The Ongoing Sodium Controversy – Between PURE and NutriCode
Abstract
Abstract. The impact of sodium intake on cardiovascular health has long been a subject of controversial debates. On the one hand, the World Health Organization (WHO) and the American Heart Association (AHA) have argued for a target of 1500-2000 mg of sodium per day (4-5 g sodium chloride daily). On the other hand, this recommendation has been accompanied by a growing body of criticism. Recently, the results of the PURE and the NutriCode study have flared up the “salt controversy”. Actually, the results of the PURE study seem to strengthen the position of those who have called into question the AHA and WHO guidelines for daily sodium intake whereas those who recommend a considerable salt reduction believe that the NutriCode study confirm their conviction. In this paper, the results of the PURE and NutriCode study will be discussed and evaluated with regard to practical consequences.
Introduction
Having been a valuable commodity in the Middle Ages, dietary salt is held responsible for various health problems today [1 – 8]. Indeed, an impressing number of studies confirmed the assumption that a high dietary sodium or salt intake increases the cardiovascular risk. Especially the impact of dietary salt on blood pressure is a well-known fact [9 – 12]. Already in 2003, the WHO judged the evidence as convincing that a high dietary sodium intake increases the risk of cardiovascular diseases [13]. Hence, measures to reduce dietary sodium intake are being discussed internationally and nationally [6].
Most medical associations set a reference intake of up to 2 g sodium per day (approx. 5 g salt). The American Heart Association (AHA) is particularly restrictive and recommends a dietary intake of not more than 1.5 g sodium per day, indicating that there is overwhelming evidence for such strong salt restriction [5, 7 – 8].
However, some critics object that the evidence for a clinically relevant advantage of a general salt restriction is not sufficient [14 – 20]. Also, the US Institute of Medicine (IOM) doubts that the evidence supports sodium reduction to below 2.3 g per day [21]. For certain people such a strong salt reduction may even be dangerous and may increase cardiovascular mortality [20, 22].
Three recent studies [23 – 25] and the respective editorial [26] have now flared up the “salt controversy”. This article will consider the study data and evaluate the results in a general context.
The PURE study
The Prospective Urban Rural Epidemiology Study (PURE) is a large prospective multinational cohort study including more than 100,000 subjects. Four study populations came from countries with low (Bangladesh, India, Pakistan, Zimbabwe) and low-to-middle income countries (China, Colombia, Iran, parts of Pakistan), while seven samples were recruited from upper middle income countries (Argentina, Brazil, Chile, Malaysia, Poland, South Africa, Turkey); three stem from highly developed countries (Canada, Sweden, United Arab Emirates). Participants were 35 to 70 years old (medium age approx. 50 years) and about 60% were female. Based on a single fasting morning urine sample the 24-hour sodium and potassium excretion was estimated and used as surrogates for dietary intake [23 – 24]. Data of sodium and potassium excretion was analysed in association with the blood pressure [23] and with the prevalence of cardiovascular events [24] after adjustment for established cardiovascular risk factors like age, sex, body mass index (BMI), smoking, lipid profile as well as energy and alcohol intake. The results were published in two different papers and are summarized in the following section [23 – 24].
Sodium excretion and blood pressure
The mean sodium excretion of the whole study population was 4.93 g per day with a large variation. 43.5% of the participants had an estimated sodium excretion of over 5 g sodium per day and 45.9% between 3 and 5 g. Only 10.6% showed a sodium excretion of below 3 g per day; this proportion of the population was further reduced to 2.1% after adjustment for regression dilution bias. Particularly high was the sodium excretion in the Chinese study sample (5.59 g / day). After adjustment for confounders, an increase of 2.11 mmHg in systolic and an increase of 0.78 mmHg in diastolic blood pressure was seen for each 1-gram increment in estimated sodium excretion. The increase was nonlinear and depended on the sodium status. If the estimated sodium excretion was >5 g per day, each 1-g increment of sodium excretion resulted in a 2.58 mmHg increase in systolic blood pressure whereas there was a much lower effect of only 0.74 mmHg per 1-g sodium increment if the sodium excretion was less than 3 g per day. The blood pressure increase was particularly strong in older (>55 years) and in hypertensive subjects with high sodium intake (sodium excretion >5g per day). Young, normotensive people with low dietary sodium intake however reacted with a comparable low increase in blood pressure. Similar results were shown for the diastolic blood pressure (blood pressure increase of 1.21 mmHg for each 1-g increment of sodium excretion in subjects over 55 years versus 0.97 mmHg in those aged 45 and below) [23].
