Link between sodium intake and CV disease less straightforward than previously thought

Literature - Mente et al., NEJM 2014

Sodium intake is generally considered a modifiable determinant of hypertension. It is however unclear whether the association between higher levels of sodium intake and higher blood pressure varies according to region, study participant characteristics or levels of sodium or potassium intake. Guidelines on cardiovascular (CV) disease prevention recommend a maximum sodium intake of 1.5 to 2.4 g per day. These values have been taken from short-term clinical trials, and CV benefits have been extrapolated from blood pressure (BP) lowering effects. No large randomised trials have been performed to check that the reduced BP as seen with reduced sodium intake in clinical trials, translates to a lower risk of CV disease.

Here we briefly summarise the main results of three research articles and an editorial published in the New England Journal of Medicine on August 14.

Data of the Prospective Urban Rural Epidemiology (PURE) study were used to estimate the association of levels of sodium and potassium intake (based on urinary excretion data) and BP, in different populations [1]. 102.216 adults (35-70 years old) from 18 different countries with different income levels are enrolled in the PURE study. 24-hour urinary excretion of sodium and potassium was estimated from a fasting morning specimen, using the Kawasaki formula. These data were also used to examine the association of urinary sodium and potassium excretion with a primary outcome of a composite of death from any cause and major CV events (death from CV causes, stroke, myocardial infarction, or heart failure) [2].
The third NEJM article on sodium is an analysis of the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NUTRICODE), of sodium consumption worldwide. Dose-response effects of sodium on blood pressure were calculated in a new meta-analysis of trials and related to CV events and mortality [3].

Mente et al.[1] report differences between estimated sodium and potassium excretion between rural and urban areas, with sodium excretion being higher in rural areas, and potassium being higher in urban areas. Positive associations (adjusted for covariates and corrected for regression dilution bias) between estimated sodium excretion and both systolic and diastolic BP were found, with an increase of 2.11 mmHg in systolic BP and of 0.78 mmHg in diastolic BP seen with each 1-g increment in sodium excretion. The positive relation between sodium excretion and BP was seen in all geographic regions, albeit less steep in Middle Eastern countries. When estimated sodium excretion was larger than 5 g per day, its relationships with both systolic and diastolic BP showed a steeper slope than at lower excretion levels. Similar, but inverse findings were seen when assessing the relationship between estimated potassium excretion and BP. The association between estimated sodium excretion and BP was stronger in persons with hypertension than in those without (2.49 vs. 1.30 mmHg systolic BP per gram). Persons older than 55 years showed a steeper slope than those between 45 and 55 years, or younger than 45 years.
Thus, the PURE study showed a positive, but non-uniform association between estimated sodium or potassium excretion and BP in data of over 100.000 adults from 18 countries on 5 continents.

The second analysis of the PURE data (O’Donnel et al. [2]) showed that an estimated sodium excretion of at least 7.00 g per day was associated with a higher risk of the primary composite outcome, as compared with estimated excretion of 4.00 to 5.99 g per day (OR: 1.15, 95%CI: 1.02-1.30). Also people with an estimated excretion below 3.00 g per day showed an increased risk of the primary outcome (OR: 1.27, 95%CI: 1.12-1.44). A higher estimated potassium excretion than the reference category of 1.50 g per day was associated with a reduction in the risks of death and CV events, mostly due to a reduced risk of death. Patients with hypertension at baseline were at greater risk of death and CV events if they had high (>6.00 g per day) estimated sodium excretion.
Thus, people with an estimated sodium excretion between 3 and 6 g per day show the lowest risk of death and CV events. People with hypertension appear to be at extra risk of the adverse effects of sodium intake on death and CV events. The J-shaped association described here suggests that an unsafe low level of sodium intake exists.

Mozzaffarian et al. report that the mean level of sodium intake worldwide was 3.95 g per day, varying from 2.18 to 5.51 g per day between regions. In 181 out of 187 countries (99.2% of the adult population), the estimated mean level of sodium intake exceeded the World Health Organization recommendation of 2.0 g per day. A strong linear dose-response relationship was seen, such that a reduction of 2.30 g of sodium per day was associated with a reduction of 3.82 mmHg (95%CI: 3.08-4.55) in BP. Greater effects of dietary sodium on BP were seen in older vs. younger persons, in black vs. white people, and among hypertensive vs. normotensive persons. Using the found correlations between sodium intake and BP and between BP and CV mortality, the authors estimate that 1.65 million deaths from CV causes (95%UI: 1.10-2.22 million) worldwide in 2010 were attributable to sodium consumption above the reference level of 2.0+0.2 g per day. 512.901 worldwide deaths from CV causes were estimated to be attributable to sodium intake above 4.0+0.4 g per day.
Thus, about 1 in 10 deaths from CV causes were attributed to sodium consumption of more than 2.0 g per day. These deaths occurred primarily in low- and middle-income countries, and before the age of 70 years, although few countries are spared.

In an editorial [4], dr. Oparil concludes based on these three publications, that the relation
between sodium excretion and blood pressure was positive but nonuniform: it was strong in participants with high sodium excretion, modest in those in the moderate range, and nonsignificant in those with low sodium excretion. The major weaknesses of the PURE study (…) include the
absence of direct measurement of 24-hour urinary excretion on multiple occasions, (…) thus making it impossible to establish causality. (…) Nevertheless, this large study does provide evidence that both
high and low levels of sodium excretion may be associated with an increased risk of death and
cardiovascular disease outcomes and that increasing the urinary potassium excretion counterbalances the adverse effect of high sodium excretion. These provocative findings beg for a randomized, controlled outcome trial to compare reduced sodium intake with usual diet. In the absence of such a trial, the results argue against reduction of dietary sodium as an isolated public health recommendation. (…)
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. However, given the numerous assumptions necessitated by the lack of high-quality data, caution should be taken in interpreting the findings of the study.
Taken together, these three articles highlight the need to collect high-quality evidence on both the risks and benefits of low-sodium diets.”

Find these articles online

1. Mente A, O’Donnell MB, Rangarajan S et al., for the PURE Investigators. Association of Urinary Sodium and Potassium Excretion with Blood Pressure. N Engl J Med 2014; 371:601-611
2.O’Donnel MB, Mente A, Rangarajan S et al., for the PURE Investigators. Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events. N Engl J Med 2014; 371:612-623
3. Mozaffarian D, Fahimi S, Singh GM et al., for the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NUTRICODE). Global Sodium Consumption and Death from Cardiovascular Causes. N Engl J Med 2014; 371:624-634
4. Oparil S. Low Sodium Intake — Cardiovascular Health Benefit or Risk? N Engl J Med 2014; 371:677-67

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