Effect of Low-Sodium Salt Substitutes on Blood Pressure

10

Effect of Low-Sodium Salt Substitutes on Blood Pressure, Detected

Hypertension, Stroke and Mortality

A Systematic Review and Meta-analysis of Randomized Controlled Trials

AV Hernandez et al. on November 30, 2018

Online-only Supplement

11

Supplementary Methods: PubMed Search Strategy

Supplementary Reference List of included randomized controlled trials Table S1. Characteristics of included randomized controlled trials

Supplementary Figures of main analyses:

Figure S1:Flow diagram of study selection

Figure S2:Risk of bias of included studies

Figure S3:Effect of salt substitutes on overall mortality

Figure S4:Effect of salt substitutes on urinary calcium excretion (mmol/day)

Figure S5:Effect of salt substitutes on glucose (mmol/L)

Figure S6:Effect of salt substitutes on total cholesterol (mmol/L)

Figure S7:Effect of salt substitutes on triglycerides (mg/dL)

Figure S8: Effect of salt substitutes on BMI (kg/m2)

Supplementary Figures of Subgroup analyses:

Figure S9: Effect of salt substitutes on SBP by subgroup of duration of intervention (≤3months

vs >3 months).

Figure S10: Effect of salt substitutes on DBP by subgroup of duration of intervention

(≤3months vs >3 months).

Figure S11: Effect of salt substitutes on detected hypertension by subgroup of duration of

intervention (≤3months vs >3 months) in hypertensive populations.

Figure S12: Effect of salt substitutes on urinary sodium excretion by subgroup of duration of


Figure S13: Effect of salt substitutes on urinary potassium excretion by subgroup of duration of


Figure S14: Effect of salt substitutes on urinary calcium excretion by subgroup of duration of


Figure S15: Effect of salt substitutes on total cholesterol by subgroup of duration of intervention

(≤3months vs >3 months) in hypertensive populations.

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Figure S16: Effect of salt substitutes on triglycerides by subgroup of duration of intervention

(≤3months vs >3 months) in hypertensive populations.

Supplementary Figures of Sensitivity analyses:

Figure S17: Effect of salt substitutes on SBP excluding high risk of bias trials.

Figure S18: Effect of salt substitutes on DBP excluding high risk of bias trials.

Figure S19: Effect of salt substitutes on detected hypertension excluding high risk of bias trials

in hypertensive populations.

Figure S20: Effect of salt substitutes on urinary sodium excretion excluding high risk of bias

trials in hypertensive populations.

Figure S21: Effect of salt substitutes on urinary potassium excretion excluding high risk of bias


Figure S22: Effect of salt substitutes on urinary calcium excretion excluding high risk of bias


Figure S23: Effect of salt substitutes on glucose excluding high risk of bias trials in

hypertensive populations.

Figure S24: Effect of salt substitutes on total cholesterol excluding high risk of bias trials in


Figure S25: Effect of salt substitutes on triglycerides excluding high risk of bias trials in


Figure S26: Effect of salt substitutes on BMI excluding high risk of bias trials in hypertensive

populations.

Meta-regression analyses Methods of meta-regression analyses

Figure S27: Mean difference of SBP (salt substitutes vs control) by mean age

Figure S28: Mean difference of SBP (salt substitutes vs control) by % of female

Figure S29: Mean difference of SBP (salt substitutes vs control) by baseline mean BP

Figure S30: Mean difference of SBP (salt substitutes vs control) by %NaCl content of salt

substitute.

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Figure S31: Mean difference of DBP (salt substitutes vs control) by mean age

Figure S32: Mean difference of DBP (salt substitutes vs control) by % of female

Figure S33: Mean difference of DBP (salt substitutes vs control) by baseline mean BP

Figure S34: Mean difference of DBP (salt substitutes vs control) by %NaCl content of salt

substitute.

