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Newberry SJ, Chung M, Anderson CAM, et al. Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Jun. (Comparative Effectiveness Review, No. 206.)
Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks [Internet].
Show detailsSummary of Key Findings and Strength of Evidence
The key points for each outcome appear in the Results section, organized by Key Question. Key points (primarily those for which the strength of evidence is moderate or higher are summarized below, along with the strength of evidence (SOE) ratings (the factors that contributed to the ratings are reported in full in Appendix F). In general, the Key Questions were organized, first, by exposure: Key Questions 1 through 4 considered sodium exposure and sodium to potassium ratio, whereas Key Questions 5 through 8 considered potassium exposures. The questions were then further organized by study design: Key Questions 1, 3, 5, and 7 assessed the findings of RCTs on the effects of studies intended to reduce sodium or increase potassium intake for the outcomes of interest, whereas the even-numbered questions assessed the associations between sodium or potassium exposures and the outcomes of interest in prospective cohort studies. The questions are then further organized by outcomes:
Key Questions 1 and 2 address the relationships between sodium intake and BP, achievement of a prespecified BP goal, incident HTN, and adverse effects.
Key Questions 3 and 4 address the relationships between sodium intake and all-cause mortality, CVD mortality, CHD mortality, stroke, MI, combined CVD morbidity and mortality, combined CHD morbidity and mortality, renal outcomes, any reported combination of CVD events, other CVD events, and adverse events.
Key Questions 5 and 6 address the relationships between potassium status and BP, achievement of a prespecified BP goal, incident HTN, kidney stones, and adverse effects.
Key Questions 7 and 8 address the relationships between potassium status and all-cause mortality, CVD mortality, CHD mortality, stroke, MI, combined CVD morbidity and mortality, combined CHD morbidity and mortality, renal outcomes, any reported combination of CVD events, other CVD events, and adverse events.
In this chapter, we discuss the overall findings for each outcome, considering all study designs together.
Key Question 1. Effect of Interventions To Reduce Dietary Sodium Intake on Blood Pressure
Conclusions
- Sodium reduction decreases systolic and diastolic blood pressure significantly in adults (moderate SoE).
- Sodium reduction in adults may increase the likelihood of achieving a prespecified blood pressure goal (low SoE).
- Sodium reduction lowers BP in both men and women (moderate SoE), and sex does not appear to moderate the effect of sodium reduction on BP in adults (low SoE).
- Short term sodium reduction interventions do not appear to show statistically significant effects on BP in children; however, a sensitivity analysis that excluded high or unclear RoB studies resulted in a statistically significant decrease in diastolic BP with sodium reduction for children.
- Sodium reduction decreases systolic BP in both those with hypertension and those with normal BP; the effect is greater in adults with HTN than in those with normal BP (moderate SoE).
- Sodium reduction decreases diastolic BP in those with hypertension (moderate SoE).
- Potassium-containing salt substitutes decrease systolic and diastolic BP (moderate SoE).
Key Question 2. Association Between Dietary Sodium Intake and Blood Pressure
Conclusions
- Prospective cohort studies suggest that sodium intake may be associated with systolic BP but not with diastolic BP in adults (low SoE). Most studies had high RoB based on the methods used to assess sodium intake (typically single 24-hour urine excretion with or without validation or estimated based on overnight urinary excretion), and findings were inconsistent across studies.
- Evidence from a small number of prospective cohort studies suggests that sodium intake may be associated with incident hypertension in adults (low SoE: Most studies had high RoB based on the methods used to assess sodium intake.
Sodium and Blood Pressure
Key Questions 1 and 2 considered the relationship between sodium intake and systolic and diastolic blood pressure. We limited inclusion to RCTs with a minimum four-week intervention (Key Question 1) and prospective observational studies with a minimum 4-week follow up (Key Question 2) to increase the applicability of the study findings to individual patient- and community interventions.
RCTs designed to assess the effects of interventions to restrict sodium intakes had significant, although somewhat inconsistent, beneficial effects on reducing both systolic BP and diastolic blood pressure, compared with usual sodium intakes in adults; follow up times were as long as 8 years, but most studies limited intervention duration and follow up to a year or less. Pooled analyses showed high heterogeneity across studies.39, 42, 45–51, 53, 86, 90, 92, 93, 95, 114, 157, 159–164, 169–171, 200, 203, 205, 206, 208–210, 212, 213, 216, 217, 230–232, 236, 260, 263, 266, 276, 282–284 Assessment of dose-response relationships between interventions, 24-hour urinary sodium excretion, and blood pressure showed significant positive effects in the DASH-Sodium trial49 but findings were inconsistent in smaller does-response studies. Prospective observational studies generally reported inconsistent associations of sodium exposure with blood pressure at follow up, however assessments of exposure often relied on high RoB methods such as single 24-hour urinary excretion without validation, estimated urinary excretion, or dietary assessments.51, 111, 135, 139, 274
Few studies assessed the effects of sodium reduction on blood pressure in subgroups of interest, and even fewer studies conducted subgroup analyses within the same study. Evidence was insufficient to determine whether race/ethnicity moderate the effect of sodium reduction on blood pressure.
