We performed a randomised, placebo-controlled, crossover study to examine the effects of sodium and potassium supplementation on blood pressure (BP) and arterial stiffness in untreated (pre)hypertensive individuals. During the study, subjects were on a fully controlled diet that was relatively low in sodium and potassium. After a 1-week run-in period, subjects received capsules with supplemental sodium (3 g d−1, equals 7.6 g d−1 of salt), supplemental potassium (3 g d−1) or placebo, for 4 weeks each, in random order. Fasting office BP, 24-h ambulatory BP and measures of arterial stiffness were assessed at baseline and every 4 weeks. Of 37 randomized subjects, 36 completed the study. They had a mean pre-treatment BP of 145/81 mm Hg and 69% had systolic BP ⩾140 mm Hg. Sodium excretion was increased by 98 mmol per 24 h and potassium excretion by 63 mmol per 24 h during active interventions, compared with placebo. During sodium supplementation, office BP was significantly increased by 7.5/3.3 mm Hg, 24-h BP by 7.5/2.7 mm Hg and central BP by 8.5/3.6 mm Hg. During potassium supplementation, 24-h BP was significantly reduced by 3.9/1.6 mm Hg and central pulse pressure by 2.9 mm Hg. Pulse wave velocity and augmentation index were not significantly affected by sodium or potassium supplementation. In conclusion, increasing the intake of sodium caused a substantial increase in BP in subjects with untreated elevated BP. Increased potassium intake, on top of a relatively low-sodium diet, had a beneficial effect on BP. Arterial stiffness did not materially change during 4-week interventions with sodium or potassium.
Hypertension is a key risk factor for renal and cardiovascular diseases (CVD)1, 2 and affects ~25% of the world’s adult population.3 Reducing population blood pressure (BP) through beneficial dietary and lifestyle changes may have important effects on CVD prevention. There is compelling evidence from randomised controlled trials that sodium reduction lowers BP.4, 5, 6, 7, 8 In a meta-analysis of randomised trials with a minimum duration of 4 weeks, He et al.7 showed reductions of 5.4 mm Hg in systolic BP (SBP) and 2.8 mm Hg in diastolic BP (DBP) in hypertensives for a 75 mmol lower 24-h sodium excretion (i.e. 1.7 g sodium or 4.4 g salt per day), with about half the effect in normotensives. Considering that most populations around the world have salt intakes higher than the recommended maximum intake of 5–6 g d−1 (equals 2.0–2.4 g sodium),9, 10, 11 global reductions in salt intake could substantially reduce the burden of CVD.7, 12
Increasing dietary potassium intake may favourably affect CVD risk. van Mierlo et al.13 reported expected reductions of 1.7–3.2 mm Hg in population SBP when current potassium intakes in 21 countries (1.7–3.7 g d−1) were increased to 4.7 g d−1, as recommended by the US Institute of Medicine.14 A recent meta-analysis of 21 randomised trials reported 3.5/2.0 mm Hg lower BP with an increased potassium intake, especially in hypertensives.15 The BP reduction was 6.9/2.9 mm Hg when habitual sodium intake was high (>4 g d−1), compared with 2.0/2.0 mm Hg for sodium intake of 2–4 g d−1. Whether potassium supplementation lowers BP in subjects who adhere to the dietary sodium recommendation has not extensively been investigated.
Arterial stiffness is an independent risk factor of CVD16 and can be assessed non-invasively, using pulse wave analysis (PWA), or directly as pulse wave velocity (PWV).17 Limited studies have examined the effects of sodium or potassium on measures of arterial stiffness, with inconclusive results both for sodium18, 19, 20, 21, 22, 23, 24, 25 and potassium.26, 27, 28, 29
We performed a randomised, placebo-controlled, crossover study to examine the effects of sodium and potassium supplementation on office BP, ambulatory BP and arterial stiffness in Dutch subjects with untreated elevated BP. Supplementation took place while subjects were on a fully controlled diet that was relatively low in sodium and potassium, with all meals provided during the study.