Correlations between change in urinary Na/ K excretion and change in SBP/DBP per trial arm

Methods of correlation analyses

Figure S35: Correlation between change in urinary Na and change of SBP per trial arm

Figure S36: Correlation between change in urinary Na and change of DBP per trial arm

Figure S37: Correlation between change in urinary K and change of SBP per trial arm

Figure S38: Correlation between change in urinary K and change of DBP per trial arm

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Supplementary Methods: PubMed search strategy (salt substitution OR salt substitute OR low-sodium salt substitute OR salt replacing OR salt

replacement OR salt replacer OR salt reduction OR salt reducer OR Low-So salt replacer OR

KcLean salt OR Kalisel OR Salt Trim OR Lacto Optitaste OR Pansalt OR Sub4salt OR

LomaSalt OR Saltwise OR Myciscent OR Salt reducer N100 OR Salt reducer N200 OR Dr

Lohmann’s Premix salt replacer OR AlsoSalt OR Nu-Tek’s modified potassium chloride OR

Soda-Lo OR Zalt OR Maxorite delite OR Maxarite Bsalt OR Maxarite Dsalt OR Maxarome

select OR Maxarome pure OR KojiAji OR Ajimate super RK OR Ajinomoto OR SaltAnswer

OR Super YE OR Fonterra Savoury Powder OR Flavour intensifier OR Savoury Flavour

enhancer OR Flavour enhancer OR SavourCrave OR UnSal20 OR Seagreens Organic

Mineral Salt OR Sense Capture Salt OR potassium OR magnesium OR KCl OR MgCl) AND

(healthy OR normotension OR prehypertension OR hypertension OR obesity OR type 2

diabetes OR stroke) AND blood pressure AND randomized controlled trial AND humans

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Supplementary reference list of included randomized controlled trials w1. Arzilli F, Taddei S, Graziadei L, et al. Potassium-rich and sodium-poor salt reduces blood

pressure in hospitalized patients. Journal of hypertension Supplement : official journal of

the International Society of Hypertension 1986;4:S347-50.

w2. Suppa G, Pollavini G, Alberti D, et al. Effects of a low-sodium high-potassium salt in

hypertensive patients treated with metoprolol: a multicentre study. Journal of hypertension

1988;6:787-90.

w3. Geleijnse JM, Witteman JC, Bak AA, et al. Reduction in blood pressure with a low sodium,

high potassium, high magnesium salt in older subjects with mild to moderate

hypertension. Bmj 1994;309:436-40.

w4. Omvik P, Myking OL. Unchanged central hemodynamics after six months of moderate

sodium restriction with or without potassium supplement in essential hypertension. Blood

pressure 1995;4:32-41.

w5. Gilleran G, O'Leary M, Bartlett WA, et al. Effects of dietary sodium substitution with

potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled

parallel study. Journal of human hypertension 1996;10:517-21.

w6. Mu JJ, Liu ZQ, Yang J, et al. [Long term observation in effects of potassium and calcium

supplementation on arterial blood pressure and sodium metabolism in adolescents with

higher blood pressure]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive

medicine] 2003;37:90-2.

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w7. Chang HY, Hu YW, Yue CS, et al. Effect of potassium-enriched salt on cardiovascular

mortality and medical expenses of elderly men. The American journal of clinical nutrition

2006;83:1289-96.

w8. Pereira MA, Galvao R, Zanella MT. Effects of potassium supplementation by salt on

arterial blood pressure and insulin resistance in hypertensive obese patients on diuretic

therapy. Rev Nutr 2005;18:5-17.

w9. China Salt Substitute Study Collaborative G. Salt substitution: a low-cost strategy for blood

pressure control among rural Chinese. A randomized, controlled trial. Journal of

hypertension 2007;25:2011-8.

w10. Mu J, Liu Z, Liu F, et al. Family-based randomized trial to detect effects on blood pressure

of a salt substitute containing potassium and calcium in hypertensive adolescents.

American journal of hypertension 2009;22:943-7.

w11. Sarkkinen ES, Kastarinen MJ, Niskanen TH, et al. Feasibility and antihypertensive effect

of replacing regular salt with mineral salt -rich in magnesium and potassium- in subjects

with mildly elevated blood pressure. Nutrition journal 2011;10:88.

w12. Zhou X, Liu JX, Shi R, et al. Compound ion salt, a novel low-sodium salt substitute: from

animal study to community-based population trial. American journal of hypertension

2009;22:934-42.

w13. Allaert FA. Double-blind, randomized, crossover, controlled clinical trial of NaCl +

Chitosan 3% versus NaCl on mild or moderate high blood pressure during the diet and

lifestyle improvement period before possible prescription of an antihypertensive treatment.