Evidence suggests that sodium reduction may not lower systolic BP in children (low strength of evidence), but evidence based on a sensitivity analysis that omitted high or unclear RoB studies suggests a significant effect on diastolic BP.114, 131, 173–175, 207, 237 Prospective observational studies suggested stronger associations of sodium intake with BP in adults than in children.104, 109 112, 132, 146
Adults with HTN39, 46–49, 51, 53, 90, 92, 93, 96, 113, 157, 159, 160, 163, 164, 169–171, 205, 206, 208–213, 216, 217, 230, 231, 236, 260, 266, 284 showed greater improvements in BP with sodium excretion interventions than did those with normal blood pressure,42, 45, 49, 50, 86, 161, 200, 263, 283 (moderate strength of evidence for systolic BP; low strength of evidence for diastolic BP). The lower heterogeneity across studies included in these pooled analyses compared with that of the pooled analysis of studies of all adults suggests the higher heterogeneity in the latter analyses might be attributable to the inclusion of studies of both those with HTN and those with normal BP. Evidence was insufficient from prospective observational studies to determine whether the association between sodium intake and blood pressure differs between those with HTN and those with normal BP.
A small number of RCTs assessed the impact of alteration of other minerals (potassium) on the effect of sodium reduction. Those that compared the effects of combining sodium reduction and increased potassium intake with that of sodium reduction alone suggested potassium has no moderating effect on that of sodium reduction for BP.42, 233, 235, 236, 275 Another group of studies, which compared the effects of using potassium-rich salt substitutes to limit sodium intake to usual diet, found that these salt substitutes significantly lower blood pressure (moderate strength of evidence);99, 101, 102, 124, 196, 199, 232, 239, 241, 265, 267, 275, 282 however 24-hour sodium excretion levels reported in these studies do not suggest that sodium intakes were consistently decreased in the groups assigned to potassium-containing salt substitutes. No studies assessed the impact of other minerals on the effects of sodium reduction. No observational studies assessed these associations.
Sodium and Achievement of a Prespecified Goal
Few studies assessed the effects of interventions on the likelihood of reaching a prespecified BP goal. Across six RCTs, sodium reduction interventions had a significant beneficial effect on the proportion of adult study participants achieving a prespecified blood pressure goal, although goals differed among the studies (low strength of evidence).49, 170, 171, 205, 206, 284
No RCTs assessed the potential moderating impact of subgroup status on this outcome. No observational studies assessed the association between sodium exposure and achievement of a prespecified BP goal.
Sodium and Incident Hypertension
RCTs showed a small, non-statistically significant beneficial effect of sodium reduction on the relative risk for incident HTN in adults (low SoE, because of the small number of studies and inconsistency). Observational studies suggested an association between urinary sodium excretion and risk for HTN (low strength of evidence due in part to high RoB and inconsistency: The small number of observational studies show mixed findings regarding the association between urinary sodium excretion and risk for HTN, ranging from no association to an association at higher exposure levels).42, 51, 53
No studies of the moderating effects of potassium or potassium salt substitutes assessed effects on incident HTN.
No RCTs assessed the potential moderating effects of sex, race/ethnicity, age, or comorbidities on the effects of sodium reduction on incident hypertension. Sodium reduction during pregnancy had no effects on incident gestational hypertension, and urinary salt excretion was not associated with risk for gestational hypertension in one cohort study.
Sodium and Adverse Events
Few RCTs reported specific adverse events associated with sodium reduction to lower BP. Three studies, including the DASH-Sodium Trial, found no effects of sodium reduction on blood lipids (low strength of evidence). Evidence was insufficient regarding other adverse effects.49, 160, 163, 171, 206
Key Question 3. Effect of Interventions To Reduce Dietary Sodium on CVD and Kidney Disease Morbidity and Mortality, and on Total Mortality
Conclusions
- In adults, evidence is insufficient to determine the effects of sodium reduction on the risk for all-cause mortality (based on seven RCTs with moderate RoB).
- In adults, evidence is insufficient to determine the effects of sodium reduction on the risk for CVD mortality (two RCTs).
- In adults, a low strength of evidence suggests that sodium reduction decreases the risk for combined CVD morbidity and mortality (eight RCTs; low RoB)
- In adults, sodium reduction does not appear to affect the risk for stroke (low SoE based on three RCTs with low RoB)
- In adults, evidence is insufficient to assess the effect of sodium reduction on the risk for myocardial infarction (one RCT; low RoB).
- In adults, a low strength of evidence suggests that sodium reduction significantly decreases the risk for a composite measure of “any CVD outcome” as reported by study authors (based on seven RCTs; low RoB).
- Evidence is insufficient to draw conclusions about the moderating effects of sex, race/ethnicity, age, or reproductive status on the effects of sodium reduction on CVD or CHD outcomes.
- Evidence is insufficient to draw conclusions on the moderating effects of hypertension, diabetes, or renal disease on the effects of sodium reduction interventions on all-cause, CVD, or CHD mortality, CVD- or CHD morbidity, or other longer term CVD outcomes.
- Conflicting evidence from two RCTs is insufficient to allow conclusions to be drawn regarding the moderating impact of overweight or obesity on the effect of sodium reduction on composite CVD outcomes (low RoB).
