织推荐的2 g/d。”

与2项PURE分析结果相反,这些数据显示了“钠摄入量与血压之间呈线性剂量-反应关系的强有力证据”,钠摄入量每减少2.30 g/d与收缩压降低3.82 mmHg明显相关,而且血压增加与CV死亡率增加有直接关系。

根据这些数据推测,“我们发现,2010年全球有165万例CV死亡可归因于钠摄入量高于推荐量2 g/d。”在全球范围内,40.4%的CV死亡属于过早死亡,即在70岁之前死亡。“总之,全球大约1/10的CV死亡和近1/5的CV所致过早死亡,可归因于钠摄入量超过推荐值。”

阿拉巴马大学血管生物学与高血压项目部的Suzanne Oparil博士随刊述评中指出:“NUTRICODE研究者在综合分析有关过多摄入钠的潜在危害的大量数据方面付出了巨大努力。然而,鉴于多项假设还缺乏必要的高质量数据的支持,应谨慎解读这项研究的结果。”

PURE研究得到了安大略心脏与卒中基金会、人口健康研究所、加拿大健康研究所、多家制药公司,以及18个参与国的全国或地方组织的支持。这些机构未参与研究的设计、实施、数据采集或分析,或稿件准备。O’Donnell博士报告称与勃林格殷格翰、拜耳、百时美施贵宝、辉瑞等公司有联系,他的同事报告称与赛诺菲安万特、阿斯利康和Cadila等公司有联系。NUTRICODE研究由比尔和梅林达盖茨基金会资助。

随刊述评:积极的钠限制的质疑

2项PURE亚研究的意外结果对“减少饮食钠摄入量作为以人群为基础的降压策略的可行性和实用性”提出了质疑(N. Engl. J. Med. 2014 Aug. 14;371:677-9 [doi:10.1056/NEJMe1407695])。

作者认为,推荐富含钾的优质膳食,可能会比单纯积极减少钠摄入量带来更大的健康益处,包括降低血压。

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By: MARY ANN MOON, Cardiology News Digital Network

Three large international studies addressing sodium intake’s effect on blood pressure and on cardiovascular and mortality outcomes are not likely to quell the controversy surrounding this issue. Rather, since the findings of one study directly oppose those of the other two, the results promise to fan the flames a bit higher.

All three studies were reported online August 14 in the New England Journal of Medicine.

Sodium and blood pressure: PURE

The first report concerned a substudy of data from the Prospective Urban Rural Epidemiology (PURE) study involving 102,216 adults aged 35-70 years residing in 667 communities in 18 low-, middle-, and high-income countries worldwide. Urinary sodium and potassium levels were used as surrogates for dietary intake of these elements, and these excretion levels were correlated with the participants’ blood pressure levels, said Andrew Mente, Ph.D., of the Population Health Research Institute, Hamilton (Ont.) Health Services, McMaster University, and his associates.

Current guidelines recommend a maximum sodium intake of 1.5-2.4 g/day, depending on the country. Only 0.6% of the study population achieved the lowest level of 1.5 g/day, the level recommended in the United States, and only 10% achieved less than 3 g/day. The largest segment of the study population, 46%, had a sodium excretion of 3-5 g/day, and the next largest segment, 44%, had a sodium excretion of more than 5 g/day.

"This suggests that, at present, human consumption of extremely low amounts of sodium for prolonged periods is rare," the investigators noted.

The investigators found, after multivariate adjustment, that for each 1-g increment in sodium excretion, there was an increment of 2.11 mm Hg in systolic blood pressure and 0.78 mm Hg in diastolic blood pressure (P less than .001 for both) for all areas of the globe.

However, this correlation was nonlinear. The association between sodium and blood pressure was weak in the largest subset of participants who had an excretion of 3-5 g/day, and was nonsignificant in those who had an excretion of less than 3 g/day.

The association between sodium intake and blood pressure was stronger in people who had an excretion of more than 5 g/day and in those who already had hypertension at baseline. It also increased with increasing patient age.

Taken together, these findings indicate that sodium’s effect on blood pressure is nonuniform and depends on the background diet of the population as well as the individual’s age and hypertension status, Dr. Mente and his associates said (N. Engl. J. Med. 2014 Aug. 14;371:601-11 [doi:10.1056/NEJMoa1311989]).

Sodium and cardiovascular mortality: PURE

The second report also was a substudy of the PURE study, this time headed by Dr. Martin O’Donnell of the Population Health Institute and McMaster University. The researchers performed a prospective cohort study involving 101,945 PURE participants to assess the association between baseline urinary sodium and potassium excretion, again as a surrogate for intake, with mortality and incident cardiovascular (CV) events during 3.7 years of follow-up.

The primary composite outcome of death or a major CV event occurred in 3,317 participants (3.3%). The mean 24-hour sodium excretion was 4.9 g.