International angiology : a journal of the International Union of Angiology 2013;32:94-

101.

17

w14. Zhou B, Wang HL, Wang WL, et al. Long-term effects of salt substitution on blood

pressure in a rural north Chinese population. Journal of human hypertension 2013;27:427-

33.

w15. Barros CL, Sousa AL, Chinem BM, et al. Impact of light salt substitution for regular salt

on blood pressure of hypertensive patients. Arquivos brasileiros de cardiologia

2015;104:128-35.

w16. Zhao X, Yin X, Li X, et al. Using a low-sodium, high-potassium salt substitute to reduce

blood pressure among Tibetans with high blood pressure: a patient-blinded randomized

controlled trial. PloS one 2014;9:e110131.

w17. Li N, Yan LL, Niu W, et al. The Effects of a Community-Based Sodium Reduction

Program in Rural China - A Cluster-Randomized Trial. PloS one 2016;11:e0166620.

w18. Yang GH, Zhou X, Ji WJ, et al. Effects of a low salt diet on isolated systolic hypertension:

A community-based population study. Medicine 2018;97:e0342.

w19. Allaert FA. Effect of NaCl + Chitosan 3% vs. NaCl on high blood pressure parameters of

healthy volunteers with prehypertension. Minerva cardioangiologica 2017;65:563-76.

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Supplementary Table 1. Characteristics of included randomized controlled trials

Study Name, Year (reference)

Study Years

Study Location

Phase Follow up time (mo.)

Population, baseline mean BP (mmHg)

Total Sample Size (salt substitute /control group)

Salt substitute name [composition] (dose)

Control salt name [composition] (dose)

Mean age (SD)

% Male

Outcomes Evaluated

Arzilli F 1986 (w1)

N/A Italy 2 0.25 Mild hypertension & hospitalized MBP: 127

10 (5/5) K/Na Salt [NaCl 50%, KCl 25% and K3C6H5O6 15%] (2g twice daily added to standard diet [20 mmol Na + 4g common salt])

Common Salt [N/A] (2g twice daily added to standard diet [20 mmol Na + 4g common salt])

Mean (range): 39.5 (28-53)

60 SBP, DBP, Na & K urinary excretion (24-h sample) No harms reported

Suppa G 1988 (w2)

N/A Italy 2 1 All hypertensive MBP: 113

322 (163/159)

Novosalt®

[NaCl 50%, KCl 25%, K3C6H5O7 15%] (2g twice daily added to lunch and dinner [34 mmol Na and 19.3 mmol K]; amount of salt for cooking and foods unchanged)

Common Salt [NaCl 100%] (2g twice daily added to lunch and dinner; amount of salt for cooking and foods unchanged)

Substitute: 47.1 (9.8) Control: 47.8(10.1)

62.7 SBP, DBP, Na & K urinary excretion (24-h sample) No harms reported

Geleijnse JM 1994

(w3)

1990-1992

Netherlands

2 6 Mild to moderate hypertensive, no previous treatment MBP: 113

100 (49/51)

SagaSalt®

[NaCl 41%, KCl 41%, Mg salts 17% and minerals 1%] (Salt for cooking and at the table and foods; Na/K ratio in foods: 1.3 to 1.8 mmol/mmol)

Common Salt [NaCl] (Salt for cooking and at the table and foods; Na/K ratio in foods: 6.7 to 22.7 mmol/mmol)

Substitute: 65.7 (4.6) Control: 67.1 (4.5)

51 Na, K & Ca urinary excretion (24-h sample) No harms reported

Omvik P 1995 (w4)

N/A Norway 2 6

All hypertensive

40 (20/20) Pansalt®

[NaCl 57%, KCl 28%, Standard Sodium Chloride

Substitute: 45.9 (N/A)

68 Hypertension, SBP, DBP, Na &

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MBP: 124

MgSO4 12%, lysine 2%] (Salt used in small amounts as cooking and table salt replacing household salt. Diet with 30% sodium restriction)