Potassium excretion and blood pressure
Mente et al. [2014] determined for the whole study population an average potassium excretion of 2.12 g per day. The lowest values were measured in South Asian countries (1.7 g per day); the highest in Canada and Sweden (2.12 g per day). The multivariate analysis showed an inverse association of potassium excretion and blood pressure after adjustment for confounders. Each 1-gram increment of estimated potassium excretion per day resulted in a calculated reduction of 1.08 mm Hg in systolic and of 0.09 mmHg of diastolic blood pressure [23].
Sodium-potassium relation and blood pressure
Both, the systolic and the diastolic blood pressure showed a linear relationship with the sodium-potassium ratio (p < 0.001). Each 1-SD-increment of the sodium-potassium ratio (Na:K = 3.26) was associated with increases of 2.3 mmHg in systolic blood pressure and increases of 0.78 mmHg in diastolic blood pressure. Thus, high dietary sodium leads to the strongest blood pressure increase if the diet is low in potassium at the same time. Conversely, high dietary potassium attenuates the blood pressure increasing effect of sodium [23].
Sodium excretion and cardiovascular events and mortality
During the follow-up (mean 3.7 years), 857 participants had myocardial infarction, 872 had stroke and 261 had heart failure. 3,317 participants died, 650 from cardiovascular causes. The multivariable logistic regression analysis adjusted for known risk factors showed that the risk for cardiovascular events and mortality was not only increased with high sodium excretion (≥7 g / d) but also with low sodium excretion of <3 g / d indicating a J-shaped association. Compared to the reference group (sodium excretion of 4.00 – 5.99 g / d) subjects with the lowest sodium excretion (<3 g / d) had a 27% increased risk for events of the composite outcome (death from any cause and cardiovascular events) (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.12 – 1.44). For the high sodium group (≥7 g / d) an increased risk of 15% was calculated (OR 1.15; 95% CI 1.02 – 1.30). This J-shaped association was unaffected by adjustment for further cardiovascular risk factors (LDL-HDL ratio, blood pressure, vegetable and fruit consumption, potassium intake) and after excluding risk groups from analysis. The authors of the PURE study conclude that a sodium excretion of 3 to 6 g per day, corresponding to a daily dietary intake of around 7.5 to 15 g salt, is associated with the lowest risk for cardiovascular diseases and all-cause mortality.
Potassium excretion and cardiovascular events and mortality
An increased risk for the composite outcome of death from any cause and cardiovascular events was observed if the potassium excretion was below 1.5 g / d. A potassium excretion of more than 3 g / d was associated with a 22% risk reduction for the composite outcome compared to potassium excretion of less than 1.5 g / d (OR 0.78; 95% CI 0.67 – 0.91). Also the risk for the individual outcomes, death from any cause and cardiovascular events like myocardial infarction, heart failure and stroke were considerably increased with low potassium excretion.
The NutriCode analysis
While the authors of the PURE study [23 – 24] reported results of new, unpublished data, researchers of the Global Burden of Diseases Nutrition and Chronic Diseases Experts Group (NutriCode) chose a different path [25]. In their work - also published in the New England Journal of Medicine - the researchers conducted a systematic analysis of all studies on dietary sodium intake which are available worldwide. Overall, the team led by Dariush Mozaffarian identified 205 studies from 66 countries. In 142 of these studies, dietary sodium intake was estimated based on the 24-hour sodium excretion; 91 studies used sodium intake from the diet and 28 studies combined both procedures. The purpose of the study was to provide an overview of the actual global sodium consumption. Additionally, the researchers conducted a meta-analysis based on data from 107 randomized controlled trials (RCT) to assess the effect of sodium reduction on blood pressure. Building on their results and the known impact of blood pressure on cardiovascular mortality, Mozaffarian and colleagues calculated the number of annual deaths from cardiovascular diseases attributable to sodium consumption above a reference level of 2 g / d [25]. The key results were as follows:
- •Global sodium consumption. The mean level of global sodium consumption was 3.95 g / d, varying from region to region (range: 2.18 to 5.51 g / d). Around 99% of the world population consume more than the WHO recommendation of up to 2 g / d.
