1. State of the Art: Salt and Health Outcomes Francesco P Cappuccio MD MSc DSc FRCP FFPH FBHS FAHA Professor of Cardiovascular Medicine & Epidemiology Head, WHO Collaborating Centre University of Warwick, Coventry, UK Disclosures: Technical Advisor to the World Health Organization, the Pan American Health Organization, Member of C.A.S.H., W.A.S.H., UK Health Forum and Trustee of the Student Heart Health Trust Vice-President, British Hypertension Society – all unpaid.

2. Salt – Blood Pressure – CVD Model SALTBPCVD

3. Salt – Blood Pressure – CVD Model SALTBPCVD Hunter-gatherers societies have low salt consumption (<1g per day) Salt entered the food chain as preservative for food Migrant populations to urbanized areas increase their salt intake by several folds Salt intake is now high (population averages 7.5 to 12.5 g per day, with higher extremes) In Westernized societies, salt in the food chain is not needed to preserve food any longer (refrigeration) 75% or more of salt in food derives from salt added in the manufacturing process Individuals only control a small part of the salt they eat High salt in processed and manufactured food leads to profit to industry through a ‘cycle of profit’ (e.g. palatability; hygroscopic properties; taste addiction; thirst)

4. High salt consumption around the world WHO target 5 g/day max. 10.0 g/day 7.5 g/day 12.5 g/day Average Global Consumption 10.2 g/day Powles J et al. BMJ Open 2013;3:e003733

5. Salt – Blood Pressure – CVD Model SALTBPCVD High salt intake is associated with high BP and with the rise in BP with age The effect is seen at all ages, in both genders, in all ethnic groups, in rich and poor. Migrant populations to urbanized areas increase their salt intake by several folds and their BP increases in parallel. Large primates fed high salt diets show a rise in BP and when fed a low salt diet their BP falls. In humans, children and adults, a reduction in salt intake in RCTs causes a dose-dependent fall in BP. The fall is greater as we get older, as a function of baseline BP and in people of black African ancestry.

6. Mozaffarian D et al. NEJM 2014:371:624-34 Effects of reduced sodium intake on systolic blood pressure

7. A reduction in dietary salt intake reduces blood pressure in adults … Cappuccio FP & Capewell S. Functional Food Rev 2015; 7: 41-61

8. … and children Aburto NJ et al. BMJ 2013; 346: f1326

9. The lower the salt, the lower the blood pressure 9 4 2 0 -2 -4 -6 -8 -10 -12 - 30 -50-70-90-110 -130 Change in Urinary Sodium (mmol/24h) Change in Systolic Blood Pressure (mmHg) Normotensives Hypertensives He FJ, MacGregor GA. J Hum Hypertens. 2002;16:761-70

10. Salt – Blood Pressure – CVD Model SALTBPCVD Large primates fed high salt diets show a rise in BP and an increase in stroke deaths. On a low salt diet the reverse is seen. High BP is a predictor of CVD in populations (observational). Countries that have reduced salt consumption have seen a reduction in CV occurrence over many years. A reduction in BP with drugs reduces CVD within 5 years or less (elderly) (RCTs) High salt intake is associated with high mortality from stroke, CHD and CVD (observational). A reduction in salt intake reduces the incidence of vascular events (small and short RCTs). Long-term surveillance confirms benefits of reduced salt on CV outcomes (observational).

11. Stroke and Ischemic Heart Disease (CHD) as a function of Systolic BP Mortality* Usual SBP (mmHg) 50–59 y 60–69 y 70–79 y 80–89 yStroke Age at risk 256 128 64 32 16 8 4 2 1 0120140160180 CHD Usual SBP (mmHg ) 50–59 y 60–69 y 70–79 y 80–89 y Age at risk 40–49 y 256 128 64 32 16 8 4 2 1 0 120140160180 Lewington et al. Lancet 2002;360:1903–13

12. Reducing % hypertensives Reducing mean BP A small shift in mean BP reduces number of hypertensives and burden of attributable disease Reducing events attributable to BP

13. Mozaffarian D et al. NEJM 2014:371:624-34 In 2010, global sodium consumption estimated at 3.95g per day (9.875g salt per day) Globally, 1.65m annual CV deaths attributed to sodium intake >2g per day (>5g salt per day) These deaths accounted for nearly 10% of CV deaths 85% of these deaths occurred in LMICs and 40% were premature (<70 years)

