Urinary Sodium and Potassium Excretion, Mortality and Cardiovascular Events

Dr. Rikka BanayatDr. Joana ThomasDr. Aasems Jacob

Sodium intake - to restrict or not?

Global Sodium Intake◎ Mean global sodium intake is 3.95 grams/day

◎ WHO recommended limit: 2 grams/day

◎ Intake in men ~10% higher

◎ Highest in East Asia, Central Asia, Eastern Europe (mean >4.2

grams/day)

◎ North America, Western Europe, Australia/New Zealand = 3.4

to 3.8 grams/day

◎ Sub-Saharan Africa and Latin America = <3.3 grams/day

John Powles Saman Fahimi, et al. Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open 2013;3:e003733

Global Sodium Intake◎ European and North American countries - 75% of

sodium intake is from manufactured foods

◎ UK and US - Cereals and baked goods were the single largest contributor to dietary sodium intake

◎ Japan and China - salt added at home and soy sauce were the largest sources

Brown IJ, Tzoulaki I, Candeias V, Elliott P. Salt intakes around the world: implications for public health. Int J Epidemiol. 2009 Jun;38(3):791-813.

How much sodium is in table salt???◎Sodium chloride or table salt is approximately 40% sodium

◎ 1 tsp salt (6 grams)= 2300 mg sodium

http://sodiumbreakup.heart.org/

How much sodium should I eat per day?

◎AHA recommendations:Lower sodium intake (Level I)

○Consume no more than 2,400 mg/day of sodium (Level IIa)

○Further reduction of sodium intake to 1,500 mg/day is desirable since it is associated with an even greater reduction in BP (Level IIa)

○Reduce sodium intake by at least 1,000 mg/day since that will lower BP, even if the desired daily sodium intake is not yet achieved (Level IIa)

Sodium intake and HypertensionEffect of longer-term modest salt reduction on blood pressure.He FJ1, Li J, Macgregor GA. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD004937

◎ A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group.

◎ Significant association between the reduction in 24-h urinary sodium and the fall in systolic BP, indicating the greater the reduction in salt intake, the greater the fall in systolic BP.

◎ The current recommendations to reduce salt intake from 9-12 to 5-6 g/d will have a major effect on BP, but are not ideal. A further reduction to 3 g/d will have a greater effect and should become the long term target for population salt intake.

Sodium intake and HypertensionEffect of lower sodium intake on health: systematic review and meta-analyses. Aburto NJ, Ziolkovska A, Hooper L, Elliott P, Cappuccio FP. BMJ 2013;346:f1326.

◎ Reduced sodium intake reduces blood pressure and has no adverse effect on blood lipids, catecholamine levels or renal function

◎ There were insufficient randomized controlled trials to assess the effects of reduced sodium intake on mortality and morbidity.

◎The associations in cohort studies between sodium intake and all cause mortality, incident fatal and non-fatal cardiovascular disease, and coronary heart disease were non-significant

Sodium Intake and Cardiovascular DiseaseCompared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis.Graudal N, Jürgens G, Baslund B, Alderman MH. Am J Hypertens. 2014 Sep;27(9):1129-37.

◎ The objective was to investigate the incidence of all-cause mortality (ACM) and cardiovascular disease events (CVDEs) in populations exposed to dietary intakes of low sodium (<115 mmol), usual sodium (low usual sodium: 115-165 mmol; high usual sodium: 166-215 mmol), and high sodium (>215 mmol).

◎ Data from 23 cohort studies and 2 follow-up studies of RCTs (n = 274,683) showed that the risks of ACM and CVDEs were decreased in usual sodium vs. low sodium intake and increased in high sodium vs. usual sodium intake

◎Within the usual sodium intake range, the number of events was stable

◎Both low sodium intakes and high sodium intakes are associated with increased mortality

Sodium Intake and Cardiovascular DiseaseSodium excretion and risk of developing coronary heart disease.Joosten MM1, Gansevoort RT, Mukamal KJ, Circulation. 2014 Mar 11;129(10):1121-8.

◎In the overall population, there was no association between sodium excretion and risk of CHD.

◎Higher sodium excretion was associated with an increased CHD risk among subjects with increased NT-proBNP concentrations or with hypertension.

Sodium Intake and Cardiovascular DiseaseFatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium ExcretionKatarzyna Stolarz-Skrzypek, MD, PhD; Tatiana Kuznetsova, MD, et al.JAMA. 2011;305(17):1777-1785.

◎In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications.

◎Lower sodium excretion was associated with higher CVD mortality.