[N/A] (Salt used in small amounts as cooking and table salt replacing household salt. Diet with 30% sodium restriction )

Control: 42.7 (N/A)

K urinary excretion (24-h sample) No harms reported

Gilleran G 1996 (w5)

N/A United Kingdom

2 3 Type 2 diabetics, mild hypertensive MBP: 118

40 (20/20) Seltin®

[NaCl 50%, KCl 40%, MgSO4 10%] (Salt replaced household salt; patients used added salt at the table or in the cooking before trial)

Ordinary Table Salt. [N/A] (Salt replaced household salt; patients used added salt at the table or in the cooking before trial)


60 SBP, DBP, Na & K urinary excretion (24-h sample), total cholesterol, triglycerides No harms reported

Mu JJ 2003 (w6)

N/A (pending)

China 2 24 All hypertensive MBP: 92

220 (110/110)

Supplementary salt [10mmol of K and 10mmol of Ca salt] (Mixed in the table salt)

Regular salt [N/A] (Table salt)

Mean: 20.6 (2.1)

51.8 SBP, DBP No harms reported

Pereira M 2005 (w8)

N/A Brazil 2 3 All hypertensive MBP: 108

22 (12/10)

N/A [NaCl 50% and KCl 50%] (Salt replaced household salt)

Common Salt [NaCl 100%] (Salt replaced household salt)

Mean: 47.5 (11.2)

14 SBP, DBP, total cholesterol, triglycerides, BMI, waist circumference No harms reported

Chang HY

2006 (w7) 1995-1999

Taiwan 2 44 General population 40% hypertensive

1981 (768/1213)

K Enriched Salt [NaCl 49%, KCl 49% and other additives 2%] (Replaced regular salt in cooking gradually,

Regular Salt [NaCl 99.6% and other additives 0.4%] (Regular salt in cooking at all times.


N/A CVD mortality No harms reported

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MBP: 91 from a KES/RS 1:3 ratio to 100% KES. Daily Na intake was 3.8g; 30% from sauces)

Daily Na intake was 5.2g; 30% from sauces)

Li N 2007 (w9)

2004- 2005

China 2 12 All hypertensive MBP: 115

608 (306/302)

N/A [NaCl 65%, KCl 25% and MgSO4 10%] (Cooking, pickling and other uses within household; ≤ 3kg salt per month. Existing salt and food previously pickled not removed )

N/A [NaCl 100%] (Cooking, pickling and other uses within household; ≤3kg salt per month. Existing salt and food previously pickled not removed)

Mean: 60 (10)

44 SBP, stroke, overall mortality Harms: No patients with severe hyperkalemia in both arms

Mu J 2009

(w10) N/A China 2 24 General

population, mixed hypertensive MBP: 92

215 (101/114)

N/A [Salt with added KCl and CaCl2] (10 mmol KCl and 10 mmol CaCl2 added per day to usual salt consumption. Na intake 144±44 mmol/day at 6mo)

N/A [N/A] (Usual salt consumption. Na intake 127±31 mmol/day at 6mo)


53.5

SBP, DBP Harms: No patients with severe hyperkalemia in both arms

Zhou X (a) 2009 (w12)

N/A China 2 6 All hypertensive MBP: 108

126 (62/62)

CiSalt®

[NaCl 65%, KCl 30%, Calcium salts 5% and 12mg/kg folic acid] (All cooking and other uses replacing regular salt. ≤3kg per month)

NSalt [NaCl 100%] (All cooking and other uses. ≤3kg per month )


42 SBP, DBP, Glucose, Na & K & Ca urinary excretion (24-h sample), total cholesterol, triglycerides No harms reported

Zhou X (b) 2009 (w12)

2003- 2004

China 2 6 Normotensive

122 (57/65)

CiSalt®

[NaCl 65%, KCl 30%, NSalt [NaCl 100%]

Substitute: 68.1 (8.3)

45 SBP, DBP, Glucose, Na & K

13

MBP: 91

Calcium salts 5% and 12 mg/kg folic acid] (All cooking and other uses replacing regular salt. ≤3kg per month)

(All cooking and other uses. ≤3kg per month )

Control: 65.4 (4.5)