- Evidence is insufficient, based on one RCT, to allow conclusions to be drawn on whether the effects of sodium reduction on long-term outcomes are moderated by higher dietary potassium.
- Evidence is insufficient, based on two RCTs, to draw conclusions on the moderating effects of potassium-containing salt substitutes on the effects of sodium reduction on long-term outcomes.
Key Question 4. Association Between Dietary Sodium and CVD, CHD, Stroke, and Kidney Disease Morbidity and Mortality, and Between Dietary Sodium Intake and Total Mortality
Conclusions
- Although sodium levels appear to be directly associated with all-cause mortality (low SOE), the shape of this relationship could not be determined (insufficient SOE).
- Evidence is insufficient to assess possible associations of sodium intake levels and risk for CVD, CHD, or stroke morbidity or mortality.
- Evidence is insufficient to assess effects of sex, race/ethnicity, age, or comorbidities on associations between sodium intake status and outcomes of interest.
Sodium and All-Cause Mortality
Key Questions 3 and 4 consider the relationship between sodium intake and all-cause mortality. Only RCTs with follow up of 6 months or longer and observational studies of 1 year or longer were included.
Decreasing dietary sodium reduced the risk for all-cause mortality non-significantly in RCTs, and evidence was considered insufficient to draw a conclusion about this relationship.51, 53, 113, 169, 170, 182, 196 The number and size of studies was relatively small, outcomes were inconsistent and imprecise, and not all studies included mortality as a prespecified outcome and sometimes reported it as an adverse event. Differences in 24-hour urinary sodium excretion of 40 mmol or more showed a trend toward being associated with greater decreases in risk.
Data from prospective cohort studies with follow up times of 1 year or longer support an association between sodium intake based on 24-hour sodium excretion and all-cause mortality, but evidence was insufficient to assess the shape of this relationship or associations.55, 56, 98, 137, 273 At 20 years’ follow up, multivariate analysis of TOHP-I and TOHP-II data showed trends toward a linear dose-response relationship between 24-hour urinary sodium excretion and mortality (for <100 mmol, 100 mmol to <150 mmol, 150 mmol to <200 mmol, and >200 mmol/24 h).281
Too few RCTs assessed the potential moderating effects of sex, race/ethnicity, age, or comorbidities to draw any conclusions. Evidence was insufficient from prospective cohort studies that assessed sodium exposure using 24-hour urinary excretion to assess the potential moderating effects of sex, race/ethnicity, age, or comorbidities of interest.
Sodium and Cardiovascular Disease Mortality
Only two RCTs that met inclusion criteria assessed the effect of sodium reduction on CVD mortality. One small RCT with only 3 years’ follow up found no effect.170 However, a block-randomized institutional trial that assessed the effect of a potassium-containing salt substitute to lower sodium intake found a significant effect of reduced sodium intake on decreasing risk for CVD mortality.182 Evidence from prospective cohort studies was determined to be insufficient on which to base a conclusion regarding CVD mortality. Two cohort studies that conducted 24-hour urinary sodium excretion analyses56, 98 (but had moderate RoB) found inconsistent effects of lower sodium intake and lower sodium-to-potassium ratios, as did studies that estimated 24-hour excretion or conducted dietary intake assessments.35, 40, 116, 129, 134, 136, 141
Sodium and CHD Mortality
No RCTs that met inclusion criteria assessed the effects of sodium reduction on CHD mortality. Two prospective cohort studies that assessed 24-hour urinary sodium excretion reported inconsistent associations of CHD mortality with sodium intake (insufficient evidence on which to base a conclusion).55, 56
Sodium and Stroke
Three RCTs that met inclusion criteria reported on the incidence of stroke, although only one of the studies included stroke risk as a prespecified outcome. None of the studies reported significant differences in stroke risk (low strength of evidence).171, 275, 282 Across prospective cohort studies, insufficient evidence was identified to draw a conclusion on an association with stroke risk for normotensives or those with HTN.40, 43, 56, 98, 129, 134, 141
Sodium and Myocardial Infarction
One RCT that reported on the incidence of MI reported no effect of sodium reduction on risk for MI (insufficient strength of evidence)171. No observational studies that measured 24-hour sodium excretion assessed the association with MI risk.
Sodium and Combined CVD Morbidity and Mortality
Among eight RCTs that met inclusion criteria, sodium reduction had a statistically significant effect on reducing the relative risk for the combined outcome of CVD morbidity and mortality.51, 53, 170, 171, 182, 196, 275, 282 Four prospective cohort studies found no consistent associations between 24-hour urinary sodium excretion and this outcome98, 107, 130, 137 (insufficient evidence to draw a conclusion based on cohort studies).
Sodium and CHD Morbidity and Mortality
No RCTs that met inclusion criteria assessed the effect of sodium reduction on the combined outcomes of CHD morbidity and mortality. Four studies that assessed non-overlapping cohorts found inconsistent associations between 24-hour urinary sodium excretion and this outcome (insufficient evidence).
Sodium and Patients With Any CVD Event
Seven RCTs reported on endpoints that included a CVD outcome or a composite of CVD outcomes. A pooled analysis showed a statistically significant decrease in the relative risk for this outcome with sodium reduction (low strength of evidence because of inconsistent outcomes and extreme imprecision).51, 53, 99, 170, 171, 182, 196 Four prospective cohort studies with moderate RoB included a comparable outcome but evidence was considered insufficient to draw a conclusion.98, 107, 130, 137
Stratified analysis by sex found no differences between males and females in RCTs.