Sodium Consumption and MortalityGlobal Sodium Consumption and Death from Cardiovascular CausesDariush Mozaffarian, M.D., Dr.P.H., et al. N Engl J Med 2014

◎1.65 million deaths from cardiovascular causes that occurred in 2010 were attributed to sodium consumption above a reference level of 2.0 g per day.

Sodium, Potassium and Cardiovascular DiseaseUrinary Sodium and Potassium Excretion and Risk of Cardiovascular EventsMartin J. O'Donnell, MB, PhD; Salim Yusuf, et al. JAMA. 2011;306(20):2229-2238.

◎In patients with established CV disease or DM, compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF.

◎Higher estimated potassium excretion was associated with a reduced risk of stroke.

Potassium and Cardiovascular DiseaseEffect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses.Aburto NJ, Hanson S, Gutierrez H. BMJ. 2013 Apr 3;346

◎Increased potassium intake reduced systolic blood pressure by 3.49 mm Hg and diastolic blood pressure by 1.96 mm Hg in adults, an effect seen in people with hypertension but not in those without hypertension.

◎Systolic blood pressure was reduced by 7.16 mm Hg when the higher potassium intake was 90-120 mmol/day, without any dose response.

◎Higher potassium intake was associated with a 24% lower risk of stroke (moderate quality evidence). These results suggest that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the prevention and control of elevated blood pressure and stroke.

156,424

Prospective Urban Rural Epidemiology (PURE) study

Study designParticipants: 156,424 (101,945) Age: 35 to 70 years

628 Communitiesin 17, low (4), middle (10) and high income countries (3)

PeriodJan 2003 to 2013 (first data), continued

Coordinated by Population Health Research Institute, Hamilton Health Sciences and McMaster University, Canada.

Funding: Sponsored by nonprofit, government and industry sponsors. Funders had no role in analyses, or design or conduct of the study or writing manuscripts

Maps

our office

Procedures◎ Initial questionnaire ◎ Fasting morning midstream urine sample collection◎ 24-hour urinary sodium and potassium excretion

estimated using Kawasaki formula◎ Considered surrogate for intake

Kawasaki T, Itoh K, Uezono K, Sasaki H. A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults. Clin Exp Pharmacol Physiol 1993;20:7-14. [Erratum, Clin Exp Pharmacol Physiol 1993;20:199.] 25. Mente A, O’Donnell MJ, Dagenais G, et al. Validation and comparison of three formulae to estimate sodium and potassium excretion from a single morning fasting urine compared to 24-h measures in 11 countries. J Hypertens 2014;32:1005- 14. 26.

Urine analyses◎ Frozen at -20C to -70C◎ Shipped to Clinical Research labs in Canada, India, China and

Turkey◎ Indirect potentiometry◎ 0.1% had implausible urine concentrations and excluded◎ All labs were within analytical range as compared to Central

Laboratory, Hamilton, Canada

Follow upo Follow up started in 2008, completed by 2013o Information on events: participants/familyo Verbal autopsies/Review of medical records

Statistical analysis

Primary outcome measures◎Death from any cause◎Death from major cardiovascular events

(stroke, MI, heart failure)

Multivariable logistic regression analysis performed to determine association between urinary sodium and potassium excretion and outcome measure using 3 sequential models

Model 1Adjusted for age, sex, educational level, ancestry, alcohol use, diabetes mellitus, BMI, history of cardiovascular events, smoking, LDL:HDL ratio

Model 2Model 1 + Caloric intake, fruit/ vegetable intake

Model 3Model 1 + 2 + systolic blood pressure, hypertension, antihypertensive therapy

Exclusion criteriaCardiovascular disease

Cancer (at baseline or follow-up)

Events in the first 2 year of follow-up

Tested for interactions of age, hypertension, sex, ancestry, history of cardiovascular disease, diabetes, BMI and estimated sodium and potassium excretion

Potential influence of unmeasured confounders on our estimates of risk using array-approach sensitivity

Potential influence of imbalanced confounders: propensity score matched sensitivity analyses

4.93 gramsMean estimated 24-hour sodium excretion

Mean systolic and diastolic blood pressure higher among those with higher sodium excretion (p<0.001)

2.12 gramsMean estimated 24-hour potassium excretion

Results

Baseline characteristics◎Proportion of participants (%)

○ <3.00 g/day : 10.6 ○ 3.00–3.99 g/day : 20.7 ○ 4.00–5.99 g/day : 45.8 ○ 6.00–6.99 g/day : 12.1○ 7.00 g/day : 10.8

3.3% (3317 subects)

