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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 modied 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 4563), 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 42 years (IQR 3050) and blood pressure.
Findings Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with
hypertension (208 mm Hg change per g sodium increase) compared with individuals without hypertension
(122 mm Hg change per g; pinteraction<00001). In those individuals with hypertension (6835 events), sodium excretion
of 7 g/day or more (7060 [11%] of population with hypertension: hazard ratio [HR] 123 [95% CI 111137]; p<00001)
and less than 3 g/day (7006 [11%] of population with hypertension: 134 [123147]; p<00001) were both associated
with increased risk compared with sodium excretion of 45 g/day (reference 25% of the population with hypertension).
In those individuals without hypertension (3021 events), compared with 45 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 090 [95% CI 076108]; p=02547), whereas an
excretion of less than 3 g/day was associated with a signicantly increased risk (7547 [11%] of the population without
hypertension; HR 126 [95% CI 110145]; p=00009).
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 studies17 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
nding has been reported in studies done in dierent
countries, in studies using dierent methods to
estimate sodium intakes, and in dierent 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,
ndings from the PURE study7 were consistent with
ndings from this previous meta-analysis, such that the
collective data for 376 628 people involving more than
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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
Methods
Study design and participants
Details of the studies designs and population
characteristics have been published before and are
described in the appendix (pp 26). In brief, the
Prospective Urban Rural Epidemiological Study (PURE
Study)1115 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 ve continents. The
sampling strategy used in PURE ensures representation
from urban and rural communities from dierent
geographical areas.1115 For this analysis, we included
101 511 participants from PURE who collected morning
fasting urine samples suitable for analysis and with
baseline blood pressure measurements. The
EPIDREAM trial was a prospective cohort study of
17 453 individuals, aged 1885 years, who were screened
for eligibility to enter the DREAM clinical trial (a
randomised, double-blind trial with a 2 2 factorial
design that assigned participants at high risk for type 2
diabetes to receive either ramipril [15 mg/day] vs placebo
or rosiglitazone [8 mg/day] vs placebo).16 The EPIDREAM
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Procedures
A morning fasting urine sample was collected from every
participant and shipped in ambient packaging (Saf-T-Pak)
for analysis at the Clinical Research and Clinical Trials
Laboratory at Hamilton General Hospital in Hamilton,
ON, Canada (the central laboratory), or the regional
laboratory in Beijing, Bangalore, India, or Kocaeli,
Turkey, for analyses with the use of validated and
standardised methods. A description of the methods
used for urinary analyses has been described previously.7,9
We used the Kawasaki formula20 to estimate
24-h urinary excretion of sodium and potassium from a
fasting morning specimen and used these estimates as
surrogates for daily sodium and potassium intake (in
grams). Previous studies have reported that this method
provides a reliable estimate of sodium intake in healthy
Japanese participants (r=073)20 and this was replicated
later in Japanese participants with hypertension (r=069
in those on blood pressure medication, r=066 in those
not medicated),21,22 and more recently in Chinese
participants with hypertension (r=064).23 We did further
validation of the method in 1083 people from
11 countries,24 and showed that the estimated sodium
excretion from the morning urine specimen shows a
good correlation with direct measures of sodium
excretion from the actual 24-h urine collection (intraclass
correlation coecient of 070 [95% CI 061077] among
individuals with hypertension and 071 [061 to 078]
among those without hypertension). Further, the blood
pressure change per g of sodium was 211/078 mm Hg,9
which is consistent with the results of a meta-analysis of
sodium lowering randomised controlled trials (appendix
pp 7, 8).25
Weight, height, and two recordings of blood pressure
after 5 min of rest in a sitting position with the use of an
Omron automatic digital monitor (Omron HEM-757 used
in all studies) were recorded in all participants. Individuals
were considered hypertensive if their untreated baseline
blood pressure was 140/90 mm Hg or greater or if they
were prescribed antihypertensive drugs at baseline.
The information about study variables was collected
with similar approaches to measure risk factor variables
and data collection forms in each of the studies.
Information about personal medical history and use of
drugs were recorded. Standardised case-report forms
was used to capture data for major cardiovascular disease
events and death during follow-up. Events were classied
according to the denitions used in each study, but they
were broadly similar. For this analysis, we included data
from the PURE study (which is ongoing) through to
March, 2015, the complete data from ONTARGET/
TRANSCEND,18,19 and case-cohort data from EPIDREAM.