Surprisingly, the lowest risk of death and CV events was seen not in people with the recommended levels of sodium excretion but in those whose sodium excretion was much higher, at 3-6 g/day. Risks actually increased at levels of sodium excretion that were lower than 3 g/day, as is recommended, as well as at levels that were higher than 6 g/day. Moreover, the association between high sodium excretion and high CV and mortality risk was significant only among adults who already had hypertension at baseline.

"The projected benefits of low sodium intake ... are derived from models ... that assume a linear relationship between sodium intake and blood pressure and between blood pressure and cardiovascular events. Implicit in these guidelines is the assumption that there is no unsafe lower limit of sodium intake," Dr. O’Donnell and his associates wrote (N. Engl. J. Med. 2014 Aug. 14;371:612-23 [doi:10.1056/NEJMoa131889]).

The findings from both of these PURE studies call those assumptions into question.

Sodium and cardiovascular mortality: NUTRICODE

The third report was a review of the literature regarding sodium intake’s effect on CV mortality worldwide; the gathered data then served as the basis for a complex statistical model that estimated how many deaths could be attributed to sodium consumption in excess of a reference level of 2.0 g/day. This study was performed by the Global Burden of Diseases, Nutrition, and Chronic Diseases Expert Group (NUTRICODE) and was headed by Dr. DariushMozaffarian, a cardiologist and epidemiologist with Tufts University and the Harvard School of Public Health, both in Boston.

These investigators quantified sodium intake in 66 countries (accounting for 74% of adults throughout the world) by age, sex, and country of residence, and correlated these data first with findings from their meta-analysis of 107 randomized trials of interventions to curb sodium intake and then with the results of two large international trials linking the effects of various blood pressure levels on CV mortality.

They estimated that the mean level of sodium intake worldwide is 3.95 g/day and that those mean levels varied by geographic region from a low of 2.18 g to a high of 5.51 g. "Overall, 181 of 187 countries – 99.2% of the adult population of the world – had estimated mean levels of sodium intake exceeding the World Health Organization recommendation of 2.0 g/day," Dr. Mozaffarian and his associates said.

Contrary to the findings of the two PURE analyses, these data showed "strong evidence of a linear dose-response relationship" between sodium intake and blood pressure, such that each reduction of 2.30 g/day of sodium was significantly linked with a reduction of 3.82 mm Hg in systolic blood pressure, as well as a direct correlation between increasing blood pressure and increasing CV mortality.

Extrapolating from these data, "we found that 1.65 million deaths from CV causes worldwide in 2010 were attributable to sodium consumption above the reference level" of 2 g/day. "Globally, 40.4% of these deaths occurred prematurely, i.e. in persons younger than 70 years of age," Dr. Mozaffarian and his associates said (N. Engl. J. Med. 2014 Aug. 14;371:624-34 [doi:10.1056/NEJMoa1304127]).

"In sum, approximately 1 of every 10 deaths from CV causes worldwide and nearly 1 of every 5 premature deaths from CV causes were attributed to sodium consumption above the reference level," they said.

In an editorial accompanying this report, Dr. Suzanne Oparil said, "The NUTRICODE investigators should be applauded for a herculean effort in synthesizing a large body of data regarding the potential harm of excess salt consumption" (N. Engl. J. Med. 2014 Aug. 14;371:677-9 [doi:10.1056/NEJMe1407695]).

"However, given the numerous assumptions necessitated by the lack of high-quality data [in the literature], caution should be taken in interpreting the findings of this study," said Dr. Oparil of the vascular biology and hypertension program, University of Alabama at Birmingham.

The PURE studies were supported by the Heart and Stroke Foundation of Ontario, the Population Health Research Institute, the Canadian Institutes of Health Research, several pharmaceutical companies, and various national or local organizations in 18 participating countries. These funders played no role in the design or conduct of the studies, in collection or analysis of data, or in preparing the manuscript. Dr. O’Donnell reported ties to BoehringerIngelheim, Bayer, Bristol-Myers Squibb, and Pfizer, and his associates reported ties to Sanofi-Aventis, AstraZeneca, and Cadila. The NUTRICODE study was funded by the Bill and Melinda Gates Foundation.

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Aggressive sodium restriction questioned

The provocative findings from both groups of PURE investigators call into question "the feasibility and usefulness of reducing dietary sodium as a population-based strategy for reducing blood pressure," said Dr. Suzanne Oparil.

The authors’ suggested alternative approach of recommending high-quality diets rich in potassium "might achieve greater health benefits, including blood pressure reduction, than aggressive sodium reduction alone," she noted.

Dr. Suzanne Oparil is in the vascular biology and hypertension program at the University of Alabama at Birmingham. These remarks were taken from her editorial accompanying the three reports on sodium consumption (N. Engl. J. Med. 2014 Aug. 14;371:677-9 [doi:10.1056/NEJMe1407695]). 

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