Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To evaluate the effect on blood pressure – measured as changes in systolic and diastolic blood pressure (mmHg) using standardised measurement methods – of substituting sodium salt with other edible salts (e.g. potassium chloride, magnesium chloride) in people with diabetes mellitus.
Background
Description of the condition
Elevated blood pressure, commonly referred to as hypertension, is a leading cause of global morbidity and mortality [1, 2]. Hypertension is often defined as blood pressure exceeding 140/90 mmHg, but clinical guidelines recognise that thresholds may vary depending on measurement methods (e.g. clinic‐based versus ambulatory blood pressure monitoring), population characteristics, and risk stratification [1, 2]. Estimates indicate that by the end of 2025, globally 1.6 billion people will be living with hypertension, with most living in low‐ and middle‐income countries [3, 4, 5]. Hypertension is an independent risk factor for various cardiovascular diseases such as myocardial infarction, ischaemic heart disease, haemorrhagic stroke, and heart failure [6]. Diabetes mellitus, another major cause of global morbidity and mortality, is a major comorbid condition and a non‐modifiable risk factor for people with hypertension [5]. Hypertension is common in people with diabetes mellitus and is a major contributor to adverse cardiovascular outcomes and mortality in this population [7]. In people with diabetes mellitus, factors such as increased peripheral artery resistance due to vascular remodelling, increased body fluid volume due to hyperinsulinaemia, and hyperglycaemia may contribute to the pathogenesis of hypertension [8]. Hence, strategies to reduce the occurrence of hypertension, particularly in people with diabetes mellitus, are important. Consequently, clinical guidelines advise people with diabetes mellitus to maintain a normal blood pressure level [9].
Reduced salt intake, leading to sodium intake reduction, is a simple lifestyle intervention tested in numerous randomised controlled trials (RCTs) for its effect on blood pressure control [10]. In a general hypertensive population, salt reduction strategies exert a beneficial effect through lowering blood pressure. However, there is heterogeneity in blood pressure responsiveness to the change in salt intake, particularly for the normotensive population. Intervention studies for salt reduction showed a minor blood pressure‐lowering effect in the normotensive population as compared to the hypertensive population [10, 11, 12]. Studies suggest that insulin‐stimulated renal sodium retention has a role in the pathogenesis of hypertension in the insulin resistance state [13, 14]. Hyperinsulinaemia, hyperglycaemia, and the activated sympathetic nervous system play a role in increased total sodium levels and elevated salt sensitivity for blood pressure in people with type 2 diabetes mellitus [15, 16]. In addition, studies assessing low sodium‐containing diet in people with type 2 diabetes mellitus have shown a blood pressure‐lowering effect [17, 18].
Other minerals, such as potassium and magnesium, also have a role in blood pressure regulation [19, 20, 21]. Substitution of edible salt with salt containing a higher concentration of potassium and other minerals (e.g. magnesium) to reduce daily sodium intake is a salt reduction strategy that significantly decreases both systolic and diastolic blood pressure in the general population [22]. People with diabetes have low levels of potassium and magnesium, which is thought to be a contributing factor for poor blood pressure control in this population [23, 24, 25, 26]. Furthermore, oral supplementation with potassium and magnesium reduce blood pressure in people with diabetes [27, 28]. Consequently, it is important to investigate the efficacy and safety of dietary sodium salt substitution with other edible salts, such as potassium or magnesium salts, in both hypertensive and normotensive diabetic populations.
Description of the intervention and how it might work
A sizeable literature has demonstrated that high salt intake is associated with an increased risk of hypertension and that reducing dietary salt intake as a strategy to reduce sodium intake has positive outcomes [29]. In people with hypertension, sodium restriction has been demonstrated to lower both systolic and diastolic blood pressure [10]. In contrast, increased intake of other salt substitutes, such as potassium‐ and magnesium‐containing salt substitutes, has been shown to significantly decrease blood pressure, especially in people with hypertension [30, 31]. In one cross‐sectional study of 102,216 adults, a higher intake of sodium was associated with higher blood pressure, whereas a higher intake of potassium was associated with reduced blood pressure when assessing 24‐hour urinary excretion using the spot urine method [32]. Hence, along with sodium, other salts such as potassium and magnesium are also believed to interact with blood pressure regulation [33, 34, 35, 36].