14. Risk of stroke associated with salt intake in population Strazzullo P et al. BMJ 2009; 339: b4567 14

15. He FJ, MacGregor GA. Lancet 2011:378:380-2

16. New Scientist, 3 December 2011

17. Domain 1 - Errors with the greatest potential to alter the direction of association Systematic error in sodium assessment  Lower risk: 24h urine collections not part of routine clinical practice, no quality assurance, not excluding incomplete collections.  Higher risk: other 24h urine collections, all dietary assessments, spot and overnight urine collections. Reverse causality  Lower risk: participants recruited from general population and pre-existing CVD excluded  Intermediate risk: sick populations not excluded or included despite stated otherwise; presence of CVD risk factors; specific sick populations  Higher risk: specific sick populations (eg: heart failure, kidney disease, diabetes); removal of sick participants from analysis changes direction of association Domain 2 - Errors with some potential to alter the direction of association Potential for residual confounding  Incomplete adjustment: not including 2 or more of age, sex, race, SES, cholesterol, BMI or weight, smoking, diabetes; if diet-based, total calories; in urine-based weight, BMI or creatinine excretion  Imbalance across sodium intake levels: age difference across sodium groups >5 years; sex or race distribution across sodium groups >20%  Inadequate follow-up: low level of follow-up (<80%) or of uncertain quality for outcome assessment Domain 3 - Errors with the potential to lead to a false null result Random error in sodium assessment  Lower risk: more than four 24h urine assessments on average; FFQs  Intermediate risk: between 22-4 24h urine collections, or corrections for regression dilution bias; dietary reports  Higher risk: urine collection <24h or single 24h urine collection; single dietary recall or 1-dat food record Insufficient power  Less than 80% power to detect a 10% reduction in relative risk for every standard deviation in sodium intake Domain 4 - Studies using same data with divergent results  NHANES I studies: same age group, same follow-up – inverse vs positive association  NHANES III studies: different age groups, different follow-up – inverse vs positive association Cobb LK et al. Circulation 2014; 129: 1173-86

18. SODIUM INTAKE AND CV EVENTS: J-SHAPE RELATIONSHIP?

19. EPOGH Study: mortality rates and CV events by thirds of 24h urinary sodium excretion MORTALITY Total CV non-CV CARDIOVASCULAR EVENTS Stolarz-Skrzypek et al, JAMA 2011;305:1777–85 All CV CHD events Stroke Population salt intake (g/day) 3 6 9 12 15 18

20. Variables Sodium intake tertile Lowest Highest p Urinary Sodium (mmol/24h) 120 290 <0.05 Urinary Volume (L/24h) 1.3 1.8 <0.05 Urinary Creatinine (mmol/24h) 12 16 <0.05 Urinary Potassium (mmol/24h) 62 85 <0.05 ≤ Elementary school education 35% 20% EXCLUSIONS: only if 24h urine volume < 300 ml EPOGH Study: characteristics of male participants Stolarz-Skrzypek et al, JAMA 2011; 305: 1777–85 He FJ et al. Kidney Int 2011; 80: 696-8

21. Model was adjusted for age, sex, race/ethnicity (white vs nonwhite); prior history of stroke or myocardial infarction; creatinine, body mass index; comorbid vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, smoking, low- and high-density lipoprotein); treatment allocation (ramipril, telmisartan, neither, or both); treatment with statins, β-blockers, diuretic therapy, calcium antagonist, and antithrombotic therapy; fruit and vegetable consumption, level of exercise; baseline blood pressure and change in systolic blood pressure from baseline to last follow-up; and urinary potassium. O’Donnell M et al. JAMA 2011; 306: 2229-38 All CVD events by “estimated” daily salt intake in ONTARGET/TRANSCEND PATIENTS

22. O’Donnell M et al. JAMA 2011; 306: 2229-38 Model was adjusted for age, sex, race/ethnicity (white vs nonwhite); prior history of stroke or myocardial infarction; creatinine, body mass index; comorbid vascular risk factors (hypertension, diabetes mellitus, atrial fibrillation, smoking, low- and high-density lipoprotein); treatment allocation (ramipril, telmisartan, neither, or both); treatment with statins, β-blockers, diuretic therapy, calcium antagonist, and antithrombotic therapy; fruit and vegetable consumption, level of exercise; baseline blood pressure and change in systolic blood pressure from baseline to last follow-up; and urinary potassium. Cause-Specific CVD events by “estimated” daily salt intake in ONTARGET/TRANSCEND PATIENTS

23. All CVD events by “estimated” daily salt intake in ONTARGET/TRANSCEND PATIENTS O’Donnell M et al. JAMA 2011; 306: 2229-38 Old and sick patients in secondary prevention 70%hypertensives 37%diabetics 48%hypertensives with previous MI 21%previous stroke / TIA 3%AF (9% at follow-up) Multiple medications (overall 29% BUT ….41% in the lowest sodium category) Inaccurate estimate of sodium intake, based on ‘spot urine samples’ using Kawasaki equation

24. Thomas FC et al. Diabetes Care 2011; 34: 861-6 Finnish Cohort (1998-2002) Multicentre 2,807 adults with T1D (no ESRD) Median f-up 10 years 217 deaths (7.7%) Baseline 24h urinary sodium 5g salt

25. Thomas FC et al. Diabetes Care 2011; 34: 861-6 424 microalbuminuric patients 122 ESRD events Very few events stratified in 5 groups Not graded relationship ‘At risk’ group?