Materials and Methods
Potential participants were recruited within a 10-km radius of the research centre from December 2011 to April 2012. Subjects filled out a medical questionnaire, underwent physical examination and provided one 24-h urine and a fasting blood sample. Eligible for participation were non-smoking men and women, aged 40–80 years, with a fasting supine SBP between 130 and 159 mm Hg. Subjects with diabetes mellitus or cardiovascular, gastrointestinal, liver or renal diseases were excluded based on the questionnaire data and laboratory parameters. Other exclusion criteria were body mass index >40 kg m−2; use of medication known to affect the cardiovascular system; use of nutritional supplements; an energy-restricted or medically prescribed diet; unstable body weight in past 2 months; alcohol use over 21 (women) or 28 (men) consumptions per week; and pregnancy or lactation (women).
The Medical Ethics Committee of Wageningen University approved the study. The trial was registered at ClinicalTrials.gov (NCT01575041). The study was conducted from March to August 2012 at the research centre of Wageningen University, Wageningen, The Netherlands. All subjects gave a written informed consent.
We performed a randomised, double-blind, placebo-controlled crossover study, in which diet was fully controlled. During the 1-week run-in (to ensure energy balance and reach basal BP) and 3 consecutive intervention periods of 4 weeks (not separated by washout) each subject consumed a diet that was targeted to provide 2 g of sodium and 2 g of potassium per day for a 2500 kcal intake. At the end of the run-in (‘baseline’), subjects were examined and randomly allocated to 1 of the 6 possible treatment orders, in strata of sex and SBP (130–139 and ⩾140 mm Hg), by an independent person who used a computer-generated table. Treatments included 3 g of added sodium (equals 7.5 g salt) per day, 3 g of added potassium per day or placebo. Subjects were examined at baseline and at the end of each intervention. Examinations included ambulatory BP monitoring (ABPM), and in a fasting state anthropometric measurements, office BP, PWA and PWV and a blood sample. Subjects collected 24-h urine by discarding the first morning urine sample and collecting all urine for the next 24 h. Measurements were done at fixed time points of the day throughout the study. BP was re-measured 2 weeks after completion of the study, when subjects had returned to their usual diet.
Diet and study procedures
Individual energy needs were estimated using an FFQ,30 which was filled out during screening, combined with results of the Schofield equation.31 The food and beverages that were supplied by the research institute covered 90% of daily energy needs. Remaining 10% was chosen by the participant from a limited number of products that were low in sodium and potassium. These products and any deviations from the diet were recorded in a diary. Subjects were not allowed to add salt or salt-containing seasonings to their food. Maximum daily consumption levels were set for coffee (3 cups), alcohol (1 consumption, equalling 10–15 g of ethanol), fruit (2 portions) and liquorice (3 pieces).
During the trial, duplicates of each daily diet were collected, homogenised and analysed for energy, macronutrients and mineral content. The average composition of the diet (see Supplementary Table 1) was calculated from these duplicate diets and from free-choice items for which nutrient values were obtained from the Dutch food composition table.32 A 2500-kcal diet provided a daily sodium and potassium intake of 2.4 and 2.3 g, respectively. We asked the subjects to maintain their usual level of physical activity during the study. Subjects were weighed twice a week and if needed, their energy intake was adjusted to keep body weight constant.
Sodium and potassium intakes were increased through the daily use of capsules (Microz, Geleen, The Netherlands), while subjects were on the study diet. Depending on the intervention period, subjects had to ingest 8 sodium chloride capsules (in duplicate analysed content: 371 mg sodium per capsule, totalling 2968 mg), 8 potassium chloride capsules (353 mg potassium per capsule, totalling 2824 mg) or 8 placebo capsules (cellulose), distributed over the day with meals. Capsules were matched in size and colour and research staff and subjects were blinded to treatment. Compliance was checked through capsule counts and subjects' diaries. Subjects who ingested over 80% of the capsules for a given intervention period were considered compliant.