Evidence suggests that a combined effect of sodium reduction and increased intake of minerals such as potassium and magnesium may help maintain blood pressure within the normal range [30, 31, 34, 36, 37]. Studies have reported that high sodium urinary excretion combined with low potassium urinary excretion is associated with higher blood pressure compared to either high sodium excretion alone or low potassium excretion alone [32, 38], demonstrating that the effects of dietary sodium on blood pressure is modified by potassium [39]. Sodium salt substitution with potassium‐containing salt to reduce the daily sodium intake has shown improved outcomes in a non‐diabetic hypertensive population [30, 40]. Consequently, for people with systolic blood pressure greater than 120 mmHg or diastolic blood pressure greater than 80 mmHg, the American Diabetes Association recommend reducing sodium intake and increasing potassium intake using the Dietary Approaches to Stop Hypertension (DASH) approach [7].
Sodium reduction is believed to exert a blood pressure‐lowering effect through extracellular fluid volume reduction [10]. The mechanisms for the blood pressure‐lowering effect of potassium may involve pathways such as inducing natriuresis [41], endothelial vasodilation and increased nitric oxide release [42, 43, 44, 45], vascular smooth muscle relaxation [43, 46], and antioxidant effects [19]. Supplementation with other salts such as magnesium has also shown promising blood pressure‐lowering effects in normotensive and hypertensive adults [31].
Why it is important to do this review
The reduction of dietary sodium intake in people with diabetes mellitus has a positive impact on outcomes such as renal dysfunction, cardiovascular disease onset, and premature death [18, 47, 48]. While low levels of potassium is a risk factor for diabetes mellitus [23, 49, 50, 51, 52], the increased levels of urinary potassium excretion are associated with the low risk for renal and cardiovascular outcomes in people with diabetes mellitus [53].
Since both diabetes mellitus and hypertension can be managed with lifestyle modifications, strategies such as salt substitution to reduce the daily sodium intake can be useful to improve disease prognosis and reduce healthcare costs. Compliance to a sodium‐restricted diet is often difficult [54, 55] and salt substitution shows great potential as a lifestyle modification for the control of blood pressure in people with hypertension [56, 57, 58]. Studies have found sodium salt substitution to be generally accepted by consumers in terms of taste rather than a salt‐restricted diet [59, 60]. The Dutch National Food Survey found that consumers were compliant with intake guidelines (European Food Safety Authority (EFSA)) when sodium chloride was replaced by potassium chloride [56]. Evidence from one study conducted in Peru applying the triangle test found that salt (used during cooking and at the table) can also be replaced by 25% with a potassium‐enriched salt substitute without consumers being able to taste the difference [61]. People with diabetes might benefit specifically from salt substitution as they have low levels of potassium and magnesium. Despite many guidelines recommending a reduction in dietary intake of sodium salt, a clear consensus on the efficacy and safety of salt substitution in people with diabetes mellitus is yet to be established [62]. Hence, in this review, we will systematically assess the benefits and harms of dietary salt substitution with other edible salts (such as potassium or magnesium salt) in people with diabetes mellitus.
Objectives
To evaluate the effect on blood pressure – measured as changes in systolic and diastolic blood pressure (mmHg) using standardised measurement methods – of substituting sodium salt with other edible salts (e.g. potassium chloride, magnesium chloride) in people with diabetes mellitus.
Methods
We will conduct this systematic review in accordance with the Methodological Expectations for Cochrane Intervention Reviews (MECIR) guidelines [63] and will report our findings following the PRISMA 2020 statement [64].
Criteria for considering studies for this review
Types of studies
This review will include randomised controlled trials (RCTs) and quasi‐RCTs. Quasi‐RCTs are defined as trials in which treatment assignment is based on alternating sequence, date of birth, registration number, or another systematic quasi‐random method.
Eligible studies must meet the following inclusion criteria.
RCTs or quasi‐RCTs comparing a sodium salt substitute diet (i.e. an edible salt in which sodium chloride is partially or fully replaced with potassium chloride, magnesium chloride, or other edible salts) with a normal sodium salt diet, a sodium restriction diet, or any other intervention as described in the following sections, in people with diabetes.
Studies in which sodium and other salt intake is estimated using 24‐hour urinary excretion.
Types of participants
We will include adults (aged 18 years or over) with type 1 or type 2 diabetes mellitus, irrespective of ethnicity, sex, or hypertensive status. Since we are focusing on type 1 and type 2 diabetes mellitus, we will exclude studies of pregnant women to avoid the gestational diabetes population.
