1. Nancy R. Cook, ScD Championing Public Health Nutrition November 25-26, 2014 Sodium and Cardiovascular Health

2. Disclosures No commercial interests TOHP was funded by NHLBI Current funding from NHLBI for unrelated projects Current funding from the AHA for continued mortality follow-up of the TOHP cohorts

3. Dietary Recommendations for Sodium in Adults Average US diet: 3,400 mg/d US Dietary Guidelines (2010): <2,300 mg/d < 1,500 for aged 51+, blacks, HTN, or CKD AHA (2012): < 1,500 mg/d WHO (2012): < 2,000 mg/d Canada’s Food Guide: 1500-2300 mg/d Based primarily on studies of BP

4. Cochrane Collaboration (He, 2002) -5.0 (-5.8 to -4.2)

5. Cochrane Collaboration (He, 2002) -2.0 (-2.6 to -1.5)

6. Effect of 2 mmHg decrease in DBP: - Reduce CHD by 6%, stroke by 15% Cook, 1995

7. DASH-Sodium Trial – SBP Results Sacks NEJM 2001 330024001500

8. Evidence Observational data support a strong positive association between sodium intake and BP Randomized trials in both hypertensive and non- hypertensive subjects show BP reduction with lower sodium intake Fewer data exist on the effect of sodium intake or excretion on subsequent morbidity and mortality Some recent studies suggest a possible adverse effect of low sodium on CVD

9. Trials of Hypertension Prevention Randomized sodium reduction interventions in those with high normal BP Blood pressure trials TOHP I (1987-1990) 744 in Na Reduction vs. in Usual Care over 1½ years TOHP II (1990-1995) 2,382 in Na Reduction vs. in Usual Care over 3-4 years Small effects on BP Follow-up for CVD TOHP Follow-up Study (to 2004) Post-trial follow-up for CVD for 10-15 years Compared randomized groups

10. Cumulative Incidence of CVD Adjusted for Clinic, Age and Sex

12. CVD by Randomized Sodium Intervention Active NA Reduction vs. Usual Care RR95%CIp Combined0.750.57 – 0.990.044 Adjusted for Baseline Sodium and Weight Combined0.700.53 – 0.940.018 TOHP I0.480.25 – 0.920.027 TOHP II0.790.57 – 1.090.16

13. Cumulative Mortality Adjusted for Clinic, Age and Sex

15. Total Mortality by Randomized Sodium Intervention Active NA Reduction vs. Usual Care RR95%CIp Combined0.810.52 – 1.270.35 Adjusted for Baseline Sodium and Weight Combined0.800.51 – 1.260.34 TOHP I0.760.33 – 1.740.52 TOHP II0.830.48 – 1.410.49

16. Chang (AJCN 2006) – Randomized Trial Five kitchens of veterans’ home in Taiwan Kitchens cluster-randomized to potassium- enriched (lower Na) or regular salt Significant reduction in CVD mortality RR = 0.59 (95% CI = 0.37-0.95) Experimental group lived longer Spent less on inpatient care for CVD

17. IOM Report – May 2013 Committee on Consequences of Sodium Reduction in Populations Charged with examining benefits and adverse effects of reducing sodium intake on health outcomes in the range of 1,500 to 2,300 mg/d The committee determined that evidence from studies on direct health outcomes is inconsistent and insufficient to conclude that lowering sodium intakes below 2,300 mg per day either increases or decreases risk of CVD TOHP trials did not lower average Na to that level

18. Quality of Sodium Measures 24-Hour diet recall (NHANES) Possible biased recall Varies day-to-day Food frequency Sodium from processed foods not captured No salt added at table or cooking Absolute levels are off Morning or spot urine Diurnal variation Day-to-day variation Absolute levels are off 24-hour excretion Gold standard, but difficult to obtain Can still vary day-to-day

19. Observational Studies of Sodium Most based on single-day diet recall or single urinary excretion Difficult to capture long-term intake Many had small numbers of events Inconsistent results Some included those with CVD or hypertension Confounding by indication Reverse causation Some did not control for prior disease

20. Trials of Hypertension Prevention Observational analysis in those not in the sodium intervention (N=2,275): TOHP I 5-7 measures of 24hr UNa over 1½ years TOHP II 3-5 measures of 24hr UNa over 3-4 years TOHP Follow-up Study Averaged ALL sodium measures to estimate usual consumption over 1½ to 4 years Post-trial follow-up for CVD over 10-15 years

21. TOHP Follow-up Data p linear = 0.05

22. CVD Events in TOHP Sodium Excretion (mg/24hr) <23002300-<36003600-<4800≥ 4800 TOHP I Events/Total (%)15/189 (7.9)48/590 (8.1)40/427 (9.4)23/191 (12.0) TOHP II Events/Total (%)2/47 (4.3)13/303 (4.3)34/341 (10.0)18/224 (8.0) HR0.680.751.001.05 95%CI0.34-1.370.50-1.11(Reference)0.68-1.62 Adjusted for age, sex, race/ethnicity, clinic, intervention, education status, baseline weight, alcohol use, smoking, exercise, potassium excretion, family history of cardiovascular disease, and changes in weight, smoking, and exercise during the trial periods

23. Findings The TOHP cohort is healthy, no prior CVD or diabetes, and pre-hypertensive High-quality repeated measurements of sodium using 24-hour urine specimens Data from TOHP support a direct and consistent linear effect of sodium intake down to <1500 mg/d on CVD No evidence of J- or U-shape

24. TOHP Follow-up Conclusions Participants in randomized sodium reduction interventions had lower rates of CVD Very precise estimate of sodium exposure Better than gold standard 24-hr excretion Direct linear association of lower CVD with lower average Na down to 1500 mg/d Consistent with trial results for BP and CVD

25. O’Donnell et al, PURE, NEJM 2014

26. PURE Study (O’Donnell et al, NEJM 2014) Sodium exposure measure weak Single morning void Kawasaki formula over-estimates Na level in non-Asians Strong differences by country/region 17 countries – did not control for differences Extremely heterogeneous population Strong differences by baseline CVD and risk factors Inadequate control for confounding Potential for much residual confounding Large study size does not imply accuracy Can have small confidence interval for biased estimate

27. <3g/d3-<4g/d4-<6g/d6-<7g/d7+g/d Region (%) Asia42.245.453.665.076.3 Africa4.22.72.42.01.6 Europe/N America31.025.218.412.79.3 Baseline disease (%) Hypertension40.038.440.844.648.0 History of CVD9.28.88.57.37.1 Diabetes10.88.69.1 8.4 Medication use (%) Beta blocker6.14.84.02.62.0 Diuretic7.55.04.5 ACE inhibitor/ARB8.26.76.15.54.7 PURE Study (O’Donnell et al, NEJM 2014)

28. Conclusions Large effect of NA on BP in those with overt htn Smaller but positive effect in normotensives Strongest evidence supports direct effect on CVD Those with htn or pre-htn likely to benefit from Na reduction to 1500 mg/d Majority of adults in US and Canada Supports dietary guidelines Whether practical to reduce sodium to 1500 mg/d remains a question 2,300 mg/d may be more achievable