- •Sodium reduction and blood pressure. There was a linear association of sodium and blood pressure reduction: Each reduction of 2.3 g of sodium per day was associated with a reduction of mmHg (95% CI 3.08 – 4.55) in systolic blood pressure. The blood pressure reaction was determined by age and ethnic origin. The strongest effects were observed in elderly, hypertensive subjects and in American Africans. For the white, normotensive population at 50 years of age the systolic blood pressure decreased by 3.74 mmHg with each 2.3 g sodium reduction per day.
- •Cardiovascular mortality. The NutriCode meta-analysis revealed a proportional dose-response relationship between blood pressure and cardiovascular mortality. Based on the overall results the authors conclude that 1.65 million deaths per year (CI 1.10 – 1.22 million) are attributable to high sodium consumption (>2 g / d). While 687,000 deaths (41.7%) resulted from coronary heart disease, 685,000 (41.6%) resulted from stroke and 276,000 (16.7%) from other cardiovascular disease. Around 40% of these deaths occurred in persons younger than 70 years of age. Thus, approximately every 10th death (9.5%; 95% CI 6.4 – 12.8) from cardiovascular causes - for premature deaths below the age of 70 years almost every 5th death - were attributable to sodium above the reference level and could have been avoided with lower dietary sodium intake.
Between PURE and NutriCode – Where are we going?
The impact of sodium on cardiovascular health has long been subject of controversial debates. It is undisputed that too much sodium is unhealthy. However, how much is too much – and against the background of cardiovascular morbidity and mortality: Is also insufficient sodium consumption a risk factor? Opinions on these questions differ considerably between those who support a general restrictive sodium recommendation [5 – 8] and those who have called into question the AHA and WHO guidelines for daily sodium intake [14 – 20; 27]. The above presented results of the PURE and the NutriCode studies provide new arguments for the discussion. Actually, the results of the PURE study [23 – 24] seem to strengthen the position of those who question the recommendations for an aggressive sodium reduction whereas those who recommend a considerable salt reduction believe that the NutriCode study [25] confirm their conviction. In the following the results of these studies that – at least at first sight seem contradictory – will be discussed and evaluated with regard to practical consequences.
Dietary sodium intake and blood pressure
Both, the PURE study [23] and the NutriCode analysis [25] found a positive association of sodium intake and blood pressure. This is consistent with several earlier trials, e.g. the INTERSALT study from 1988 that was conducted in 52 study centers worldwide including more than 10,000 participants [28]. The extent of the individual blood pressure increasing effect of sodium depends – among other influences – on age and basal blood pressure. This was also confirmed in the PURE study in accordance with previous trial results. Actually, the blood pressure reaction on sodium intake varies strongly between individuals. In around 60% of the population no salt-induced blood pressure increase can be expected [29]. Major determinant of the blood pressure reaction is salt sensitivity, which depends on body fat, genetics and several other factors (Table 1). This explains why increasing dietary intake of sodium chloride – but not of other sodium compounds [30] – is associated with increased plasma volume and subsequently increases blood pressure [31]. Therefore, salt-sensitive, normotensive subjects are at increased risk to become hypertensive compared to salt-resistant subjects [32].
In this context, dietary potassium consumption has an important influence. In both studies, the PURE and the Intersalt study, blood pressure was the lower, the higher the potassium intake was [23; 28]. This is consistent with the results of population-based European [33] and US studies [34 – 35], and with results of a systematic review from 2013 [36].