Office BP and heart rate
Office BP and heart rate (HR) measurements were performed in a temperature-controlled (20–24 °C) quiet room by 1 trained staff member. BP and HR were measured in supine position after at least 10 min rest with 2-min intervals using an automated oscillometric device (Dinamap Pro 100, KP Medical, Houten, The Netherlands) with an appropriate cuff size on the left upper arm with the arm rested on the bed. The first measurement was discarded and the 3 subsequent measurements were averaged. Subjects remained blinded towards the BP and HR values until the end of the study.
Ambulatory BP and HR
Blinded ambulatory BP and HR monitoring was performed for 24 h using Spacelabs 90217 devices (Spacelabs Medical Inc. Redmond, WA, USA). Recordings were taken every 30 min at daytime (7 AM to 11 PM) and every 60 min at nighttime (11 PM to 7 AM) on the non-dominant arm ~2 cm above the antecubital fossa. Subjects were asked to maintain their normal daily activities during the recording period, to avoid intense exercise and to register their activities in a diary. Subjects were instructed to perform ABPM 1 or 2 days before the end of each intervention period, at fixed times (i.e. same day of the week and time of the day). A weighted 24-h mean ambulatory BP and HR was calculated, as well as daytime (8 AM to 22 PM), nighttime (midnight to 6 AM) and early-morning (6 AM to 9 AM) means. Ambulatory BP and HR was based on at least 6 daytime and 4 nighttime recordings.
PWA and PWV
Radial artery PWA and carotid-femoral PWV were determined by applanation tonometry using the SphygmoCor system (version 8.0; AtCor Medical, Sydney, NSW, Australia) by the same staff member each occasion. Central aortic pressures and HR-corrected augmentation index (AIx), which are surrogate measures of arterial stiffness, were derived from PWA.17 One subject was excluded in the PWA and PWV analysis as no reliable pressure wave could be recorded because of an irregular heartbeat.
Serum samples were stored at −80 °C until the end of the study for the determination of sodium, potassium, triglycerides, total cholesterol, HDL-cholesterol and creatinine. LDL-cholesterol was calculated from the Friedewald formula.33 Twenty-four-hour urine samples were stored at −80 °C for the determination of sodium, potassium, creatinine (unprocessed samples) and calcium and magnesium (acidified samples). Serum and urinary sodium and potassium were determined using the ion-selective electrodes module on the Modular P of Roche (Roche Diagnostics, Mannheim, Germany) in a certified laboratory. Other serum and urine parameters were assessed using standard laboratory methods. Inter-assay coefficients of variation were <3% for all biochemical measurements, except for calcium (5.0%).
Double-data entry was performed and data were analysed according to the intention-to-treat principle, using a predefined protocol. Treatment codes were broken after data-analysis results had been verified by an independent statistician. For each outcome measure, mixed-effects model with covariance structure compound symmetry was used to estimate the effect of the active treatment compared to placebo. The effects on office SBP were defined as the primary outcomes. Differences in the occurrence of adverse events between treatments were assessed by the X2-test. Sensitivity analysis was conducted by excluding periods in which subjects were noncompliant (see Supplementary Table 2).
Values reported in text and tables are means with s.d. or treatment effects with 95% confidence interval. Two-sided P-values<0.05 were regarded as statistically significant. Analyses were performed using SAS 9.2 software (SAS Institute, Cary, NC, USA).
Figure 1 shows the number of subjects screened, randomised and withdrawn during the study. Of 37 randomised Caucasian subjects, one dropped out because of gastrointestinal complaints due to capsule use. Baseline characteristics of the 24 men and 12 women who completed the study are reported in Table 1. Subjects were on average 65.8 y (range 47–80 y) and their body mass index was 27.2 kg m−2.