Stratified analysis by race/ethnicity in the two TOHP trials combined found that only the response for white participants was statistically significant (evidence insufficient on which to draw a conclusion).
Stratified analysis by age in one large RCT found a greater benefit of sodium reduction among adults in the 60 to 69 age group than among older adults. None of these findings have sufficient strength of evidence to permit conclusions.
Sodium and Mean Difference in eGFR and Number of Patients With End Stage Renal Disease
No RCTs that met inclusion criteria reported on these outcomes. One cohort study found no association between sodium excretion and mean difference in eGFR. Another cohort study found that lower sodium excretion was associated with a slower decline in kidney function among individuals with HTN. Evidence was considered insufficient to draw any conclusions on sodium intake and renal outcomes.
Sodium and Left Ventricular Hypertrophy
Two RCTs reported no effect of sodium reduction on this outcome. No prospective cohort studies that met inclusion criteria reported on this outcome. Evidence is insufficient to draw conclusions from either RCTs or prospective cohort studies.
Key Question 5. Effect of Interventions To Increase Potassium Intake on Blood Pressure and Kidney Stones
Conclusions
- Increased potassium intake from dietary supplements reduces blood pressure in adults (moderate SoE based on 10 parallel RCTs and 8 crossover RCTs). However the effect is limited to studies of adults with prehypertension or hypertension (moderate SoE). Studies of adults with normal BP did not show evidence that increased potassium intake decreases blood pressure in this group (3 RCTs; low SoE)
- Evidence does not support an effect of increasing potassium intake through changes in food intake alone on BP in adults (low SoE, based on 4 RCTs).
- Evidence is insufficient to support a conclusion regarding the effect of increasing potassium intake on kidney stone formation (one RCT).
Key Question 6. Association Between Potassium Intake and Blood Pressure and Kidney Stones
Conclusions
- Higher potassium intake is not consistently associated with lower adjusted BP in cohort studies of adults (six RCTs; low SoE based on inconsistent findings and studies with high RoB).
- Higher potassium intake appears to be associated with a lower risk for kidney stones in cohort studies of adults (low SoE, based on four prospective cohorts reported in two publications with high RoB).
Potassium and Blood Pressure
Increased potassium intake significantly decreased systolic (by more than 5 mm Hg) and diastolic BP (by more than 3 mm Hg) in pooled analyses of 18 RCTs (moderate strength of evidence) but the evidence is based predominantly on studies that employed dietary supplements.48, 51, 60, 65, 70–74, 89, 94, 110, 125, 126, 236, 264, 277, 280 Prospective cohort studies and multivariate analyses found inconsistent associations between urinary potassium excretion and BP, and three additional prospective cohort studies found inconsistent associations with potassium intake based on dietary assessment.48, 51, 60, 65, 70–74, 89, 94, 110, 125, 126, 236, 264, 277, 280
Evidence was insufficient to determine whether the effect of potassium was moderated by sex, race/ethnicity, or age, or by baseline hypertensive status.
Potassium and Incident Hypertension
No RCTs that met inclusion criteria assessed the effect of increased potassium intake on incident HTN compared with placebo. Among five prospective cohort studies, one study found a significant association between the lowest quantile of potassium excretion and higher risk for HTN, whereas four studies found inconsistent associations with dietary potassium; this evidence was considered insufficient on which to base a conclusion.37, 76, 120, 145, 274
Potassium and Percent Participants at Blood Pressure Goal
No RCTs that met inclusion criteria assessed the effect of increased potassium intake on potassium compared with placebo. No prospective cohort studies assessed this outcome.
Potassium and Kidney Stones
One RCT that met inclusion criteria reported that potassium (citrate) supplementation for 3 years significantly decreased the risk for kidney stone recurrence compared with placebo (insufficient strength of evidence).176 Multivariate analysis of a large RCT dataset found only a nonsignificant association between dietary potassium and kidney stone risk. Across three large prospective cohort studies assessed together, dietary potassium intake was inversely associated with risk for incidence kidney stones (low strength of evidence; high RoB based on intake assessment).67, 153
Key Question 7. Effect of Interventions To Increase Potassium Intake on CVD and Kidney Disease Morbidity and Mortality, and on Total Mortality
- Evidence was insufficient to address this question (one RCT).182
Key Question 8. Association Between Dietary Potassium Intake and CVD, CHD, Stroke, and Kidney Disease Morbidity and Mortality, and Between Dietary Potassium and Total Mortality
- Evidence is insufficient to identify associations of potassium intake with long-term chronic disease outcomes of interest, primarily due to the limitations in the potassium intake assessments.
Potassium and All-Cause Mortality
One RCT reported that the use of a potassium-containing salt substitute in place of sodium chloride significantly reduced all-cause mortality at 2 ½ years (insufficient evidence).