Statistical analysis
Mean estimated 24-h urinary excretion values of sodium
were computed overall and by hypertension status.
Multivariable linear regression was used to obtain
www.thelancet.com Vol 388 July 30, 2016
Correspondence to:
Prof Andrew Mente, Clinical
Epidemiology and Biostatistics,
McMaster University, Hamilton,
ON L8L 2X2, Canada
andrew.mente@phri.ca
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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 586 years (SD 103) in individuals with
hypertension and 505 (107) in those without
hypertension. Individuals with hypertension were more
likely to be men, heavier, less physically active, and had
more previous cardiovascular disease and diabetes
(appendix pp 10, 11).
300399 g/day
(N=27 463)
600699 g/day
(N=15 893)
700 g/day
(N=13 331)
1323 (9%)
1996 (7%)
2487 (7%)
1965 (7%)
1148 (7%)
937 (7%)
Univariable analysis
126 (117136)
104 (098111)
100
100 (093106)
109 (101118)
128 (118139)
Multivariable analysis
131 (121142)
108 (101116)
100
098 (091105)
104 (096113)
118 (108129)
138 (123155)
114 (103126)
100
102 (092113)
102 (091116)
114 (1003130)
127 (115140)
109 (1002119)
100
100 (092109)
106 (096117)
1001 (7%)
1472 (5%)
1852 (5%)
1461 (5%)
857 (5%)
117 (105131)
725 (5%)
Univariable analysis
127 (117138)
103 (096111)
100
100 (093107)
110 (101121)
137 (125150)
Multivariable analysis
134 (123147)
106 (098115)
100
096 (088104)
103 (094113)
121 (110134)
136 (118157)
114 (098129)
100
103 (091117)
104 (089120)
115 (098135)
130 (116146)
105 (095116)
100
095 (086105)
103 (092116)
All-cause mortality
812 (6%)
1177 (4%)
1377 (4%)
1102 (4%)
644 (4%)
121 (106137)
573 (4%)
Univariable analysis
138 (127151)
111 (103120)
100
101 (093109)
110 (100122)
142 (128158)
Multivariable analysis
141 (128154)
115 (106124)
100
100 (091109)
105 (095117)
131 (117147)
152 (132174)
118 (105132)
100
102 (089118)
103 (088122)
128 (108151)
134 (119151)
115 (104127)
100
101 (091115)
106 (093122)
128 (111148)
7547
393 (5%)
15 166
668 (4%)
18 508
837 (5%)
14 240
632 (4%)
7827
6271
293 (4%)
198 (3%)
Univariable analysis
123 (108140)
104 (094116)
100
100 (090112)
095 (082109)
095 (081112)
Multivariable analysis
126 (110145)
105 (094118)
100
099 (088111)
092 (079107)
090 (076108)
138 (115166)
110 (094129)
100
103 (087121)
081 (065100)
081 (064103)
122 (102144)
107 (093123)
100
100 (087116)
091 (076109)
262 (347)
452 (298)
573 (310)
409 (287)
209 (267)
091 (073113)
131 (209)
Univariable analysis
118 (101138)
103 (091117)
100
095 (083108)
102 (086120)
098 (080120)
Multivariable analysis
128 (109151)
105 (091121)
100
092 (079106)
097 (081115)
090 (072111)
134 (104171)
116 (094143)
100
099 (079123)
089 (067117)
069 (049096)
131 (107161)
107 (090127)
100
095 (080114)
094 (075118)
All-cause mortality
257 (3%)
403 (3%)
475 (3%)
374 (3%)
166 (2%)
090 (070118)
122 (2%)
Univariable analysis
142 (121167)
111 (097128)
100
105 (091120)
095 (079114)
104 (084127)
Multivariable analysis
139 (117166)
110 (095128)
100
104 (090121)
095 (078115)
100 (080124)
150 (119190)
110 (090136)
100
103 (083128)
078 (059104)
093 (069124)
118 (094148)
106 (088127)
100
102 (085123)
091 (071116)
096 (073126)
(Table continues on next page)
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300399 g/day
(N=27 463)
600699 g/day
(N=15 893)
700 g/day
(N=13 331)
7006
930 (13%)
12 297
15 700
1328 (11%)
1650 (11%)
13 430
1333 (10%)
8066
855 (11%)
7060
739 (11%)
Univariable analysis
128 (117141)
105 (097114)
100
097 (090105)
111 (101121)
131 (119145)
Multivariable analysis
134 (123147)
109 (1002119)
100
097 (089105)
107 (097118)
123 (111137)
137 (119158)
116 (101132)
100
099 (087114)
112 (096130)
126 (108147)
129 (114145)
110 (099123)
100
099 (089110)
111 (098125)
124 (109141)
170 (139206)