Sodium and potassium excretion
During screening, 24-h urinary excretion was 153.7 mmol for sodium and 81.8 mmol for potassium, which were reduced to 90.8 and 49.0 mmol, respectively, after run-in. Twenty-four-hour urinary sodium excretion was 105.1 mmol on placebo and 202.9 mmol on sodium supplementation, a mean difference of 97.6 mmol (equals 2.2 g sodium or 5.7 g salt). Urinary potassium excretion was increased from 55.3 mmol on placebo to 118.1 mmol on potassium supplementation, i.e. by 62.9 mmol (equals 2.5 g) (Table 2). The molar sodium-to-potassium ratio was 2.0 during placebo, 4.0 during sodium supplementation and 0.9 during potassium supplementation (ratios based on weight: 1.2, 2.4 and 0.5, respectively).
Office BP and HR
During screening, subjects had a mean office BP of 145.3/80.6 mm Hg and 69% (25/36) had SBP ⩾140 mm Hg. After run-in, BP was 133.4/75.7 mm Hg. Table 3 shows the treatment effects for office BP and HR. During sodium supplementation, SBP was increased by 7.5 mm Hg (3.8, 11.1), DBP by 3.3 mm Hg (1.5, 5.2) and pulse pressure (PP) by 4.1 mm Hg (1.5, 6.7) compared with placebo, with no effect on HR. Potassium supplementation resulted in a nonsignificantly lower SBP of 3.0 mm Hg (−0.6, 6.7), and significantly lower PP of 2.8 mm Hg (0.1, 5.4) compared with placebo, with no significant differences in DBP and HR. Two weeks after completion of the study, mean office BP was 132.1/74.8 mm Hg (data not shown), which was comparable to post-run-in values.
Ambulatory BP and HR
Figure 2 shows the mean unadjusted ambulatory SBP (A) and DBP (B) values, by treatment. Sodium supplementation resulted in a higher 24-h SBP of 7.5 mm Hg (4.4, 10.5) and DBP of 2.7 mm Hg (1.1, 4.2), compared with placebo. In 78% (28/36) of the subjects, 24-h SBP was higher during sodium supplementation than during placebo supplementation (Figure 3). For SBP, the effect did not essentially differ over the day, but for DBP a larger effect was seen during early-morning (4.1 mm Hg). Sodium supplementation did not significantly affect ambulatory HR (Table 3).
Potassium supplementation resulted in a lower 24-h SBP of 3.9 mm Hg (0.9, 6.9) and 24-h DBP of 1.6 mm Hg (0.1, 3.2) compared with placebo (Figure 2, Table 3). For SBP, the effect did not essentially differ over the day, but for DBP no effect was seen during early-morning. In 67% (24/36) of the subjects, 24-h SBP was lower during potassium supplementation than during placebo supplementation (Figure 3). During potassium supplementation, 24-h HR was 2.6 beats per minute (1.1, 4.1) higher than during placebo.
PWA and PWV
Sodium supplementation resulted in a significantly higher central SBP of 8.5 mm Hg, central DBP of 3.6 mm Hg and central PP of 4.8 mm Hg compared with placebo. PWV was unaffected by sodium supplementation (Table 3). Potassium supplementation resulted in a significantly lower central PP of 2.9 mm Hg, and a nonsignificantly lower central SBP and DBP of 3.0 and 0.2 mm Hg, respectively. PWV was nonsignificantly decreased by 0.35 m s−1. Central HR-corrected AIx was unaffected by sodium or potassium supplementation (Table 3).
Serum and urine parameters, and body weight
Sodium supplementation resulted in a nonsignificantly higher serum sodium of 0.39 mmol l−1, and significantly lower serum potassium of 0.10 mmol l−1, serum creatinine of 3.7 μmol l−1, total cholesterol of 0.19 mmol l−1 and LDL-cholesterol of 0.18 mmol l−1, compared with placebo. Serum HDL-cholesterol, total-to-HDL-cholesterol ratio and triglycerides did not differ significantly between sodium and placebo supplementation. Twenty-four-hour urinary calcium excretion was significantly higher by 1.16 mmol (equals 46.4 mg) during sodium supplementation than during placebo. Urinary magnesium and creatinine excretion were not significantly affected (Table 2).
