Understanding the science that supports population‐wide salt reduction programs

Independent systematic reviews of the totality of the evidence by governments and international agencies throughout the world uniformly conclude that population-wide interventions to reduce salt are beneficial for health. However, some scientists continue to produce and cite studies with paradoxical findings that conflict with the evidence base used to develop national and World Health Organization (WHO) guidelines on salt reduction.1-5 While conflicting studies are not uncommon in any area of research,6 in the case of salt, such studies attract widespread attention in the media; misinform program leaders, clinicians, and the general public; and impede program implementation. Such impediments to progress have occurred despite the fact that the designs and methods of studies with paradoxical findings have been criticized by international experts who highlight the fact that the results are not valid.7-9 To address this problem, a consortium of national and international health and scientific organizations is leading a program of work through its Standards for Salt Research group. The objective of this consortium is to develop a clear set of processes and criteria to which new scientific projects relating to salt should adhere, in order to achieve at least a minimum quality of research in the field.10 While general criteria for judging the scientific evidence for studies are available,11 they do not address the complexity inherent in accurately assessing salt intake and its relationship with health outcomes. The new Standards for Salt Research will help to ensure that only robust scientific studies are used when national and international recommendations relating to salt reduction are reviewed. In the meantime, the objective of this paper is to provide an overview of the main arguments used against reducing salt and to counter these arguments with evidence in support of reducing population-wide salt intake. This work updates previous similar reviews that have explained some of the controversies.12-14 The intent of this paper is to assist policy makers, program implementers, and clinicians in understanding the science in support of salt reduction and provide them with tools to counter arguments against population-wide salt reduction. 1. Can we make recommendations about salt without consensus on the science? Salt is an unsettled and hot topic for investigation and so it would be premature to make recommendations in the absence of trial data. Response: There is consensus about the need to reduce population salt intake from the organizations that have systematically and independently examined the totality of the evidence. Public health policy recommendations need to be based on critical appraisals of the totality of the evidence by expert scientific groups overseen by governmental or nongovernmental health and scientific organizations. As in most areas of public health, the evidence base is incomplete, as it is lacking in definitive randomized controlled trials (RCTs) for cardiovascular disease (CVD) outcomes, due to practical and ethical considerations. Nevertheless, multiple independent review processes in different countries15-19 have all concluded that typical dietary salt intake is too high, that it creates serious health problems, and that consequently salt intake should be reduced. The current WHO recommendation is that salt (sodium chloride) intake should be <5 g/d1 for adults, with lower levels in children based on their lower caloric needs.20 The evidence supporting the need to reduce salt and the impact of reducing salt on health is increasing.21-23 However, every year there are a few controversial studies that get most of the media coverage and cause some people to question current recommendations. These studies are usually linked to a small group of individuals, several with ties to commercial interests.14 Such studies are not appropriately designed to assess the association between salt intake and disease as outlined below. 2. What are the estimated potential benefits of salt reduction on the burden of disease and death? Some estimates of the potential benefits of salt reduction in terms of burden of disease and deaths are much lower than initially thought. Response: Reducing salt intake would save millions of lives a year globally. High dietary salt is associated with wide-ranging health problems including hypertension, stroke, CVD, bone demineralization, kidney stones, gastric cancer, and kidney disease.24-29 The greatest health risk is the increase in blood pressure (BP) caused by excess salt intake. Although the magnitude of change in BP from modest changes in dietary salt are relatively small in individuals, on a population scale,21 a reduction in salt explains between one fifth30 and one third19 of cases of hypertension. The Global Burden of Disease Study31 estimated that increased dietary salt is the second leading behavioral risk for death and the third leading behavioral risk for disability globally, such that 4.129 million deaths and more than 83 million disability-adjusted life years lost could be attributed to high dietary sodium consumption in 2015. Health economic analyses have found that reducing dietary salt is cost saving or highly cost effective in different investigations.32, 33 Such evidence has provided the rationale for the WHO and the World Economic Forum to identify population-wide sodium reduction as a "best-buy" intervention for public health.34 3. Does reducing salt reduce BP long term? Most evidence shows that reducing salt reduces BP only in the short term (<6 months). Should we be cautious in extrapolating from short-term studies of a few months or weeks to what might be expected in the long term? Response: A large body of evidence supports the fact that reducing dietary salt has a long-term effect on BP. In a wide variety of animal studies, BP continues to increase