Studies including populations with additional comorbidities will be eligible if outcome data specific to participants with type 1 or type 2 diabetes mellitus can be separately extracted and analysed. If a study includes both eligible and ineligible participants but does not provide separate data for the diabetic population, we will attempt to contact the authors to request subgroup data. If separate data cannot be obtained, we will assess the study's relevance to our review question and determine its inclusion on a case‐by‐case basis.
Types of interventions
Intervention
The intervention of interest is the substitution of dietary sodium salt intake with other edible salts, such as potassium chloride or magnesium chloride, either as a complete replacement or as a partial substitution.
Control
Acceptable control groups will include:
regular sodium salt diet: participants consume standard sodium chloride‐based table salt;
sodium‐restricted diet: participants reduce their sodium intake without substituting with other edible salts;
placebo or non‐intervention: if a study includes a placebo or no intervention group, it will also be considered a valid control.
Studies where participants have concomitant interventions will also be included providing they are non‐randomised co‐interventions. Studies comparing different types or proportions of sodium salt substitutes (e.g. varying potassium‐to‐sodium ratios) without a true control group will be excluded.
We will include trials with a study period of at least one week.
Outcome measures
The list of outcomes below is not a strict eligibility criterion and will not influence the inclusion of the studies. If a study does not report the below‐listed outcomes and qualifies all other inclusion criteria, we will evaluate the trial protocol, if available, and contact the study authors to determine whether any of the outcomes of interest were measured but not reported. For studies that assessed any of the below‐listed outcomes but did not report the data or reported the data in a format not suitable for quantitative synthesis, we will include the study in the review and present a narrative synthesis.
Critical outcomes
Change in systolic blood pressure (mmHg) measured as the difference between baseline and the longest available follow‐up.
Change in diastolic blood pressure (mmHg) measured as the difference between baseline and the longest available follow‐up.
Change in mean blood pressure (mmHg) measured as the difference between baseline and the longest available follow‐up.
Important outcomes
Serious adverse effects, total withdrawals, or both.
Change in urinary levels of sodium, potassium, magnesium, albumin, and micro‐albumin at the longest available follow‐up.
Change in serum creatinine and blood glucose at the longest available follow‐up.
Change in quality of life at the longest available follow‐up.
Adherence to the therapy.
Search methods for identification of studies
Electronic searches
The Cochrane Hypertension Information Specialist will search the following databases without language, publication year, or publication status restrictions.
Cochrane Hypertension Specialised Register via the Cochrane Register of Studies
Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies
Ovid MEDLINE(R) ALL
Ovid Embase
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (https://www.clinicaltrials.gov)
World Health Organization International Clinical Trials Registry Platform (https://trialsearch.who.int)
The Information Specialist will model the subject strategies for databases on the search strategy designed for MEDLINE. We present the MEDLINE search strategy in Supplementary material 1.
Searching other resources
The Cochrane Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Embase for systematic reviews) to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials.
We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.
We will check the included studies for retractions and errata via PubMed (https://pubmed.ncbi.nlm.nih.gov) and the Retraction Watch Database (http://retractiondatabase.org) and report the search dates in the review.
We will search Epistemonikos for related systematic reviews (https://www.epistemonikos.org).
Where necessary, we will contact experts/organisations in the field to obtain additional information on relevant trials.
We may contact study authors or funders of included studies for clarification and further data if trial reports are unclear.
Data collection and analysis
Selection of studies
Two review authors (AS and SH) will independently screen the titles and abstracts of search output and code them as 'eligible/potentially eligible for inclusion' or 'not eligible'. To ensure the reliability of the selection, one review author (BA) will re‐inspect a random sample of 20% of abstracts. All the retrieved eligible studies will then undergo full‐text screening by two review authors (AS and SH). One review author (BA) will re‐inspect a random sample of these full reports to ensure the reliability of selection. We will resolve disagreements by discussion. If not resolved, then we will contact the study authors for further clarification.
Data extraction and management
Two review authors (AS and SH) will independently extract data using a standard data extraction template. They will extract the following data from each eligible study: study author, study design (single‐blind, double‐blind, open, parallel, cross‐over), duration of study, mean age of the participants, gender, comparator, concomitant medications, ascertainment of exposure and outcomes, primary and secondary outcomes, missing data, and final sample size. We will resolve any disagreement in data extraction from the included studies by discussion or by involving the third review author (BA). One review author (BA) will spot‐check the extracted data to ensure accuracy.
