Long-term effects of salt substitution on blood pressure in a rural North Chinese population

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Abstract

Dietary sodium and potassium intake can influence blood pressure. The effects of salt substitution on patients with hypertension and normotensive family member controls, however, have not been evaluated in a rural Chinese population. The objective of this study, accordingly, was to assess the long-term effects of salt substitution on blood pressure. We conducted a double-blind, randomized controlled trial among 200 families in rural China to establish the 2-year effects of a reduced-sodium, high-potassium salt substitute (65% sodium chloride, 25% potassium chloride, 10% magnesium sulfate) compared with normal salt (100% sodium chloride) on blood pressure. Of the 462 individuals in the trial, 372 completed the study (81%). For normotensive subjects, the mean overall difference in systolic and diastolic blood pressure between the two groups at the 24-month follow-up was 2 mm Hg (95% confidence interval (CI) 0–4 mm Hg, P<0.05) and 2 mm Hg (95% CI 1–3 mm Hg, P<0.05), respectively. For subjects with hypertension, the mean overall decrease in systolic blood pressure showed a 4-mm Hg (95% CI 2–6 mm Hg, P<0.05) decrease between the two groups. Diastolic blood pressure was not affected by salt use in the hypertensive group. Salt substitution lowers systolic blood pressure in hypertensive patients and lowers both systolic and diastolic blood pressure in normotensive controls. Salt substitution, therefore, may be an effective adjuvant therapy for hypertensive patients and the potential efficacy in preventing hypertension in normotensive individuals.

Introduction

Hypertension is a major cause of cardiovascular disease, accounting for two-thirds of stroke cases and one-half of coronary heart disease cases.1 Lowering blood pressure, therefore, may limit the incidence and mortality rates related to cardiovascular disease. The DASH trial showed that a diet rich in fruits, vegetables and low-fat dairy foods, with reduced saturated and total fat, can substantially lower blood pressure.2 This diet offers a nutritional approach to prevent and treat hypertension. In addition, there is strong evidence from animal, genetic, epidemiological and human intervention studies to demonstrate that a high-salt diet is a major risk factor for increased blood pressure.3, 4, 5, 6, 7, 8 The DASH-sodium trial demonstrated that a reduction in sodium intake and the DASH diet both lowered blood pressure substantially, with greater effects seen in combination than either alone.9 Sufficient dietary salt reduction, however, is difficult because of the wide use of salt in processed foods. The relationship between sodium, potassium and blood pressure has been explored in recent years, in an attempt to find alternative ways to inhibit the harmful effects of salt loading. Sodium can increase blood pressure, whereas potassium can decrease blood pressure, an effect that has been associated with increased natriuresis in salt-loaded hypertensive patients and animal models.10, 11, 12, 13, 14, 15

Salt substitution replaces sodium with potassium. Despite several animal studies that showed a benefit,16, 17, 18 there have been few intervention trials investigating the relationship between salt substitution and hypertension. Of the few trials that have taken place, the sample sizes have been small, the intervention periods have been short or subjects with malignant hypertension (systolic blood pressure 160 mm Hg) were enrolled. There have been few, if any, trials on subjects with normal blood pressure levels or modest hypertension. Accordingly, we designed a randomized controlled trial to evaluate the long-term use of salt substitution in the diet and its effect on blood pressure.

Subjects and methods

Participants

The First Hospital of China Medical University committee approved the study, and all participants gave written informed consent before taking part in the study.

We collected 200 families from five villages in Liaoning, North China. We based this study on our previous epidemiology work in this same geographical location.19 The families were potentially eligible for the study, if the family members satisfied all the following conditions: (1) At least one member in the family was a hypertensive patient. We defined hypertension as having systolic blood pressure >140 mm Hg or a diastolic blood pressure >90 mm Hg. (2) The participant had an estimated daily sodium intake of 260 mmol per day. If any of the study members, except the hypertensive patients, moved, the member was excluded. If one of the hypertensive patients moved during the follow-up period, all family members were also excluded. Additional inclusion criteria included being at least 18 years of age and having no significant renal impairment or other indication for a potassium-sparing medication.