Potassium supplementation resulted in a significantly lower serum sodium of 0.68 mmol l−1, higher serum potassium of 0.13 mmol l−1 and higher urinary creatinine of 0.82 mmol per 24 h compared with placebo. Other serum and urinary parameters did not differ significantly (Table 2). Body weight was kept constant during the study through adjustments in caloric intake, and did not differ between the intervention periods.
Reported side effects in subjects’ diaries indicated that 19 persons experienced gastrointestinal complaints during sodium, 21 during potassium and 8 during placebo supplementation (P=0.004). Other side effects including dizziness, headache, illness, shortness of breath and oedema were not significantly different among the 3 treatments.
In Dutch adults with untreated elevated BP, increasing the intake of sodium by 3.0 g d−1 (equals 7.6 g d−1 of salt) strongly raised office, ambulatory and central SBP by ~8 mm Hg. Increasing the potassium intake by 2.8 g d−1 significantly lowered ambulatory SBP by 4 mm Hg in these individuals on a relatively low-sodium diet. Measures of arterial stiffness did not materially change after 4 weeks of sodium or potassium supplementation.
In most Western societies, mean sodium intakes are above recommended levels,9 whereas potassium intakes are relatively low.13 This could have a major impact on population health, including risk of CVD. A 7.5-mm Hg lower SBP, in our study achieved by decreasing sodium intake from a level common in Western societies to the recommended level, would be associated with a 30% lower risk of stroke mortality and 22% lower risk of ischaemic heart disease in a middle-aged population.2 Increasing the intake of potassium, even when subjects adhere to guidelines for dietary salt intake, may further reduce the risk.
A major strength of the present study is the fully controlled diet, which strongly reduced the intra-individual variability in BP resulting from dietary influences (for example, use of alcohol, coffee and salt) and thereby increasing power to demonstrate effects on BP. Subjects were also instructed to keep other lifestyle behaviours, such as physical activity, constant. Fasting BP was repeatedly measured at the research centre using a strict protocol, at fixed times in the morning. All subjects underwent ABPM, which is considered a better predictor of CVD than office BP.34 Because we provided a (relatively) low-sodium, low-potassium diet, combined with capsules that contained ~3 g of sodium or potassium, we were able to achieve large contrasts in sodium and potassium intake. Eighty-six percent of the subjects were compliant during all periods, as also reflected in 24-h urinary excretions.
Our study showed a 7.5 mm Hg increase in SBP with an increase in 24-h urinary sodium of 98 mmol. Assuming a linear relation, this is equivalent to an effect of 0.7–0.8 mm Hg per 10 mmol change in 24-h urinary sodium. This finding is comparable to the result of a meta-analysis of randomised trials of at least 4 weeks duration, in which a reduction in 24-h urinary sodium of 75 mmol decreased SBP by 5.4 mm Hg (0.7 mm Hg per 10 mmol) in hypertensives.7
Potassium supplementation in our study increased 24-h urinary potassium by 63 mmol and reduced SBP by 3–4 mm Hg. In a meta-analysis of 16 randomised controlled trials,15 potassium lowered SBP by ~5 mm Hg in hypertensives. The smaller effect in our study may result from the inclusion of prehypertensives (31% of our subjects) who may show smaller BP responses. Also, our subjects consumed a relatively low-sodium diet (2.2 g d−1). In the meta-analysis, BP reductions after increased potassium intake depended on sodium intake, i.e. SBP was reduced by 7 mm Hg for sodium intake of >4 g d−1 and by 2 mm Hg for sodium intake of 2–4 g d−1.15 Therefore, the beneficial effect of increased potassium intake on BP in individuals with Western, high-salt diets may be greater than observed in the present study.