We will extract the following measurements where available.
Blood pressure (mmHg) systolic, diastolic, and mean at baseline and at the end of the intervention or change between the baseline and end of the intervention, or both
Change in urinary sodium excretion (millimoles/24 hours)
Change in urinary potassium excretion (millimoles/24 hours)
Change in urinary magnesium excretion (millimoles/24 hours)
Change in serum creatinine (milligrams/decilitre, micromoles/litre)
Change in urine albumin (milligrams/24 hours or micrograms/minute), micro‐albumin (milligrams/24 hours or micrograms/minute) or protein (milligrams/24 hours)
Change in blood glucose levels (millimoles/litre) and glycaemic control glycated haemoglobin (HbA1c)
Body mass index (kilograms/metre2)
Death (any cause)
Death (cardiovascular)
Change in quality of life assessed using validated (e.g. 36‐Item Short Form (SF‐36), EuroQol – 5‐Dimensions (EQ‐5D)) or non‐validated outcome measures
Adverse events and serious adverse events (as defined by the authors)
Adherence to the intervention
Risk of bias assessment in included studies
Two review authors (SH and AH) will independently assess the risk of bias in the included studies using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions [65]. Any disagreement in the assessment will be resolved by discussion or by involving the third review author (BA). We will assess the risk of bias using the Cochrane RoB 1 tool, evaluating the following domains.
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other bias
We will stratify the risk of bias as high risk, low risk, or unclear risk. We will plot the risk of bias graph and risk of bias summary.
Measures of treatment effect
We will use mean difference (MD) if studies use the same scale, or the standardised mean difference (SMD) if studies use different scales, with 95% confidence intervals, for the treatment effect of continuous outcome variables such as blood pressure. For parallel studies, where changes from baseline values are not reported, we will calculate the MD by subtracting the mean value at the end of the intervention from the baseline values. In the case of cross‐over studies that do not report the MD, we will calculate the MD by subtracting the value from the end of the salt substitution phase from the normal salt phase. Where appropriate, we will impute the standard deviations for change using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions [66, 67]. For binary outcome data (e.g. adverse events), we will calculate risk ratios (RR) with 95% confidence intervals. We will perform separate meta‐analyses for each outcome measure assessed, as per the availability of data.
Unit of analysis issues
If findings are reported for more than one follow‐up period, then we will conduct subgroup analysis for various follow‐up periods. If a study has more than two intervention arms, we will split the sample size of the control group by the number of comparisons per subgroup for that study. For cluster‐RCTs, we will use the approach of multiplying the effect estimate standard error (ignoring the clustering) by the square root of the design effect [65].
Dealing with missing data
We will contact the corresponding authors of included studies where the required data are not available. If we do not receive any response from the corresponding authors, then we will categorise missing data as 'missing at random' or 'not missing at random'. In the former case, we will ignore the missing data, but in the latter case, we will conduct sensitivity analyses with different assumptions.
Reporting bias assessment
If at least 10 studies qualify for inclusion in an analysis, we will use funnel plots to assess publication bias followed by Egger's and Begg's test for further confirmation [68].
Synthesis methods
We will assess clinical, methodological, and statistical diversity among the included studies. If the extracted data are sufficiently homogeneous and suitable for pooling, we will conduct a meta‐analysis using Review Manager [69]. Given the expected variability in PICO characteristics (Population, Intervention, Comparison, Outcome), we will apply a random‐effects model to account for between‐study heterogeneity [70]. We will evaluate the statistical heterogeneity using the I² and Q statistics [65]. I² values will be interpreted as follows: 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may indicate substantial heterogeneity, and 75% to 100% may suggest considerable heterogeneity [70]. In the primary analysis, we will include all studies, regardless of risk of bias, ensuring a comprehensive assessment of the evidence. If the included studies do not allow data pooling, we will present the results in a narrative synthesis, following the Synthesis Without Meta‐analysis (SWiM) guideline [71].
Investigation of heterogeneity and subgroup analysis
We will conduct subgroup analyses of our primary outcomes based on the following factors, if possible.
Salt reduction comparator (salt substitution versus normal salt; salt substitution versus other salt reduction interventions): the type of comparator may influence the effect of salt substitution on blood pressure, as different salt reduction strategies may have varying physiological effects.
Type of salt substitute (e.g. potassium‐based versus magnesium‐based substitutes): different types of salt substitutes may have distinct effects on blood pressure due to their unique biochemical properties, such as potassium's known role in vasodilation.