Study design and measurements

The study was a double-blind, randomized controlled trial performed at five sites distributed throughout Liaoning, North China. The intervention period of the study lasted for 2 years. All families were randomized by a computerized randomization scheme into one of the two groups. Everyone in the same family received the same treatment (normal salt or salt substitute). One was the normal salt group (control group) and the other was the salt substitution group. The salt substitute used was made-up of 65% sodium chloride, 25% potassium chloride and 10% magnesium sulfate. This formulation was commercially available in China and has been previously tested for safety and effects on patients with malignant hypertension.18, 20 The normal salt group was given 100% sodium chloride. The two kinds of salt were delivered in 1 kg bags that were identical in appearance and were differentiated by a three-digit code. The study investigators and the participants were blinded to the treatment allocation and the meaning of the three-digit code until the end of the study. All study treatments were manufactured, packaged and labeled by the Shenyang Hongmei Salt Industrial Company (Shenyang city, Liaoning Province, China) in accordance with Chinese Manufacturing Standards. Quality control confirmed the complete quality and accuracy of that process. Participants were asked to prepare all foods using their assigned study salt during the study period. During the first visit, we computed how much salt was consumed by each family. This same amount of salt was given at each subsequent visit, and we questioned the families on their salt consumption.

Participants were followed up every 3 months after randomization. At registration, participants completed a baseline questionnaire and underwent a brief physical examination. Daily sodium intake was estimated based on responses to the questionnaire, which included the following (translated) questions about daily sodium intake. What are the main sources of dietary salt? How much salt does your family consume in one month? How many people are in your family and how many meals do you eat at home? We estimated the amount of daily sodium intake according to the answers to these questions. Blood pressure was measured at each visit by trained doctors using an Omron HEM-770A automatic sphygmomanometer (OMRON (China) Co., Ltd. (OCE/OCE-HCB/OCE-SH), Shanghai, China). Blood pressure was measured in the right arm at the heart level in the seated position. The mean of two readings was recorded and used for the analysis, and the interval between the readings was at least 2 min. In addition, first morning urine samples were sought from some participants at registration and a 24-month visit as randomly selected. Concentrations of sodium and potassium were measured in blood and urine using the ion selective electrode method. These values were used as confirmation that the groups were receiving the salt or substitution.

Statistics

Mean±s.e. of the mean (s.e.m.) and proportions were calculated for baseline and follow-up parameters. Analysis of treatment effects was by intention to treat, between randomized groups for the overall blood pressure difference from randomization to 24 months made using mixed linear models for repeated measures of analysis of variance. The baseline blood pressure and all follow-up blood pressure measurements were included in the mixed model with an overall estimate of effect, a confidence interval (CI) and a P-value calculated with weighting of data points according to the lengths of the respective follow-up intervals. All analyses were repeated with adjustment for alcohol consumption and family history of hypertension, which showed random baseline imbalances but had no impact on any conclusions. For continuous variables that were normally distributed, we used the Student’s t-test to compare the differences between the two groups. When variables were not normally distributed, the results were shown as the median, and a Wilcoxon sign ranks test was used to analyze groups. The χ2-tests were used to compare the proportions of categorical variables between the groups. A value of P<0.05 was considered statistically significant. All statistical tests were performed using SPSS 10.0 for Windows software (SPSS Inc. Chicago, IL, USA).

Results

Baseline characteristics

For the study, 200 families including 462 subjects were enrolled and randomized. The subjects included 234 females (51%) and 237 subjects with hypertension (51%). Of the participants, 182 of 200 families (91%) and 372 of 462 subjects (81%) completed the 24-month follow-up visit (Figure 1). The main reason for withdrawing from the study was participant’s reluctance to continue with the prescribed follow-up schedule. The mean age of the participants was 46±1 years.

Figure 1
figure1

Participant flow diagram. *All analyses conducted on an intention to treat.

Baseline characteristics are presented in Table 1. More than 50% of the participants noted a family history of hypertension. The overall mean baseline blood pressure was 152±1 mm Hg for systolic and 90±1 mm Hg for diastolic blood pressure. A comparable number of participants in the two treatment groups reported current use of antihypertensive or cardiovascular medications, with the most common medications being Captopril, Compound Reserpine and Nifedipine. With the exception of alcohol consumption and a family history of hypertension, the baseline characteristics were not different among the two groups.

Table 1 Characteristics of study participants by randomized group

Effects on blood pressure

The mean overall difference in systolic and diastolic blood pressure between the randomized groups during the 24-month follow-up period was 3 and 1 mm Hg, respectively (95% CI 2–5 and 0–2, P<0.05). A difference in blood pressure change between the groups was present at the 18-month visit and persisted to the end of the trial (all P<0.05; Figure 2 and Table 2).

Figure 2
figure2

Mean systolic (top) and diastolic (bottom) blood pressure for all the participants at each clinic visit. The mean overall difference in systolic and diastolic blood pressures between the randomized groups were significant (P<0.05 for both). A difference in blood pressure change was present at the 18-month visit and persisted through the end of the trial (all P<0.05).

Table 2 Difference of the mean systolic and diastolic blood pressure levels at each clinic visit between the two groups

For subjects with normal blood pressure, the mean overall difference in systolic and diastolic blood pressure between the salt substitution group and normal salt group during the 24-month follow-up period was 2 mm Hg for both (95% CI 0–4 and 1–3, respectively, P<0.05 for both; Figure 3).