Hence, meta-analysis of interventional studies investigating the effects of supplemental potassium confirmed a decrease in blood pressure, both in normotensive (-2.4 mmHg systolic; -1.6 mmHg diastolic) [37] and in hypertensive (-3.5 to -4.4 mmHg systolic; -2.5 mmHg diastolic) [37 – 38] subjects. Potassium reduces the salt sensitivity by lowering the cardiovascular reactivity to norepinephrine [39 – 40] and has hypotensive effects by enhancing renal elimination of sodium [41]. This explains amongst other mechanisms why the effect of sodium on blood pressure is modulated by potassium consumption. Also, in earlier studies like the DASH study (Dietary approaches to stop hypertension) [42], this effect of potassium which has now been confirmed in the PURE study [23] was observed. High dietary potassium attenuates the sodium induced blood pressure increase considerably. Thus, the sodium-potassium ratio should be a better predictor for blood pressure than sodium intake alone. Results of the NutriCode meta-analysis of 107 RCT [25] that showed a decrease in blood pressure when dietary sodium consumption is restricted, confirmed earlier study results. Reduced sodium consumption leads to a decrease in blood pressure both, in normotensive and hypertensive subjects [43]. Each 2.3 g / d decrease in sodium consumption (around 5.8 g / d salt) was associated with a reduction in blood pressure of 3.82 mmHg [25]. This effect is stronger in hypertensive and elderly subjects compared to normotensive and younger subjects [25]. These data are also in line with an earlier meta-analyses. A Cochrane analysis of 34 RCT with 320 participants published in 2013 investigated the effect of an average sodium reduction of 4.4 g / d and showed the following results: Overall blood pressure reduction by 4.18 mmHg systolic (95% CI -5.18 to -3.18 mmHg) and 2.06 mmHg diastolic (95% CI -2.67 to -1.45). In hypertensive subjects, the decrease in blood pressure was -5.39 and -2.82 mmHg (systolic and diastolic; 95% CI -6.62 to -4.15 and -3.54 to -2.11, respectively) and thus far stronger than in normotensive subjects: -2.42 mmHg systolic and -1.00 mmHg diastolic (95% CI -3.56 to -1.29 and -1.85 to -0.15, respectively) [44].
The fact is that the sodium or salt consumption is an important determinant of blood pressure. However, the hypertensive effect of sodium depends on several lifestyle factors. Beside dietary factors (potassium, magnesium, calcium consumption, dietary intake of long-chain omega-3 fatty acids and protein), important determinants are physical activity / sedentary behaviour and smoking habits [45 – 47]. Nevertheless, non-pharmacological treatment of hypertension is often reduced to the simple recommendation ‘salt reduction!’.
Actually, the adaptation of salt consumption is only one element of the modern lifestyle treatment concept of hypertension, as it is favoured in the current guideline of the European Society of Hypertension (ESH) and Cardiology (ESC) [45] (Table 2). Such an integrative lifestyle modification includes a diet according to the DASH-principle (Dietary approaches to stop hypertension), rich in vegetables, fruits, legumes, whole grain products, nuts, dairy products, fish and lean meat. Merely by these means in combination with an adaptation of salt consumption (ESH and ESC target level: around 6 g / d) systolic blood pressure of hypertensive subjects can be decreased by 11.5 mmHg [42]. Blood pressure reduction is even stronger when around 10% of energy intake from carbohydrates is replaced by protein or fat, rich in monounsaturated fatty acids as shown by the results of the Omni- Heart study (Optimal macronutrient intake trial to prevent heart disease) [48]. When lifestyle is additionally changed (increased physical activity, weight reduction in overweight / obese persons) even more pronounced effects can be achieved [49].
In case of moderate hypertension (up to 159 mmHg systolic and 99 mmHg diastolic) such a lifestyle modification is sufficient in most cases. Treatment with blood pressure lowering drugs may be required (target: <140 / 90 mmHg) on an individual basis, if a sufficient reduction cannot be achieved by lifestyle changes alone, if blood pressure is above 159 / 99 mmHg or if there is an increased cardiovascular risk (e.g. diabetes mellitus, renal insufficiency) [45].