Trial duration (four weeks or less versus greater than four weeks): the duration of intervention may impact blood pressure outcomes, as short‐term effects may differ from long‐term effects due to adaptation mechanisms or adherence issues.
Disease status (hypertensive type 1 diabetes mellitus versus hypertensive type 2 diabetes mellitus, normotensive type 1 diabetes mellitus versus normotensive type 2 diabetes mellitus): the impact of salt substitution may vary based on diabetes type and hypertension status, as these conditions may have distinct pathophysiological mechanisms affecting blood pressure regulation.
Intervention (participants with concomitant antihypertensive treatment versus participants only on substituted salt): the effect of salt substitution may be influenced by the concurrent use of antihypertensive medication, which could modify blood pressure outcomes differently compared to participants solely relying on dietary interventions.
We will use a Cochran's Q statistic to determine whether the effect differs by subgroups (with P < 0.10 indicating a significant difference).
Equity‐related assessment
We do not intend to examine health inequity in this review.
Sensitivity analysis
We will perform the sensitivity analyses to assess the impact of the following factors on effect size.
Repeating the analysis by excluding grey literature (unpublished studies)
Repeating the analysis by considering the risk of bias
Repeating the analysis excluding any open‐label studies
Repeating the analysis excluding studies with a large sample size to understand the dominance in the results
Certainty of the evidence assessment
Two review authors (SH and AS) will independently apply the GRADE approach to rate the certainty of the evidence, based on five domains: limitations in study design and implementation (risk of bias), indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision in results, and high probability of publication bias. We will resolve any disagreement in the assessment by discussion or by involving the third review author (BA). We will rate the certainty of evidence as high, moderate, low, or very low. All RCTs begin initially at the highest rating for certainty, but may be subsequently downgraded by one level for each of the five domains. Any severe problems for any domains (e.g. loss of blinding, attrition of over 50% of participants during follow‐up) will cause the study to be downgraded by two levels due to a single domain alone (Schünemann 2013).
We will summarise the findings in a summary of findings table using GRADEpro GDT [72] as outlined in Chapter 14 of the Cochrane Handbook of Systematic Reviews of Interventions [73]. The summary of findings table will present the findings for the following outcomes.
Systolic blood pressure (mmHg) at the longest available follow‐up
Diastolic blood pressure (mmHg) at the longest available follow‐up
Trial‐defined serious adverse effects at the longest available follow‐up
Consumer involvement
Consumer involvement is not planned for this review.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD014721.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
New
Additional information
Acknowledgements
Editorial and peer‐reviewer contributions
Cochrane Hypertension supported the authors in the development of this protocol.
The following people conducted the editorial process for this article.
Sign‐off Editor (final editorial decision): Dr James M Wright, University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Sue Marcus, Central Editorial Service
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported editorial team): Jessenia Hernandez, Central Editorial Service
Copy Editor (copy editing and production): Anne Lawson, Cochrane Central Production Service
Peer‐reviewers (provided comments and recommended an editorial decision): Aoming Jin, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (clinical/content review); Zeev Konstantin G Gurevich, Inter‐Parliamentary Union (consumer review); Jennifer Hilgart, Cochrane (methods review); Jo Platt, Central Editorial Information Specialist (search review)
Contributions of authors
AS: conceptualisation; methodology; writing (original draft); writing (review and editing); supervision.
SH: conceptualisation; methodology; writing (original draft); writing (review and editing).
MN: conceptualisation; methodology; writing (review and editing).
LH: conceptualisation; methodology; writing (review and editing).
BA: conceptualisation; methodology; supervision; writing (review and editing); project administration.
All authors approved the final protocol.
Declarations of interest
AS: none.
SH: none.
MN: Bayer Healthcare travel and payment for an advisory board meeting (unrelated to submitted work).
LH: none.
BA: none.
Sources of support
Internal sources
-
Menzies Institute for Medical Research, University of Tasmania, Australia
Graduate research scholarship for Ambrish Singh
External sources
-
National Health and Medical Research Council (NHMRC), Australia
Salary support for Benny Antony
Registration and protocol
Cochrane approved the proposal for this review in April 2024.
Data, code and other materials
Data sharing is not applicable to this article because it is a protocol, and no datasets were generated or analysed.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Data Availability Statement
Data sharing is not applicable to this article because it is a protocol, and no datasets were generated or analysed.