We found significant effects of sodium and potassium on BP, but not on arterial stiffness as measured by PWV and the surrogate measure AIx. The differences in several indices of central BP may have resulted from changes in brachial artery pressure, which was used in the algorithm to estimate the central pressures.17 Since no effect was found for PWV, a direct indicator of arterial stiffness, we consider effects of sodium and potassium on arterial stiffness in our study unlikely. The 4-week duration of the intervention periods may have been too short to induce changes in the vascular structure. However, short-term interventions may affect arterial stiffness by influencing functional properties, such as vascular tone and endothelial function.35 Moreover, other studies with a 4–6-week duration did find effects of sodium intake on PWV in (pre)hypertensives,21, 22, 24 although 2 studies in normotensives19, 25 did not. Therefore, further studies of longer duration in subjects with untreated hypertension are warranted to assess the effects of sodium intake on arterial stiffness.
For potassium supplementation, limited data are available on the effects of arterial stiffness and results are inconsistent. A randomised controlled trial in 42 untreated hypertensives showed a significant reduction of 0.8 m s−1 in PWV for 2.5 g d−1 higher potassium intake.28 Another trial in 40 subjects at increased CVD risk with the same potassium dose found a reduction in PWV of 0.4 m s−1.27 A trial in 48 early hypertensives with lower doses of potassium, however, found no effect.26 In our study, PWV was 0.35 m s−1 lower during potassium but this finding was not statistically significant, despite a high potassium dose. Our study had ample power (>80%) to detect an effect of 0.7 m s−1 in PWV, which has been associated with a 11% lower risk of mortality.16
Sodium supplementation had no significant effect on HR. Potassium supplementation, however, significantly increased ambulatory HR, although no effect was seen for office HR. The reason for this finding remains unclear. During high potassium intake, serum potassium was increased by 0.13 mmol l−1 but levels of all participants remained within the normal range, not posing them at increased risk for hyperkalaemia or cardiac rhythm disturbances. Possibly, decreases in plasma volume contributed to the effect on HR. Another trial in healthy humans reporting the effects of 4-week potassium supplementation of 3.9 g d−1, however, found no differences in ambulatory HR.29 Because an effect was found only on 24-h and not on office HR in our subjects, we cannot exclude the possibility that our finding was due to chance.
Sodium supplementation resulted in lower total and LDL-cholesterol levels of 3.4 and 4.6%, respectively, in our study. Other studies showed raised serum total or LDL-cholesterol during sodium restriction or use of thiazide diuretics, which is in line with these findings.36 In a meta-analysis of sodium interventions that lasted 4 weeks or more, differences in serum cholesterol were not significant, suggesting a transient response.37 Urinary calcium excretion in our subjects was higher during sodium supplementation, as has also been reported by others.38 When urinary calcium losses occur, calcium mobilisation from bone may be increased. It has been suggested that this side effect of high sodium intake, if sustained over time, may lead to osteoporosis.38
In conclusion, the current study demonstrates that increasing the intake of sodium from a recommended level to a level that is common in Western societies, has a strong adverse effect on BP in untreated (pre)hypertensive individuals. Increasing potassium intake, however, lowers BP even when people are on a relatively low-sodium diet. Measures of arterial stiffness were not materially affected by sodium or potassium supplementation. Our findings support the recommendations to reduce sodium intake and to increase potassium intake, which will likely lower BP in older individuals with untreated elevated BP, and the burden of CVD in Western societies.
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The research is funded by TI Food and Nutrition, a public–private partnership on pre-competitive research in food and nutrition. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We gratefully acknowledge the assistance of Harrie Robins, Sarah Mount and Danielle Schoenaker in the conduct of the study. We thank the dieticians for dietary calculations and catering, Karin Borgonjen-van den Berg for randomisation and blinding procedures, Anita Bruggink-Hoopman and Diana Emmen-Benink for blood sampling, Marlies Diepeveen-de Bruin for analysing duplicate diets and Hendriek Boshuizen for statistical support.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Journal of Human Hypertension website
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Gijsbers, L., Dower, J., Mensink, M. et al. Effects of sodium and potassium supplementation on blood pressure and arterial stiffness: a fully controlled dietary intervention study. J Hum Hypertens 29, 592–598 (2015). https://doi.org/10.1038/jhh.2015.3
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