Figure 3
figure3

Mean systolic (top) and diastolic (bottom) blood pressure for the normal blood pressure subjects at each clinic visit. The mean overall difference in systolic and diastolic blood pressures between the randomized groups were significant (both P<0.05). There was a difference in systolic blood pressure between the two groups at both the 6-month and 24-month visit (P<0.05). There was a difference in diastolic blood pressure between the two groups was at the 6-month, 15-month, 18-month and 24-month visits (P<0.05 for all).

For subjects with hypertension, the mean overall difference in systolic blood pressure between the salt substitution group and normal salt group during the 24-month follow-up period was 4 mm Hg (95% CI 2–6, P<0.05). There was no significant difference between the randomized groups for overall diastolic blood pressure (0 mm Hg reduction, 95% CI −1 to 1, P=0.66; Figure 4)

Figure 4
figure4

Mean systolic (top) and diastolic (bottom) blood pressure for hypertensive patients at each clinic visit. The mean overall difference in systolic blood pressure between the randomized groups was significant (P<0.05) but not in diastolic blood pressure (P=0.66). There was a difference in systolic blood pressure between the two groups at the 18-month, 21-month and 24-month visits (all P<0.05). There was a difference in diastolic blood pressure between the two groups at the 12-month, 18-month, 21-month and 24-month visits (all P<0.05).

Effects on urinary electrolytes

We randomly selected 80 subjects at baseline and 93 subjects at the 24-month follow-up visit to compare first morning urine sodium and potassium concentrations for the two study groups. At baseline, there were no significant differences between the salt substitution group and the normal salt group for median urine sodium and potassium (P=0.87 and P=0.74, respectively). These results are presented in Table 1. At the 24-month follow-up visit, first morning urine sodium concentrations were 177 mmol l−1 (interquartile range 137–261) for the salt substitution group and 184 mmol l−1 (interquartile range 108–228) for the normal salt group. The corresponding potassium concentrations were 29 mmol l−1 (interquartile range 18–45) for the salt substitution group and 29 mmol l−1 (interquartile range 18–51) for the normal salt group. There were also no significant differences between the two groups for median urine sodium and potassium (P=0.36 and P=0.66, respectively).

Discussion

This trial was carried out in a rural region of North China, which has a high prevalence of hypertension.19 Farming is the major livelihood, and many farmers in this region have lost their ability to work due to hypertension. The major findings of this study were that: (a) salt substitution lowers both systolic and diastolic blood pressure in all the participations; (b) salt substitution lowers systolic, but not diastolic blood pressure in hypertensive patients; and (c) salt substitution lowers both systolic and diastolic blood pressure in normotensive patients. Our results indicate that salt substitution may be a beneficial adjuvant therapy for both hypertension and prehypertension.

We have previously performed epidemiological studies on this same population for more than 10 years, in order to gain therapeutic insight for hypertension and other related cardiovascular and cerebrovascular diseases.19, 21 The subjects of our studies included both adults and children, and the risk factors included environment, diet and genetic influences. Before this study, we carried out a pilot trial of salt substitution on blood pressure with a 1-year follow-up period at one of the study sites.18 In that study, we concluded that reducing sodium using a salt substitution diet lowered systolic blood pressure, but not diastolic blood pressure. Here, we extended those findings to show that this effect persisted through the 24-months of follow-up, and that salt substitution also has an effect on normotensive family members.

In this study, the salt we provided was composed of sodium, potassium and magnesium. This could have contributed to a comparatively larger blood pressure effect than the change of one ingredient alone. Many studies have confirmed that decreasing sodium can decrease blood pressure.6, 9, 22, 23 In the INTERSALT Cooperative Research study,3 urinary sodium was related to the slope of blood pressure increases with age. Increases in 100 mmol per day of dietary sodium were associated with an average increase in systolic blood pressure of 2.2 mm Hg. Several clinical trials have shown that increasing potassium can decrease blood pressure both for hypertension patients and subjects with normal blood pressure.14, 24, 25, 26 INTERSALT demonstrated that potassium intake is an important independent determinant of population blood pressure.3 A 30–45 mmol increase in potassium intake was associated with an average reduction in population systolic blood pressure of 2−3 mm Hg. In addition, magnesium intake can also lower blood pressure.27, 28, 29, 30, 31 Although our results indicate that the combined effect of the three components may be therapeutically beneficial, this fact, however, remains to be determined.