126 (107150)
100
102 (086120)
107 (088129)
113 (093137)
739 (11%)
1020 (8%)
1279 (8%)
1052 (8%)
648 (8%)
594 (8%)
Univariable analysis
130 (118144)
103 (095113)
100
100 (091109)
108 (097119)
137 (124153)
Multivariable analysis
135 (121150)
106 (097117)
100
097 (088106)
102 (092114)
126 (112142)
127 (106152)
136 (114163)
113 (096132)
100
103 (088121)
106 (089127)
129 (112147)
105 (093118)
100
095 (084107)
104 (091120)
126 (109145)
164 (130208)
121 (099148)
100
104 (085127)
096 (076121)
115 (091145)
All-cause mortality
555 (8%)
774 (6%)
902 (6%)
728 (5%)
478 (6%)
451 (6%)
Univariable analysis
137 (123154)
112 (101124)
100
098 (088108)
113 (101128)
150 (133170)
Multivariable analysis
139 (123158)
117 (105131)
100
097 (087108)
108 (095123)
139 (122159)
152 (125186)
125 (105149)
100
100 (084120)
117 (095143)
143 (117175)
143 (123168)
122 (106140)
100
101 (088116)
112 (096132)
139 (117164)
177 (138227)
137 (111170)
100
100 (080124)
111 (086142)
127 (099163)
Data are hazard ratios (95% CI) or n of individuals (%). CVD=cardiovascular disease. *Major cardiovascular events included death from cardiovascular causes, myocardial infarction, stroke, and heart failure.
The univariable model included age, sex, and ancestry (Asian vs non-Asian). The primary model included age, sex, ancestry (Asian vs non-Asian), educational level, alcohol intake, body-mass index, current
smoking, physical activity, status with respect to diabetes mellitus and a history of cardiovascular events, treatment allocation (ramipril, telmisartan, or both, and treatment with statins, blockers, diuretic
therapy, calcium antagonist, and antidiabetes medication). Additional sensitivity analyses with estimated potassium excretion included in the model or exclusion of participants from the EPIDREAM study
(case-cohort design) did not materially alter estimates of association.
Table: Association of estimated urinary sodium excretion with death and major cardiovascular events*
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18
14
10
06
0
2000
296
2644
Events (n)
Number at risk
4000
3023
39 372
6000
4452
61 878
8000
1666
23 384
10 000
319
4607
12 000
100
1233
18
14
10
06
0
2000
226
1464
Events (n)
Number at risk
4000
2032
17 839
6000
2983
29 130
8000
1253
11 976
10 000
259
2498
12 000
82
652
18
14
10
06
0
Events (n)
Number at risk
470
2000
70
1180
4000
6000
8000
Urinary sodium excretion (mg/day)
991
21 533
1469
32 748
413
11 408
10 000
60
2109
12 000
18
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Hypertension
No hypertension
Modelled HR
Observed HR
13
p<00001
for interaction
144
124
12
11
10
120
09
116
<300
Hypertension 7006
No hypertension 7547
Hazard ratio
148
14
08
300399 400499 500599 600699
12 297
15 700
13 430
8066
15 166
18 508
14 240
7827
700
7060
6271
91
13
90
12
89
88
p<00001
for interaction
87
77
Hazard ratio
152
11
10
09
08
07
76
06
<200
75
700
700
12 297
15 166
15 700
18 508
13 430
14 240
8066
7827
7060
6271
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 signicant 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 g/day. However, an increase in risk of
cardiovascular disease associated with high sodium
excretion (surrogate for intake) was only seen in
individuals with hypertension (which represents 24% of
those with hypertension but only about 10% of the overall
populations enrolled in the four cohorts included in this
analysis), but not in those without hypertension.
Our results are consistent with another recently
published cohort study (PREVEND study;10 n=7543),
which reported an association between increased sodium
intake and cardiovascular disease, that was conned to
participants with baseline hypertension (pinteraction=008)
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