Prospective cohort studies were inconsistent in their assessments of potassium status and all-cause mortality: four studies showed inconsistent associations between urinary potassium excretion and all-cause mortality, whereas three studies showed consistent associations between dietary potassium intake and adjusted all-cause mortality.55, 100, 116, 129, 137, 140, 141
Potassium and CVD Mortality
The RCT described above reported that the potassium-containing salt substitute produced a significant decrease in age-adjusted CVD mortality compared with usual diet (insufficient evidence).
Prospective cohort studies reported no consistent association between potassium status and CVD mortality. Two of three cohort studies reported inverse associations between dietary potassium intake and CVD mortality, whereas two studies found no association between estimated 24-hour urinary excretion and CVD mortality.116, 129, 141
Potassium and CHD Mortality
The salt substitute study also reported a significant decrease in age-adjusted CHD mortality at 2 ½ years (insufficient evidence).
Potassium status was inversely associated with CHD mortality risk across two cohort studies, one of which assessed 24-hour urinary potassium excretion (insufficient evidence).55, 116
Potassium and Stroke
No RCTs assessed the effect of increased potassium intake on the risk for stroke.
Among thirteen prospective cohort studies that assessed associations of potassium status with stroke risk among healthy cohorts, findings were inconsistent and could not be predicted by method used to assess potassium status (insufficient evidence).58, 59, 62, 63, 69, 78, 103, 108, 128, 129, 137, 140, 141
Potassium and Myocardial Infarction
No RCTs assessed the effect of increased potassium intake on the risk for MI.
Two prospective cohort studies found no association between potassium status and risk for MI (insufficient evidence).129, 141
Potassium and Combined CVD Morbidity and Mortality
No RCTs assessed the effect of potassium supplementation on the combined outcome of CVD morbidity and mortality.
No significant associations were found between urinary potassium levels and combined CVD morbidity and mortality outcomes across three prospective cohort studies (insufficient evidence).
Potassium and Combined CHD Morbidity and Mortality
No RCTs assessed the effect of increased potassium intake on the combined outcome of CHD morbidity and mortality.
Two prospective cohort studies showed inconsistent associations between 24-hour urinary potassium excretion and combined CHD morbidity and mortality outcomes (insufficient evidence).55, 137
Potassium and Any CVD Outcomes
No RCTs assessed the effect of increased potassium intake on “any CVD outcomes” as reported by authors.
One cohort study reported no association between potassium intake and a combination of outcomes that included left ventricular hypertrophy (insufficient evidence).
Potassium and Renal Disease
No RCTs assessed the effect of increased potassium intake on risk for renal disease.
One prospective cohort study assessed the association between potassium status and renal outcomes. The study found that lower urinary potassium excretion was associated with an increased risk of developing chronic kidney disease (lower eGFR), but evidence is insufficient to draw a conclusion.
Summary of Findings in Relation to What Is Already Known
Since the Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate was published in 2005, a number of systematic reviews have been conducted on the effects of sodium intake and sodium reduction on BP, as well as CVD and CHD outcomes. We briefly review our findings in light of the findings of the most recent reviews. Aburto and colleagues conducted reviews on the relationship between sodium and potassium intake and BP, CVD, CHD, and stroke from observational studies and the effects of sodium reduction and increased potassium intake as reported in RCTs; these reviews were sponsored by the WHO in support of their current guidelines. The WHO review on sodium and BP, which included 37 RCTs, found significant beneficial effects of interventions to reduce sodium on blood pressure in adults and children but no difference between very low- (defined as a target of 50mmol/d) and low- (defined as a target of 100mmol/d) sodium interventions.4, 296 Our report found similar effects of sodium reduction on BP in adults, but only statistically non-significant beneficial effects in children. When we conducted a sensitivity analysis that omitted high- and unclear RoB studies, we found that when only low- and moderate-RoB studies were pooled, sodium reduction resulted in a statistically significant decrease in diastolic BP in children (the decrease in systolic BP remained non-significant). The WHO report did not assess effects of sodium reduction on incident hypertension or achievement of specific BP goals. The inclusion criteria for our report and those of the WHO report differed in several ways. Our review included sodium reduction RCTs regardless of achieved sodium excretion, whereas the WHO review excluded RCTs with a mean difference in achieved sodium excretion of less than 40 mmol/d; although excluding such studies might be expected to increase pooled effect sizes, visual inspection of the forest plots for our analyses does not appear to show strong associations between sodium intake and BP outcomes across all RCTs. The WHO review also included abstracts, whereas our report included only full, peer-reviewed publications.
More recently, Graudal and colleagues systematically reviewed the trial literature on sodium reduction and BP and reached similar conclusions to those of Aburto and our review; the Graudal review excluded only trials with a duration of less than 4 days, resulting in a larger number of included trials.297 Our current review also corroborates the findings of the Graudal review regarding a larger effect of sodium reduction on individuals with HTN than on normotensive individuals.
The WHO report found no effect of sodium reduction on plasma epinephrine, norepinephrine, blood lipids, or kidney function, as measured by serum creatinine and creatinine clearance; four studies that met our inclusion criteria corroborated the apparent absence of effect of sodium reduction on blood lipids (reported as adverse effects or primary outcomes), but no studies met our inclusion criteria for assessing changes in kidney function or catecholamines. In contrast, the Graudal review reported significant increases in cholesterol and triglycerides, possibly due to the much shorter followup of some included studies.297
Several recent systematic reviews also appraised the evidence linking sodium with all-cause mortality, CVD, CHD, or stroke.