& Ca urinary excretion (24-h sample), total cholesterol, triglycerides No harms reported

Sarkkinen ES 2011 (w11)

N/A Finland 2 2 All hypertensive (130-159/85-99 mmHg) MBP: 105

45 (22/23) Smart Salt®

[NaCl 50%, KCl 25%, magnesal 25%] (Used for cooking and baking as well as table salt; 6.8±3.3 g NaCl intake per day )

Regular Salt [NaCl 100%] (Used for cooking and baking as well as table salt; 10.1±3.1 g NaCl intake per day)

Substitute: 57 (12) Control: 54 (11)

51.1 SBP, DBP, Na & K urinary excretion (24-h sample), BMI No harms reported

Allaert FA 2013 (w13)

N/A France 2, cross-over

2 Mild hypertension, no previous treatment MBP: 112

40 (19/21) Symbiosal®

[NaCl 97% and chitosan 3%] (max 3g per day, added to regular salt intake)

Standard NaCl sea salt [NaCl 100%] (max 3g per day, added to regular salt intake)

Mean: 58.6(12)

40 Hypertension, SBP, DBP No harms reported

Zhou B 2013 (w14)

N/A China 2 24 General population, mixed hypertensive MBP: 111

462 (224/238)

Salt substitute [NaCl 65%, KCl 25%, MgSO4 10%] (Salt used to prepare all foods)

Normal Salt [NaCl 100%] (Salt used to prepare all foods)

Mean: 46 (16)

49 SBP, DBP No harms reported

Zhao X 2014 (w16)

2009 China 2 3 All hypertensive MBP: 129

282 (141/141)

Salt Substitute [NaCl: 65%, KCl: 25%, MgSO4: 10%] (20±5.4g average per family daily NaCl consumption)

Regular salt [NaCl 100%] (26.9±8.1g average per family daily NaCl consumption)


41.1 Hypertension, SBP, DBP No harms reported

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Barros CL 2015 (w15)

2012 Brazil 2 1 All hypertensive MBP: 108

35 (19/16) Light Salt®

[Na: 130mg/g, K: 346mg/g, I: 44mcg/g] (3g per day; consumed only provided salt; reduced sodium-rich food consumption during study)

‘Regular salt’ [Na: 390mg/g, I: 25mcg/g] (3g per day; consumed only provided salt; reduced sodium-rich food consumption during study)

Mean: 55.5 (7.4)

34.3 SBP, DBP, Na & K urinary excretion (24-h sample), BMI No harms reported

Li N 2016 (w17)

2011- 2012

China 3- Clustered

18 General population, township MBP: 105

2566 (1294/1272)

Salt substitute [NaCl 65%, KCl 25%, MgSO4 10%] (Available at shops; Used to replace all household salt use –cooking, pickling, discretionary mealtime use-)

Regular salt [NaCl 100%] (Available at shops; Use for all household salt use)

Substitute: 55 (15) Control: 55 (14)

50 Hypertension, SBP, DBP, Na & K urinary excretion (24-h sample), BMI No number of patients with harms reported. No difference between arms for hyperkalemia or renal failure.

Allaert FA 2017 (w19)

N/A France 2 2 Pre-hypertension (SBP 130-139 mmHg; DBP: 80-89 mmHg) MBP: 99

41 (22/19) Symbiosal®

[NaCl 97% and chitosan 3%] (max 3g per day {table salt consumption 2.2±1.1 g/day}, added to regular salt intake; no change in nutritional habits during study)

Standard NaCl sea salt [NaCl 100%] (max 3g day {table salt consumption 2.5±1.2 g/day}, added to regular salt intake; no change in nutritional habits during study)

Mean: 51 (16)

51.2 SBP, DBP No harms reported

Yang G-H 2018 (a) (w18)

N/A China 2 6 Isolated systolic hypertension (ISH;

51 (24/27) LSSalt (Low sodium salt) [NaCl 65%, KCl 30%, Ca salts 5% and

NSalt (Regular salt) [NaCl 100%] (Used for regular salt consumption)


41.2 SBP, DBP, Na, K, & Ca urinary excretion (24-h sample), total

15

SBP≥140 mmHg & DBP<90 mmHg) MBP: 107

12mg/kg folic acid] (Used for regular salt consumption)

cholesterol, triglycerides No harms reported

Yang G-H 2018 (b) (w18)