26. Mente A et al. NEJM 2014:371:601-11 Sodium estimated by single fasting morning urine – unreliable and biased Sodium Study (n~100K) not comparable to Overall Study (n~160K) – selection bias Fewer from India (5 v 18%) and more from China (42% v 30%) More participants with ill-health (hypertension, BP medication, CHD, CVD) Lower sodium excretion group ( see Table 1, p. 603 ): <3g per day (<7.5g of salt per day) – unable to discriminate on low sodium intake Small sample size - wide confidence intervals

27. Outcome, sodium dose and statistical power Dietary Sodium Outcome They really must think everyone is real stupid Courtesy of Norm Campbell

28. O’Donnell M et al. et al. NEJM 2014:371:612-23 10 g salt <7.5 g salt

29. O’Donnell M et al. et al. NEJM 2014:371:612-23 Cappuccio FP et al. Eur Heart J 2013; May 8: on-line Sodium estimated by single fasting morning urine – unreliable and biased Sodium Study (n~100K) not comparable to Overall Study (n~160K) – selection bias Fewer from India (5 v 18%) and more from China (42% v 30%) More participants with ill-health (hypertension, BP medication, CHD, CVD) Lower sodium excretion group (see Table 1, p.616): <3g per day (<7.5g of salt per day) – unable to discriminate on low sodium intake compared to higher sodium: 3y older; fewer men, Asians, smokers; more Africans and non-Asians, urban; lower blood pressure; higher LDL-cholesterol, history of CVD and diabetes, F&V intake, medication use – biased towards lower sodium excretion due to age and gender, and presence of ill-health (reverse causality)

31. Cook NR et al. Circulation 2014; 129: 981-9 ‘Graded’ and ‘linear’ association between salt intake and cardiovascular disease 5g salt

32. REVERSE ASSOCIATIONS OR J CURVE Studies in people with disease Reverse/J Dong 2010 Y Ekinci 2011 Y O’Donnell 2014Y Tikellis 2013*Y Lennie 2011Y Studies in people without disease Reverse/J Cohen 2006Y Cohen 2008Y Geleijinse 2007Y Larsson 2008Y Stolarz-Skrzypek 2011Y from IOM 2013 analysis

33. Linear relationship of CVD outcomes with dietary sodium Sodium mg/day Fresh foods with meat 500-< 1000 Fresh food vegans <500 Kempner rice diet ~150 Hunter gather populations <1000 Yaminano ~ 100 Long term physiological studies~ 100 Studies in people that support a linear association (from IOM report) Cook 2007 Cook 2009* Costa 2012 Gardener 2012 Heerspink 2012 Jafar 2006 Kono 2011 Arcand 2011 McCausland 2012 Nagata 2004 Takachi 2010 Thomas 2011 Umesawa 2008 Yang 2011 14 studies, 9 free of methodology flaws 1250 mg sodium/day from IOM 2013 analysis

34. Salt – Blood Pressure – CVD Model SALTBPCVD HOW FAR SHOULD WE GO WITH REDUCTION OF SALT INTAKE? THE LOWER THE BETTER ?

35. Role of salt in hypertension and CVD overestimated? A RANDOMIZED CONTROLLED TRIAL OF SALT INTAKE REDUCTION AND CVD MORTALITY ? IS IT FEASIBLE?

36. Need to recruit >28,000 participants >2,500 cardiovascular events Duration of at least five years Design challenges: –Multi-centre – multi-national – multi-cultural –Maintain two groups at different sodium intakes in an unfavorable environment (declining salt consumption) –Appropriate methodology for salt assessment in individuals Ethical problems Budget unlikely Strazzullo P. J Hypertens 2011; 29: 829-31 Randomized controlled trial of salt reduction and CVD mortality

37. Changes in diastolic blood pressure, salt intake and stroke deaths in Finland 5600 mg 3360 mg DBP SaltStroke Karppanen H et al. Progress, Cardiovascular Disease. 2006;49:59-75. 37

38. Changes in salt intake, blood pressure, stroke and IHD mortality in England from 2003 to 2011 He FJ et al. BMJ Open 2014; 4: e004549 Health Survey for England aged ≥16 years 2003 N=9183 2006 N=8762 2008 N=8974 2011 N=4753 -42% -40% -3.0 mmHg -1.4 mmHg -1.4 g/d

40. “ What is truly meaningful in life is inversely related to what is measurable”