A 2014 systematic review by Adler and colleagues that reviewed eight RCTs assessing effects of sodium reduction on these longer-term outcomes reported no effect on all-cause mortality.
Graudal and colleagues (2014) conducted a meta-analysis of cohort studies that assessed the association between sodium exposures and all-cause mortality: They reported an increased mortality risk at both low- and high intakes of sodium (which they referred to as a “U-shaped curve”).298 The review included only observational studies, and the findings could be explained by errors in estimation of sodium intake at the lower- or the upper end as well as reverse causality..
Our review of RCTs that reported on the effects of sodium reduction on all-cause mortality found a non-statistically significant decrease in the risk for all-cause mortality. Our review of prospective cohort studies found an association between higher intakes of sodium and increased risk but insufficient evidence to draw any conclusions regarding the shape of the curve. The methods used to estimate sodium intake varied across the prospective cohort studies, and few used multiple 24-hour sodium excretion measures with validation to ensure complete collection; in addition, these studies could not rule out reverse causation: In sodium studies, reverse causality arises when study participants with medical morbidity have reduced their sodium intake on medical advice or because their illness has resulted in decreased food consumption.
Our current review also adds to the evidence by identifying an effect of sodium reduction on reducing combined CVD morbidity and mortality across RCTs. The review by Adler found similar effects on CVD mortality and morbidity; they largely attributed the observed effect on mortality to one study that implemented use of a potassium salt substitute to reduce sodium intake.182 We also reported statistically significant effects of sodium reduction on a composite of any CVD outcomes. The Adler review included one RCT299 that we excluded, as it was a multicomponent intervention that did not control for other dietary changes (the remaining RCTs were included in our review).15 The WHO also reviewed the evidence linking sodium with CVD, CHD, and stroke; that report, which included 14 prospective cohort studies and five RCTs, found sufficient evidence only to conclude (based on the evidence from cohort studies) that increased sodium intake was linked to increased risk for stroke, stroke mortality, and CHD mortality.4
We identified few studies on individuals with chronic kidney disease, and no studies that met our inclusion criteria addressed renal endpoints. A Cochrane review by McMahon and colleagues appraised the evidence on effects of sodium reduction on cardiovascular outcomes in persons with kidney disease.300 However like our review, they identified no studies with long enough follow up to assess long term chronic disease outcomes. Instead they reported only on studies that assessed effects of sodium reduction on BP outcomes in persons with kidney disease, reporting that sodium reduction decreased systolic BP and diastolic BP in these studies.. Across the studies that met our inclusion criteria, we also noted that sodium reduction generally decreased BP; however, we determined that the populations were too dissimilar (based on comorbidities) to permit studies to be pooled.
Aburto and colleagues subsequently reviewed the evidence for an association of potassium intake with BP, HTN, and CVD, for the WHO, concluding that higher potassium intake was associated with reduced BP in individuals with HTN but not in normotensive persons.301 That report found insufficient evidence to draw conclusions regarding the association of potassium intake with risk for CVD or CHD morbidity or mortality. Our current review confirmed the association of potassium with BP lowering, by identifying RCTs that assessed the effects of increased potassium intake and also extended their finding to healthy populations. We found insufficient evidence to draw any conclusions on the effects of increased potassium intake on incident HTN, and like the WHO review, we identified insufficient evidence to draw conclusions regarding the effects of increased potassium intake on CVD/CHD morbidity or mortality. In addition, the beneficial effects of increased potassium intake on BP were not reflected in any association between (urinary or dietary) potassium intake and BP.
Limitations of the Evidence Base
The purpose of this review was to assess the evidence for the intermediate and clinical health effects of reduced sodium intake, mainly as reflected in reduced 24-hour urinary sodium excretion. We did not assess the evidence regarding the most effective intervention design(s).
Most RCTs demonstrated an overall low or moderate RoB. However, a number of studies omitted many details of study design and conflict of interest, so actual RoB was unclear for some items. Nearly all observational (prospective cohort) studies that met inclusion criteria relied on single 24-hour urinary excretion measures, single or 2-day dietary recall without 24-hour urinary excretion, estimated sodium excretion to assess status, or food frequency questionnaires. The implications of assessment of sodium and potassium status in observational studies are discussed further below. Additional limitations are listed here, organized by a PICOTSS framework.
Populations
- Few to no studies conducted subgroup analyses by sex, age, race/ethnicity, or comorbidities such as HTN.
- RCTs may enroll individuals who are more motivated than average, although compliance across studies (usually based on 24-hour sodium excretion) does not necessarily support this possibility.
- Studies defined prehypertension and mild-moderate HTN differently or not at all, and some studies included individuals with pre- or mild HTN along with individuals with more advanced HTN.
- Although most RCTs either prohibited or required use of antihypertensive medications or withdrew participants from medications at baseline and assessed need to resume their use, at least 25 percent of studies did not consider use of these medications or allowed participants to remain on medications but did not account for their use. Studies that enrolled only participants taking antihypertensive medications usually did not control for the class of medication, thus potentially introducing a confounding factor. Concurrent use of some antihypertensive medications could have masked the potential effects of a reduced sodium diet.
- Observational studies had limited ability to control for pre-existing health conditions at study baseline that might have resulted in decreased sodium intakes, contributing to potentially spurious associations of lower sodium intakes with morbidity or mortality outcomes of interest.
- Observational studies may have residual confounding, as they could not adjust for all factors that may increase risk for HTN, CVD, CHD outcomes.
Interventions/Exposures
- RCTs used widely varying methods to achieve different sodium intake levels, and most RCTs actually employ multicomponent lifestyle interventions or at least multicomponent dietary interventions; thus not all changes in outcomes of interest might be attributable to reduced sodium or increased potassium intake. The potential implication of this variation in background diet for study findings is highlighted by the findings of the DASH Sodium trial, which showed that at each dietary sodium level, mean BP was higher (2.2 to 5.9 mm Hg) among control diet participants than among the DASH diet groups, that the decreases in BP achieved with decreasing sodium intake were greater for those on the control diet than for those on the DASH diet, but that nevertheless, the low-sodium DASH participants achieved the greatest reduction in BP overall49 Thus a diet that includes more fruits and vegetables (and, as a result, more vitamins, minerals, and fiber, and less saturated fat), as well as whole grains, and low-fat dairy has effects on BP that are independent of sodium intake.49, 302 Thus, a diet that includes more fruits and vegetables (and, as a result, more vitamins, minerals, and fiber, and less saturated fat) has effects on BP that are independent of sodium intake.
- Only a small number of studies assessed effects of natural experiments, or community- or government-level interventions.
- Many RCTs failed to report intended goals of the intervention (e.g., achieving 70 mmol/d urinary sodium excretion or a difference between the intervention group and the control group of 40 mmol/d or more).
- Effectiveness of behavioral/lifestyle interventions in reducing sodium intake may be affected by unmeasured or unreported factors, such as intensity of counseling.
- Few prospective cohort studies used multiple 24-hour urinary excretion analyses, although increasing evidence demonstrates that multiple, non-consecutive 24-hour urinary sodium excretion measurements needs to be used as the indicator of exposure in observational studies.19, 303 Thus nearly all included prospective cohort studies had high risk for both systematic (24-h urine collections without evidence of quality control measures, spot or overnight urine collections, FFQ, 24-h recalls, and food records) and random error (e.g., single 24-hour or spot urine collections or single-day food recalls).
- Inconsistencies in apparent sodium intakes in studies over time may be attributable to changes in assessment methods used.
- Both RCTs and prospective cohort studies vary widely in baseline sodium intake. Most RCTs employed 24-hour urinary sodium excretion as a measure of compliance with the intervention. However, differences in baseline intake could affect the potential to achieve sodium reduction goals through dietary interventions and introduce a source of heterogeneity among prospective cohort studies. Evidence in support of this idea is presented by a recent post hoc assessment of data from the DASH Sodium trial found that reducing sodium intakes in the context of the control or the DASH diet were associated with progressively greater reductions in BP with higher baseline BP (through baseline systolic BP of 150 mm Hg or higher).290
- Wide variation in achieved intakes across RCTs introduces another potential source of heterogeneity and calls into question whether differences in achieved sodium intake can accurately predict changes in outcomes of interest.
- Few RCTs reported sodium-to-potassium ratios. Potentially related to this observation, studies that employed potassium-containing salt substitutes to reduce sodium intake or tested the effects of potassium supplements tended to find no consistent effects on sodium excretion.
- Few studies employ food-based interventions to assess the effects of increasing potassium intake. Those that do use dietary interventions do not consistently control for differences in other micronutrients, carbohydrates, and fiber.
- Potassium supplementation studies range from about 15 to 120 mmol/d in the amounts provided (average intakes from food range from 50 to 150 mmol/d and the current AI for adults is 120 mmol/d), introducing a potential source of heterogeneity across studies.
Comparators
- Confounding in dietary intervention studies (for example, adoption of use of salt substitutes or other salt reduction practices by control groups) was difficult to control or measure, and blinding had limited effectiveness when the comparison group consumed their usual diet (most dietary intervention studies that relied on counseling reported that participants were not blinded).
- Studies with usual diet as the control may not be comparable with studies that impose a low-sodium diet on all participants and then achieve differences in sodium intake using sodium tablets to mimic usual sodium intake.
Outcomes
- Studies defined HTN, CVD, and CHD outcomes differently.
- Few RCTs assessed the effect of sodium reduction or increased potassium intake on the risk for incident HTN as an outcome.
- Of the small number of studies that assessed long term CVD outcomes, few assessed these as primary or even prespecified outcomes, were not powered to assess them as prespecified outcomes, and reported them instead as adverse events.
- Little research assesses effects of sodium reduction on CHD outcomes.
Timing/Duration
- Few to no RCTs were identified that assessed longer-term clinical outcomes of most interest: RCTs seldom had adequate duration of interventions or follow up to assess longer-term outcomes.
- Renal outcomes, including kidney stones, require longer follow ups to observe potential effects of interventions than were employed in any of the studies identified.
- Long-term outcomes resulting from brief interventions may not show any effects.
Setting
- RCTs in clinical research settings are resource intensive and may have limited practical application. RCTs in populations confined to residential settings such as long-term care facilities, schools, or prisons may provide more useful results in terms of assessing outcomes but still fail to address the potential effects of voluntary efforts (individual or community) to reduce dietary sodium intake.