This study was the first randomized, double-blind trial to explore the use of a salt substitution diet on blood pressure over a 2-year follow-up period. The results clearly demonstrate that a significant blood pressure reduction can be achieved by using reduced sodium, high potassium salt substitution, both in patients with hypertension in Northern China. Before this study, there have been few intervention trials for the effect of salt substitution on blood pressure,16, 17, 18 and most of those trials were of short duration (for example, 6 months or 1 year) or were with inconsistent results. This trial has the longest follow-up to date with sample sizes that are adequate to draw conclusions.

In China, especially in North China, salt intake is high,32 and most dietary salt come from home-cooked foods. This source of salt can easily be replaced with a salt substitute. Although the salt substitute is about 50% more expensive than normal salt, it is still a very low-cost commodity. Salt substitute, therefore, is affordable to the majority of patients and would be a good complement to drug therapy for blood pressure control. Compared with those studies that can be difficult and pharmacologically expensive to conduct,6, 33 salt substitution may be a feasible and successful dietary approach for lowering blood pressure among North China populations. There are several significant health concerns due to the high prevalence of hypertension in rural Chinese populations.34, 35 For one, it is estimated that 1 000 000 rural Chinese suffer from stroke each year.36 This high incidence could be reduced by 15–25% if systolic blood pressure could be lowered an average of 5 mm Hg with the salt substitute.37, 38 The potential reduction in cardiovascular disease events would be achieved from a combination of effects on lowering blood pressure as well as due to additional effects.39, 40

Our results indicate a variation in blood pressure measurements, with the measurements showing different values depending on the time of year. The reason for this variation may be the changing of seasons, changes in temperatures or other circumstances. The negative effect of very hot and very cold temperatures on blood pressure has already been confirmed.41 This trial began in the spring in North China, and temperature rose from that point. For the first 3 months of the trial, the mean blood pressure showed a notable decrease that was likely not entirely due to our intervention. For this reason, it was important to have follow-up periods of more than 1 year. In our previous study, we observed the effect of salt substitute on blood pressure for 1 year, which indicated that salt substitution could lower systolic blood pressure, but not diastolic blood pressure.18 In this study, we extended these past results to show that salt substitution not only lowered the systolic blood pressure, but also lowered the diastolic blood pressure after 24 months of intervention. The mean overall difference in systolic and diastolic blood pressure between the two groups was 3 and 1 mm Hg, which is comparable to effects achieved with medication.6, 33 The fact that diastolic blood pressure did not change until 18 months into the study is also consistent with the previous trial, which did not find a difference in diastolic blood pressure with a 1 year follow-up period.18

Studies have demonstrated that a rise in blood pressure occurs with age.3 There remains a controversy over whether a reduction in sodium intake has a significant effect on blood pressure in persons without hypertension.33, 42, 43 A major strength of this study is the large sample size and well-controlled trial in a northern China population, which provided reliable estimates about the effects of treatments. In this study, we recruited not only patients with hypertension, but also subjects with blood pressures within the normal range. Interestingly, there was a significant difference in both systolic and diastolic blood pressure in this group, indicating that salt substitution may be effective for the treatment of prehypertension or to prevent the development of hypertension in at-risk patients. This finding has important implications for preventing the future occurrence of both hypertension and cardiovascular and cerebrovascular events in the entire population.

In addition, we found that the baseline blood pressure in the salt substitution group was higher than the regular salt group (Tables 1 and 2). Whether there was a biological difference in baseline blood pressure could alter the effects of salt substitution was not explored here.

The magnitude of the reduction also compares favorably with large scale trials for drug therapy,44 indicating that a salt substitution may be a practical choice for patients with hypertension who are resistant to antihypertensive medications or who experience side effects of medications. This could have an important role in lowering health-care costs in rural populations.

At the 24-month follow-up visit, first morning urine samples were randomly sought from participants. Because the previous study demonstrated good safety profiles for participants using the salt substitute, we did not collect 24 h urine samples from the participants in the current study. For this reason, the lack of significant differences in urinary electrolytes between groups should be interpreted with caution. In our study, some subjects reported that the taste of the salt substitution was lighter than normal salt. Some families added comparable amounts of the salt substitute during cooking as previously used, while other families added more than previous to accommodate for the change in taste. As we could not compute precisely for the amount of salt consumed, we could not judge whether the amount of the salt used affected the final effect of the salt substitution on blood pressure. More studies are warranted to determine the amount of substitute sufficient to lower blood pressure, and whether the flavor of substitute is still acceptable to patients. In summary, our results are the first to show that salt substitution can be an effective way to lower blood pressure in a rural population in North China.

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Acknowledgements

This work was supported by the grants from Program of the National Natural Science Foundation of China (30800944 and 30671796).

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Correspondence to J-P Shi.

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Keywords

  • salt substitution
  • sodium
  • potassium
  • blood pressure

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