N/A China 2 6 Non-ISH (NISH; SBP≥140 mmHg & DBP≥90 mmHg) MBP: 109

75 (38/37) LSSalt (Low sodium salt) [NaCl 65%, KCl 30%, Ca salts 5% and 12mg/kg folic acid] (Used for regular salt consumption)

NSalt (Regular salt) [NaCl 100%] (Used for regular salt consumption)


44 SBP, DBP, Na, K, & Ca urinary excretion (24-h sample), total cholesterol, triglycerides No harms reported

SBP: systolic blood pressure; DBP: diastolic blood pressure; MBP: mean blood pressure; BMI: body mass index; Na: Sodium; K: Potassium; Ca: Calcium; Mg: magnesium, I: Iodine; ISH: isolated systolic hypertension; N/A: Not available. Harms of interest included hyponatremia, hyperkalemia, renal failure, and sudden death.

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Supplementary Figures Figure S1. Flow diagram of study selection

Included

Eligibility

Screening

Identification Records identified through

database searching: 3081

Records after duplicates removed: 2572

Records screened by title/abstract Records excluded: 2543

Full text articles assessed for eligibility: 29

RCTs included in qualitative synthesis: 21

(19 articles)

RCTs included in quantitative synthesis: 21

(19 articles)

Reasons for full text article exclusion:

Lack of outcomes (n=7)Duplicated data (n=3)

17

Figure S2. Risk of bias of included studies

a. Risk of bias Summary format

18

b. Risk of bias Study-specific format

19

Figure S3. Effect of salt substitutes on overall mortality

20

Figure S4. Effect of salt substitutes on urinary calcium excretion (mmol/day)

21

Figure S5. Effect of salt substitutes on glucose (mmol/L)

22

Figure S6. Effect of salt substitutes on total cholesterol (mmol/L)

23

Figure S7. Effect of salt substitutes on triglycerides (mg/dL)

24

Figure S8. Effect of salt substitutes on BMI (kg/m2)

25

Figure S9: Effect of salt substitutes on SBP by subgroup of duration of

intervention (≤3months vs >3 months).

26

Figure S10: Effect of salt substitutes on DBP by subgroup of duration of

intervention (≤3months vs >3 months).

27

Figure S11: Effect of salt substitutes on detected hypertension by subgroup of

duration of intervention (≤3months vs >3 months) in hypertensive populations.

28

Figure S12: Effect of salt substitutes on urinary sodium excretion by subgroup of


29

Figure S13: Effect of salt substitutes on urinary potassium excretion by subgroup

of duration of intervention (≤3months vs >3 months) in hypertensive populations.

30

Figure S14: Effect of salt substitutes on urinary calcium excretion by subgroup of


31

Figure S15: Effect of salt substitutes on total cholesterol by subgroup of duration

of intervention (≤3months vs >3 months) in hypertensive populations.

32

Figure S16: Effect of salt substitutes on triglycerides by subgroup of duration of


33

Figure S17: Effect of salt substitutes on SBP excluding high risk of bias trials.

34

Figure S18: Effect of salt substitutes on DBP excluding high risk of bias trials.

35

Figure S19: Effect of salt substitutes on detected hypertension excluding high

risk of bias trials in hypertensive populations.

36

Figure S20: Effect of salt substitutes on urinary sodium excretion excluding high


37

Figure S21: Effect of salt substitutes on urinary potassium excretion excluding

high risk of bias trials in hypertensive populations.

38

Figure S22: Effect of salt substitutes on urinary calcium excretion excluding high


39

Figure S23: Effect of salt substitutes on glucose excluding high risk of bias trials

in hypertensive populations.

40

Figure S24: Effect of salt substitutes on total cholesterol excluding high risk of

bias trials in hypertensive populations.