Dietary sodium intake and cardiovascular disease
What is true for other nutrients is also true for sodium: The amount determines the health effects. How much sodium should be ingested to minimise cardiovascular risk?
There is clear evidence that excessive sodium intake increases cardiovascular disease risk not only through pressure-related effects [50]. On the other hand studies indicate that a considerable salt restriction is associated with several unfavourable effects (Table 3) and thus may increase cardiovascular mortality [20; 51]. For a recommendation regarding sodium and salt consumption both aspects have to be considered [21]. Whether blood pressure – a surrogate parameter for ‘hard’ endpoints such as cardiovascular disease or mortality – will be increased or reduced by 1 to 10 mmHg due to a change in salt consumption is ultimately not decisive. It is crucial, however, which effects result on cardiovascular morbidity and mortality and also on overall mortality. Actually, the number of studies indicating a J- or U-shaped dose-response relationship of sodium and cardiovascular events increases [20, 22, 27, 54 – 56].
Also the data of the PURE study referred to in this article confirm such an association. Both, consumption of less than 3 g per day as well as of more than 6 g sodium per day increase the risk of cardiovascular diseases and all-cause mortality [56].
This result is supported by a meta-analysis published in the American Journal of Hypertension [22] that included 23 cohort studies and the follow-up results of two RCT with a total of 274,683 participants. It was shown that both, a low (<2645 mg / d) and a high (>4945) sodium consumption is a risk factor for cardiovascular diseases and increases all-cause mortality. According to this analysis, daily salt consumption of about 6.5 to 12 g seems appropriate for most people [22].
Contradictory to this, results of the NutriCode analysis indicate that more than 1.65 million deaths worldwide are attributable to sodium consumption of more than 2 g / d (5 g / d salt). However, this result is based on biostatic modelling and the assumption of a (mono)causal relationship of sodium consumption, blood pressure and mortality [25]. However, the direct and causal link between reduction of sodium intake and mortality is missing in the NutriCode modelling. Instead, the analysis considers three separate, sequential steps, as pointed out by Alderman [57]: “First the effect of sodium intake (A) on blood pressure (B) is determined, then the effct of blood pressure (B) on cardiovascular disease (C), and finally the association between (A) and (C), in which the cardiovascular effect of sodium intake is predicted. The validity of this analysis requires a linear relation between A and B, B and C, and A and C. The analysis further assumes that there are no other pathophysiological consequences of sodium intake.” However, neither the association between sodium intake (A) and blood pressure (B) nor the relationship between blood pressure (B) and cardiovascular disease are linear [22, 57]. In addition, the relationship between sodium intake and cardiovascular and cardiovascular disease or mortality is “J”- or “U”-shaped [22]. Also, the NutriCode analysis did not include potential side effects of sodium reduction in the biostatic model, although such side effects are well established, as reviewed earlier [51].Therefore, the extrapolations calculated by Mozaffarian et al. [25] on mortality should be interpreted with caution [22, 58].
Conclusions for clinical practice
‘All things are poison, there is nothing without poison: only the dose makes a thing non-poisonous.’ This much-cited knowledge of Theophrastus Bobastus von Hohenheim, alias Paracelsus (1493 – 1541) is also valid for sodium and sodium chloride, respectively [10]. Considering the overall study results, there is currently no convincing evidence that a drastic sodium reduction to below 2 g / d is beneficial for the general population [21]. Actually, the intake of sodium shows a “J”- or “U”-shaped relation to health outcomes [22, 59]. When integrated in a reasonable lifestyle with physical activity and a diet based on minimally processed foods, including vegetables, fresh fruits, legumes, whole grains and nuts, supplemented with fish, poultry, non-sugared milk products and moderate amounts of meat, a salt intake of around 6 g / d [21], possibly even 6.5 to 12 g / d [22] should be appropriate for most people. For hypertensive persons restriction of salt consumption to about 6 g per day should still be recommended [45].
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