Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies

doi:10.1016/S0140-6736(16)30467-6

The Lancet

Volume 388, Issue 10043, 30 July–5 August 2016, Pages 465-475

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https://doi.org/10.1016/S0140-6736(16)30467-6 Get rights and content

Summary

Background

Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status.

Methods

In this pooled analysis, we studied 133 118 individuals (63 559 with hypertension and 69 559 without hypertension), median age of 55 years (IQR 45–63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4·2 years (IQR 3·0–5·0) and blood pressure.

Findings

Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2·08 mm Hg change per g sodium increase) compared with individuals without hypertension (1·22 mm Hg change per g; p_interaction<0·0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 1·23 [95% CI 1·11–1·37]; p<0·0001) and less than 3 g/day (7006 [11%] of population with hypertension: 1·34 [1·23–1·47]; p<0·0001) were both associated with increased risk compared with sodium excretion of 4–5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4–5 g/day (18 508 [27%] of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥7 g/day in 6271 [9%] of the population without hypertension; HR 0·90 [95% CI 0·76–1·08]; p=0·2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 [11%] of the population without hypertension; HR 1·26 [95% CI 1·10–1·45]; p=0·0009).

Interpretation

Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets.

Funding

Full funding sources listed at end of paper (see Acknowledgments).

Introduction

Several prospective cohort studies1, 2, 3, 4, 5, 6, 7 have reported that the association between sodium consumption and cardiovascular disease or mortality is U-shaped, with increased risk at both high and low sodium intake. This finding has been reported in studies done in different countries, in studies using different methods to estimate sodium intakes, and in different types of populations (ie, people with diabetes, those with vascular disease, and in the general population). A meta-analysis of 23 epidemiological studies (n=274 683) also reported a U-shaped relation.⁸ Subsequently, findings from the PURE study⁷ were consistent with findings from this previous meta-analysis, such that the collective data for 376 628 people involving more than 15 000 clinical events, showing a U-shaped association, are robust. In view that increasing sodium intake is related to increased blood pressure, and that this is steeper in those individuals with hypertension compared with in those without hypertension,9, 10 we hypothesised that there might be differences in the association between sodium intake and cardiovascular disease outcomes in individuals with hypertension compared with in those without hypertension. In this analysis, we explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. We also compare the observed magnitude (and pattern) of association between sodium intake and clinical events with the predicted hazard ratio (HR) derived from modelling the association between sodium intake and blood pressure, and assuming that all reductions in blood pressure should translate into cardiovascular disease reduction, with no other off-target effects (eg, activation of the renin system or increases in blood lipids).

Research in context

Systematic review

We searched PubMed for relevant research published between Jan 1, 1960, and April 1, 2016, using the term “sodium” or “salt” AND “mortality” OR “cardiovascular” OR “myocardial” OR“stroke” OR “heart failure” OR “sudden cardiac death” in English. We screened papers by title and abstract to identify full-text reports that were relevant to the study aims. We also screened citation lists from these full-text reports to identify other relevant research. We considered papers if they contained an evaluation of the relation between sodium intake and at least one of the outcomes of interest. The papers cited in this report were selected to be representative of the existing evidence base, and are not an exhaustive list of relevant research.

Added value of this study

Several prospective cohort studies have recently reported that the association between sodium consumption and cardiovascular disease or mortality is U-shaped, with increased risk at both high and low sodium intake. Subsequently, the PURE study showed similar results in 101 945 people worldwide. Whether these associations vary between those individuals with and without hypertension is unknown. In this analysis of four international prospective studies with 9856 events and based on an analysis of 133 118 people (63 559 with hypertension and 69 559 without hypertension) selected from 49 countries in six continents, we assess whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. To our knowledge, this is the largest individual-level data study of any kind relating sodium intake to cardiovascular disease events and mortality.

Interpretation

The results showed that cardiovascular disease and death are increased with low sodium intake (compared with moderate intake) irrespective of hypertension status, whereas there is a higher risk of cardiovascular disease and death only in individuals with hypertension consuming more than 6 g of sodium per day (representing only 10% of the population studied). These data indicate that lowering sodium is best targeted at those individuals with hypertension who also consume high sodium.

Section snippets

Study design and participants

Details of the studies' designs and population characteristics have been published before and are described in the appendix (pp 2–6). In brief, the Prospective Urban Rural Epidemiological Study (PURE Study)11, 12, 13, 14, 15 is an ongoing large-scale epidemiological cohort study that has enrolled 156 424 individuals between 35 years and 70 years from the population in 628 communities in 17 low-income, middle-income, and high-income countries on five continents. The sampling strategy used in

Results

133 118 individuals, (63 559 with hypertension and 69 559 without hypertension), were included in the study. 98 612 (74%) individuals were without previous cardiovascular disease, and 118 232 (89%) were without diabetes. Baseline characteristics of the study participants are shown in the appendix (pp 9, 10). The mean age was 58·6 years (SD 10·3) in individuals with hypertension and 50·5 (10·7) in those without hypertension. Individuals with hypertension were more likely to be men, heavier, less

Discussion

In this analysis of four international prospective studies with 9856 events and based on an analysis of 133 118 people selected from 49 countries in six continents (appendix pp 5, 6), we noted significant heterogeneity in the association between sodium excretion and the composite outcome by hypertension status. In both individuals with or without hypertension, there is an increased risk of cardiovascular disease events and deaths associated with 24-h urinary sodium excretion of less than 3

References (59)

S Yusuf et al.
Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low income countries (the PURE Study): a prospective epidemiological survey
Lancet
(2011)
J Jantsch et al.
Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense
Cell Metab
(2015)
N Rakova et al.
Long-term space flight simulation reveals infradian rhythmicity in human Na(þ) balance
Cell Metab
(2013)
J Titze et al.
Taking another “look” at sodium
Can J Cardiol
(2014)
HC Diener et al.
Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study
Lancet Neurol
(2008)
S MacMahon et al.
Blood pressure, stroke, and coronary heart disease. Part 1: Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias
Lancet
(1990)
MC Thomas et al.
The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes
Diabetes Care
(2011)
EI Ekinci et al.
Dietary salt intake and mortality in patients with type 2 diabetes
Diabetes Care
(2011)
K Stolarz-Skrzypek et al.
Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion
JAMA
(2011)
MJ O'Donnell et al.
Urinary sodium and potassium excretion and risk of cardiovascular events
JAMA
(2011)

A Mente et al.

Validation and comparison of three formulae to estimate sodium and potassium excretion from a single morning fasting urine compared to 24-h measures in 11 countries

J Hypertens

(2014)

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ArticlesAssociations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

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Cell Metab

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Articles
Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies