Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies

Abstract

Background: The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood pressure. However, non-linear patterns, dose-response associations, and sex differences in the relationship between sodium and potassium intakes and overall and cause-specific mortality remain to be elucidated and a comprehensive examination is lacking. Our study objective was to determine whether intake of sodium and potassium and the sodium-potassium ratio are associated with overall and cause-specific mortality in men and women.

Methods: We conducted a prospective analysis of 237,036 men and 179,068 women in the National Institutes of Health-AARP Diet and Health Study. Multivariable-adjusted Cox proportional hazard regression models were utilized to calculate hazard ratios. A systematic review and meta-analysis of cohort studies was also conducted.

Results: During 6,009,748 person-years of follow-up, there were 77,614 deaths, 49,297 among men and 28,317 among women. Adjusting for other risk factors, we found a significant positive association between higher sodium intake (≥ 2,000 mg/d) and increased overall and CVD mortality (overall mortality, fifth versus lowest quintile, men and women HRs = 1.06 and 1.10, P_nonlinearity < 0.0001; CVD mortality, fifth versus lowest quintile, HRs = 1.07 and 1.21, P_nonlinearity = 0.0002 and 0.01). Higher potassium intake and a lower sodium-potassium ratio were associated with a reduced mortality, with women showing stronger associations (overall mortality, fifth versus lowest quintile, HRs for potassium = 0.96 and 0.82, and HRs for the sodium-potassium ratio = 1.09 and 1.23, for men and women, respectively; P_nonlinearity < 0.05 and both P for interaction ≤ 0.0006). The overall mortality associations with intake of sodium, potassium and the sodium-potassium ratio were generally similar across population risk factor subgroups with the exception that the inverse potassium-mortality association was stronger in men with lower body mass index or fruit consumption (P_interaction < 0.0004). The updated meta-analysis of cohort studies based on 42 risk estimates, 2,085,904 participants, and 80,085 CVD events yielded very similar results (highest versus lowest sodium categories, pooled relative risk for CVD events = 1.13, 95% CI: 1.06-1.20; P_nonlinearity < 0.001).

Conclusions: Our study demonstrates significant positive associations between daily sodium intake (within the range of sodium intake between 2,000 and 7,500 mg/d), the sodium-potassium ratio, and risk of CVD and overall mortality, with women having stronger sodium-potassium ratio-mortality associations than men, and with the meta-analysis providing compelling support for the CVD associations. These data may suggest decreasing sodium intake and increasing potassium intake as means to improve health and longevity, and our data pointing to a sex difference in the potassium-mortality and sodium-potassium ratio-mortality relationships provide additional evidence relevant to current dietary guidelines for the general adult population.

Systematic review registration: PROSPERO Identifier: CRD42022331618.

Keywords: Cause-specific mortality; Multivariate analysis; Overall mortality; Sex-specific; Sodium and potassium intake; Systematic review and meta-analysis.

Fig. 1

a Sex Stratified Associations Between Sodium Intake and Overall and Cause-specific Mortality in Multivariable-Adjusted Cubic Spline Regression Models. Analyses were adjusted for age at baseline, BMI, alcohol consumption, smoking status (never, former, current or missing), physical activity, race or ethnic group, education, marital status, diabetes (yes vs. no), health status, vitamin supplement use, total energy intake, and the Healthy Eating Index 2015 (HEI-2015) score excluding the sodium component. For women, the risk estimates were additionally adjusted for postmenopausal hormone therapy (yes vs. no). The solid line denotes the HR of overall mortality according to sodium intake with a four-knot cubic spline selected at the 5th, 25th, 75th, and 95th percentiles of intake, dashed lines and shaded areas represent the 95% confidence intervals, blue indicates men and red indicates women. b Sex Stratified Associations Between Potassium Intake and Overall and Cause-specific Mortality in Multivariable-Adjusted Cubic Spline Regression Models. Analyses were adjusted for age at baseline, BMI, alcohol consumption, smoking status (never, former, current or missing), physical activity, race or ethnic group, education, marital status, diabetes (yes vs. no), health status, vitamin supplement use, total energy intake, and the Healthy Eating Index 2015 (HEI-2015) score components of sodium, seafood and plant protein, saturated fat, fatty acids and refined grains. For women, the risk estimates were additionally adjusted for postmenopausal hormone therapy (yes vs. no). The solid line denotes the HR of overall mortality according to potassium intake with a four-knot cubic spline selected at the 5th, 25th, 75th, and 95th percentiles of intake, dashed lines and shaded areas represent the 95% confidence intervals, blue indicates men and red indicates women. c Sex Stratified Associations Between Sodium–Potassium Ratio and Overall and Cause-specific Mortality in Multivariable-Adjusted Cubic Spline Regression Models. Analyses were adjusted for age at baseline, BMI, alcohol consumption, smoking status (never, former, current or missing), physical activity, race or ethnic group, education, marital status, diabetes (yes vs. no), health status, vitamin supplement use, total energy intake, and the Healthy Eating Index 2015 (HEI-2015) score components of seafood and plant protein, saturated fat, fatty acids and refined grains. For women, the risk estimates were additionally adjusted for postmenopausal hormone therapy (yes vs. no). The solid line denotes the HR of overall mortality according to sodium–potassium ratio with a four-knot cubic spline selected at the 5th, 25th, 75th, and 95th percentiles of intake, dashed lines and shaded areas represent the 95% confidence intervals, blue indicates men and red indicates women