Study Design
- Observational studies predominated for long term chronic disease outcomes.
- As described, RCTs with parallel arm designs present challenges that are difficult to overcome regarding blinding, allocation concealment, and contamination.
- RCTs with crossover designs may provide some advantages, but existing crossover trials seldom describe washout periods or assess potential carryover effects of short (or no) washouts.
Limitations of This Review
Since the inclusion of participants with pre-existing conditions could confound attempts to link the outcomes of interest with changes in sodium intake, studies that enrolled sick participants were excluded from the affected analyses. For example, studies of patients with CVD were excluded from analysis of risk for CVD morbidity, but not analysis of CVD mortality, and studies of patients with cancer, HIV/AIDS, and end stage renal disease were excluded from all analyses.
We did not take use of antihypertensive medications into account in our analyses of RCT data, primarily because studies did not consistently report or adjust for such use. Thus, we could not eliminate the possibility that potential effects of reduced sodium might be masked by the effects of such medications.
Similarly, we did not conduct sensitivity analyses to assess the effects of the methods used to measure blood pressure, which may strongly affect outcomes. The duration of interventions or exposures is likely critical. For that reason, we set strict lower limits on the durations of studies we included, especially for long term clinical outcomes. However, we did not attempt to assess the effects of intervention or exposure duration on outcomes, mainly because we identified too few studies to enable realistic comparisons.
We excluded crossover studies that did not describe the use of washout or duration of washout and did not describe a process to assess the possible effects of carryover. As a result, we excluded one dose-response study, the findings of which supported the conclusion that decreasing sodium intake decreases blood pressure.304 However, some evidence suggests potential carryover may need to be considered.23
Research Gaps Identified by This Review
In light of the large body of evidence on the effects of sodium reduction on blood pressure in healthy adults and those with hypertension, the determination that the effect of reducing sodium intake on blood pressure is supported by moderate but not high strength evidence is attributable to inconsistency in the direction of study findings and to study heterogeneity. Sensitivity analyses that omitted high- and unclear RoB studies did not appreciably alter consistency, heterogeneity, or effect sizes; thus, other factors—such as differing participant comorbidities, intervention design or blood pressure measurement methods—may be contributing to the variation.
Studies to assess whether those with HTN may benefit more or less from reduced dietary sodium than those with normal blood pressure showed greater benefits for those with HTN, but at least one fourth of studies that enroll adults with HTN do not report controlling for use of antihypertensive medication.
Among studies that met inclusion criteria, only a small number directly compared effects of sodium reduction on participants with normal blood pressure with those on participants with HTN. Studies to assess the benefits of reducing dietary sodium for those with normal blood pressure were fewer in number than studies of populations with HTN, and some studies of normotensive populations included individuals with high normal blood pressure.
Few studies that met inclusion criteria directly compared the effects of sodium reduction on men with those on women, the effects on one racial/ethnic group with those on other racial/ethnic groups, and the effects among different age groups. Few studies designed to determine whether dietary interventions reduce blood pressure among younger individuals—both children, adolescents, and young adult—met inclusion criteria.
Few trials that met inclusion criteria assessed the effects of sodium reduction or increased potassium intake on CVD, CHD, stroke, or renal outcomes, including the effect of increasing potassium intake on the incidence of kidney stones. Most dietary intervention studies to reduce sodium (or increase potassium) from food sources involved counseling, making it difficult to isolate the effects of sodium reduction or increased potassium intake, either because of poor adherence or because of the challenge of ruling out alterations in intake of other nutrients.
Few trials that met inclusion criteria assessed the effects of sodium reduction or increased potassium intake on CVD, CHD, stroke, or renal outcomes, including the effect of increasing potassium intake on the incidence of kidney stones.
Conclusions
We undertook this systematic review to appraise the evidence from trials regarding the effects of dietary sodium reduction and/or increased potassium intake on blood pressure and risk for cardiovascular diseases—as well as the evidence on associations of dietary sodium and potassium with blood pressure and cardiovascular diseases. This review finds that interventions that reduce dietary sodium intake (including those that use potassium-containing salt substitutes in the diet) reduce blood pressure in both normotensive adults and, to a greater extent, those with hypertension. Interventions to reduce sodium intake increase the likelihood of reaching a prespecified blood pressure goal and may decrease the incidence of hypertension in adults, in agreement with prospective cohort studies, which show that higher sodium intakes may be associated with greater risk for hypertension.
Increasing potassium intake via potassium supplements significantly decreases blood pressure, but the effects of increasing potassium intake through food alone remain unclear.
Interventions to assess the effects of reducing sodium intake on the risk for all-cause mortality are small in number and provide an insufficient basis on which to draw a conclusion. Prospective cohort studies suggest sodium intake may be associated with all-cause mortality. Findings from randomized controlled trials also suggest that interventions to reduce sodium intake may decrease the risk for composite measures of cardiovascular disease outcomes.
- Discussion - Sodium and Potassium Intake: Effects on Chronic Disease Outcomes an...Discussion - Sodium and Potassium Intake: Effects on Chronic Disease Outcomes and Risks
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