857 MI

872 stroke

261 heart failure

1976 deaths◉ 650 from cardiovascular causes

Primary composite outcome of death or major CVE

Urinary sodium excretion >7.00g per day

◎ Increased risk of primary composite outcome (Odds Ratio: 1.15; 95% CI: 1.02 to 1.30)

◎ Death from any cause (Odds Ratio: 1.25; 95%CI: 1.07 to 1.48)

◎ Major CVE (OR:1.16; 95%CI: 1.01 to 1.34)

◎ Death from CVE (OR:1.54; 95% CI: 1.21 to 1.95)

◎ Stroke (OR: 1.29; 95%CI: 1.02 to 1.63)

Not significant after adjustment for blood pressure and history of hypertension except death from any cause

Urinary sodium excretion <3.00g per day◎ Increased risk of primary composite outcome

(OR:1.27; 95% CI:1.12 to 1.44)

◎ Death from any cause (OR:1.38; 95% CI:1.15 to 1.66)

◎ Major CVE (OR:1.30; 95% CI:1.13 to 1.50)

◎ Death from CVE (OR:1.77; 95% CI:1.36 to 2.31)

◎ Stroke (OR: 1.37; 95% CI:1.07 to 1.76)

Significant after adjustment for blood pressure or history of hypertension

Potassium excretion >1.50g per day

◎ Reduction in the risks of death and CVEs◎ Reduction in the risk of death ◎ No evidence of an interaction between estimated

potassium and sodium excretion with respect to the primary composite outcome

Maps

our office

Maps

our office

Maps

our office

Association between Estimated Sodium Excretion and Composite Outcome (All-cause Mortality and CVD) in Subgroups

Association between Estimated Sodium Excretion and Composite Outcome (All-cause Mortality and CVD) in Subgroups

“An estimated sodium excretion between 3g and 6g per day was associated with a lower risk of death and cardiovascular events than either a higher or lower estimated level of

sodium intake.

“As compared with an estimated potassium excretion of less than 1.50 g per day, higher potassium excretion was associated with a

reduction in the risk of the composite outcome.

Discussion

Current guidelines recommend maximum intake of 1.5 to 2.4 g per day (derived from BP trials that assume a linear relationship)

Na intake = blood pressure

blood pressure = CV events

Discussion

◎ higher risk of CV disease and death only in individuals with HTN consuming >6g/day (representing only 10% of the population)

◎ increased risk of CV disease and death in low sodium intake (compared with moderate intake) irrespective of HTN status

Discussion

◎ A very small proportion of the worldwide proportion consumes a low Na diet; Na intake not related to BP in these people

◎? Lower Na best targeted at those individuals with HTN who also consume high Na

◎ Previous studies has shown a J-shaped association between Na intake and CV disease or death

◎ Some of theses studies included participants at high CV risk and were vulnerable to biases from reverse causation (e.g. people with CV disease or increased CV risk reduce their Na intake due illness or recommendations)

Discussion

Discussion◎ PURE study: vast majority did not have a

history of cardiovascular disease◎ DM and history of CV disease were more

common in those with low Na excretion, they had a similar overall mean INTERHEART Modifiable Risk Score

◎ exclusion criteria did not alter findings◎ reverse causation still cannot be ruled out, may

account for the increased risk in low Na excretion group

Discussion

◎ interaction between Na excretion and K excretion: higher Na strongly associated with increased BP in people with lower K excretion

◎ alternative approach to BP management? Recommend K-high diets to achieve greater health benefits, including BP reduction, than aggressive Na reduction alone

◎ Higher K excretion was associated with a lower CV risk or deaths

◎ A small, cluster-randomized, controlled trial which showed participants increased K consumption and reduced high Na consumption reduced CV mortality

◎ High K - effect on BP or maker of diet high in fruits and vegetables

◎ Large definitive trials needed

Study limitations

◎ Method of estimating Na and K intake was a formula-derived estimate of 24-hour urinary excretion and not actual 24-hour urinary collection

◎ True probability - sampling approach was not undertaken – issues with practical constraints of studying Na excretion in a wide range of countries and settings

Study limitations

◎ epidemiologic comparison of groups that consume different levels of Na, does not provide information on the effect on clinical outcomes of reducing Na intake

◎ lack of intervention component to assess the direct effects of altering Na and K intake on BP and cardiovascular-disease outcomes, impossible to establish causality

Should we take these results with a grain of salt?◎ estimated Na intake between 3-6g per day was

associated with a lower risk of death and cardiovascular events than either a higher or lower estimated level of sodium intake

◎ higher K excretion (1.5 g /day) was associated with a reduction in the risk of the composite outcome

Thank you