Fig. 2

a Associations Between Intakes of Sodium, Potassium, Sodium–Potassium Ratio and Overall and Cause-specific Mortality in Multivariable-Adjusted Models Stratified by Selected Characteristics Among Men. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall mortality comparing the highest versus the lowest quintile. Multivariable analyses were adjusted for age at baseline, BMI, alcohol consumption, smoking status (never, former, current or missing), physical activity, race or ethnic group, education, marital status, diabetes (yes vs. no), health status, vitamin supplement use, and total energy intake. For sodium intake, models were further adjusted for Healthy Eating Index 2015 (HEI-2015) score excluding the sodium component; for potassium intake and the sodium–potassium ratio, models were additionally adjusted for HEI-2015 components for sodium (potassium model only), seafood and plant protein, saturated fat, fatty acids and refined grains. P for interaction was examined by the likelihood ratio test, entering the cross-product term of exposure factors (categories) and the stratification variables (categorized as shown), all as ordinal variables, to the Cox proportional hazard regression model. b Associations Between Intakes of Sodium, Potassium, Sodium–Potassium Ratio and Overall and Cause-specific Mortality in Multivariable-Adjusted Models Stratified by Selected Characteristics Among Women. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall mortality comparing the highest versus the lowest quintile. Multivariable analyses were adjusted for age at baseline, BMI, alcohol consumption, smoking status (never, former, current or missing), physical activity, race or ethnic group, education, marital status, diabetes (yes vs. no), health status, postmenopausal hormone therapy (yes vs. no), vitamin supplement use, and total energy intake. For sodium intake, models were additionally adjusted for Healthy Eating Index 2015 (HEI-2015) score excluding the sodium component; for potassium intake and the sodium–potassium ratio, models were additionally adjusted for HEI-2015 components for sodium (potassium model only), seafood and plant protein, saturated fat, fatty acids and refined grains. P for interaction was examined by the likelihood ratio test, entering the cross-product term of exposure factors (categories) and the stratification variables (categorized as shown), all as ordinal variables, to the Cox proportional hazard regression model

Fig. 3

Association of Sodium Intake with Cardiovascular Disease Risk for the Highest Versus Lowest Intake Category Using Random-Effects Meta-Analysis According to Baseline Only and Repeated Assessment of Sodium Intake (P for interaction = 0.027). Squares represent study-specific relative risks, with their areas being proportional to the specific-study weight in the meta-analysis. Horizontal lines denote 95% Cis. I² refers to the proportion of heterogeneity among studies. Abbreviations: AF = atrial fibrillation; CHD = coronary heart disease; CI = confidence interval; CVD = cardiovascular disease; HF = heart failure

Fig. 4

Association Between Sodium Intake and Risk of Cardiovascular Disease Using a Cubic-Restricted Spline Model in the Dose–Response Meta-Analysis Based on 29 Published Studies. The solid line represents the relative risk of cardiovascular disease according to sodium intake, and the dashed lines denote the 95% confidence intervals (P_nonlinearity < 0.001). The spline was computed on the basis of three knots selected at 5^th, 50^th, 95^th percentiles of sodium intake, and the red line depicts the sodium intake of 2,300 mg/day. The analysis included 2,056,043 participants from 29 cohort studies with 66,526 CVD events