41

Figure S25: Effect of salt substitutes on triglycerides excluding high risk of bias


42

Figure S26: Effect of salt substitutes on BMI excluding high risk of bias trials in


43

Methods of meta-regression analyses

Meta-regressionanalyseswereperformedtoevaluatethevariabilityofMDofbloodpressurebetween

saltsubstitutesandcontrolgroupsbysomestudyvariablessuchasmeanage,proportionoffemale,and

baselinemeanbloodpressure.Meta-regressionswerebasedonlinearregressionsofMD,whichwere

calculatedinrandomeffectsmeta-analyseswiththeinversevariancemethodandtheDerSimonian-

Lairdestimatorsfortau2.TwoMDswereevaluated:SBPandDBP.Theinfluenceofastudyvariableon

theMDwasquantifiedastheslopeofthelinearregressionmodel;alsotheR2(i.e.variabilityofMD

explainedbythestudyvariable)andpvalueswerecalculated.Themetaregcommandofthemeta

packageofR3.5.1(www.r-project.org)wasusedforallanalyses.

44

Figure S27: Mean difference of SBP (salt substitutes vs control) by mean age

MDdecreasesby0.05perincreaseinoneyearofage(R2=0.01,p=0.4)

Covariate mage

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

20 30 40 50 60

−12

−10

−8−6

−4

45

Figure S28: Mean difference of SBP (salt substitutes vs control) by % of female

MDdecreasesby0.1perincreaseinonepercentoffemale(R2=0.01,p=0.3)

Covariate pfemale

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

30 40 50 60 70 80

−12

−10

−8−6

−4

46

Figure S29: Mean difference of SBP (salt substitutes vs control) by baseline mean

BP

MDincreasesby0.01perincreaseinonemmHgofbaselinemeanBP(R2=0.001,p=0.9)

Covariate bmbp

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

90 100 110 120 130

−12

−10

−8−6

−4

47

Figure S30: Mean difference of SBP (salt substitutes vs control) by %NaCl

content of salt substitute.

MDdecreasesby0.02perincreaseinonepercentofcontentofNaClinsaltsubstitute(R2=0.01,p=0.6)

Covariate naclperc

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

0 20 40 60 80 100

−12

−10

−8−6

−4

48

Figure S31: Mean difference of DBP (salt substitutes vs control) by mean age

MDdecreasesby0.007perincreaseinoneyearofage(R2=0.002,p=0.9)

Covariate mage

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

20 30 40 50 60

−6−4

−20

49

Figure S32: Mean difference of DBP (salt substitutes vs control) by % of female

MDdecreasesby0.07perincreaseinonepercentoffemale(R2=0.03,p=0.2)

Covariate pfemale

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

30 40 50 60 70 80

−6−4

−20

50

Figure S33: Mean difference of DBP (salt substitutes vs control) by baseline mean

BP

MDincreasesby0.05perincreaseinonemmHgofbaselinemeanBP(R2=0.02,p=0.4)

Covariate bmbp

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

90 100 110 120 130

−6−4

−20

51

Figure S34: Mean difference of DBP (salt substitutes vs control) by %NaCl

content of salt substitute.

MDdecreasesby0.01perincreaseinonepercentofcontentofNaClinsaltsubstitute(R2=0.005,p=0.7)

Covariate naclperc

Trea

tmen

t effe

ct (m

ean

diffe

renc

e)

0 20 40 60 80 100

−6−4

−20

52

MethodsofcorrelationanalysesWeevaluatedthecorrelationbetweenurinaryNaorKchangeandSBPorDBPchangepertrialarm.

BothSpearmancorrelationcoefficientsandscatterplotswereweightedbythesamplesizeofarms.The

ggplot2andwCorrpackagesofR3.5.1(www.r-project.org)wereusedforallanalyses.

Figure S35: Correlation between change in urinary Na and change of SBP per trial

arm

Weighted Spearman correlation coefficient: 0.56, p=0.01

53

Figure S36: Correlation between change in urinary Na and change of DBP per trial

arm

Weighted Spearman correlation coefficient: 0.45, p=0.03

54

Figure S37: Correlation between change in urinary K and change of SBP per trial

arm

Weighted Spearman correlation coefficient: -0.49, p=0.07

55

Figure S38: Correlation between change in urinary K and change of DBP per trial

arm

Weighted Spearman correlation coefficient: -0.39, p=0.2

Documents

Effect of Low-Sodium Salt Substitutes on Blood Pressure