if salt intake is increased, and this is not attenuated over time.35-37 In human epidemiological studies, habitually high dietary salt intake is associated with high BP and increasing BP with age.38-40 BP would not continue to rise with age if changes in BP were only for a short time after exposure.37 In long-term population intervention studies that reduced dietary salt and lasted for decades, decreases in BP have matched or exceeded reductions predicted from results of shorter-term clinical trials.41, 42 In clinical trials of reducing dietary salt, BP reduces in proportion to reductions in dietary salt.43-48 Many trials lasting 4 weeks or longer have shown reductions in BP.45 Several high-quality randomized clinical trials that reduced dietary salt have demonstrated reductions in BP up to 18 months with no attenuation in reduction of BP.44, 49 Most longer-term trials have not been able to sustain reductions in dietary salt among participants and have been challenged regarding confounding with other cointerventions.44, 50 Nevertheless, in the sodium reduction arm of the Trials of Hypertension Prevention (TOHP) 2 study,50 systolic BP was still reduced in the intervention arm compared with control after 3 years. In conclusion, well-designed meta-analyses of salt reduction trials clearly demonstrate that salt reduction will have a long-term impact on BP.9 4. What is the evidence that lowering BP in nonhypertensive persons will reduce CVD mortality? Some studies suggest that lowering BP increases mortality and cardiovascular events (other than stroke) in people without hypertension. Response: Lowering BP will reduce CVD mortality, including in persons without hypertension. The extensive evidence from epidemiology and higher-quality analyses of randomized clinical trials shows a direct relationship between BP and CVD.48, 49, 51-54 This relationship between BP and CVD is evident at SBP values beginning at ≈115 mm Hg,55 a finding that suggests that nonhypertensive persons will also benefit from reductions in BP. The long-term follow-up from the TOHP studies, which showed that reduced sodium was associated with reduced CVD, were all performed in prehypertensive patients.56 Reductions in CVD are related to the extent to which BP is reduced as well as to the absolute cardiovascular risk of the study population.51-54, 57 The controversy arises from retrospective nonrandomized analyses of studies that include individuals who are already sick. Some such studies have found a U- or J-shaped curve that can be explained by reverse causality (whereby BP may be low because of preclinical or prevalent diseases such as myocardial infarction or heart failure, which then lead to increased risk of premature death).1-3, 58 Studies where aggressive BP-lowering therapy is used in populations susceptible to clinical hypotension may also cause cardiovascular and renal disease.59 A recent study that suggested a relationship between reduced BP and increased CVD events included patients with diabetes, and therefore treatment and other factors were likely to have influenced the results.60 Such studies do not provide evidence to counter support for population-wide salt reduction strategies.7, 8, 61-63 An overview of some of the main weaknesses in these studies is provided below. 5. Why are there no randomized clinical trials proving that salt reduction reduces CVD? These must be performed to provide robust data proving that salt reduction reduces CVD before we implement interventions. Response: Pooled data from RCTs with long-term follow-up for CVD suggest that salt reduction reduces CVD.64 The reasons few RCTs have been designed and conducted specifically to examine whether salt reduction reduces CVD is because adequately designed and appropriately powered trials would be too expensive, impractical, or potentially unethical, given the high quality of evidence documenting the benefits of salt reduction. This is the same in many other fields of public health (eg, tobacco control, obesity reduction, actions to reduce climate change, air pollution, physical inactivity, and excessive alcohol consumption). Because of the high content of salt in the food supply, long-term RCTs of salt reduction have found it hard to sustain reduced dietary salt for more than 3 years in free-living patients.44, 65 The alternative approach of asking patients to increase dietary salt would be unethical due to the evidence that eating too much salt harms health. In most clinical trials, the relatively small number of people who have a CVD event precludes the establishment of any relationship between salt intake and CVD. However, studies that have pooled the data from RCTs of salt reduction, or salt replacers, using meta-analyses, have demonstrated a reduction in cardiovascular events with reduced dietary sodium.64, 66 The existing evidence is strong enough to support the implementation of strategies to reduce salt intake. Meta-analyses of cohort studies of salt intake in healthy populations, or where filters were used to exclude low-quality research, have also shown that salt intake is associated with CVD.21, 67 Long-term experience with salt reduction in Finland, Japan, and the United Kingdom has shown an association between salt reduction and reduced BP and CVD at the population level.41, 68 Long-term follow-up of individuals in the TOHP trials, which carefully assessed usual salt intake through repeat 24-hour urine collections, found that salt intake <2300 mg/d was associated with reduced CVD.56, 69 6. Aren't low levels of sodium consumption associated with increased CVD events and mortality? Some studies show that low levels of sodium (<3000 mg sodium or 7.5 g salt/d) are associated with increased mortality, especially in nonhypertensive persons. The most recent study quoted is the Prospective Urban Rural Epidemiology (PURE) study. Response: It is important to emphasize that consumption of <3 of sodium a day is not considered low sodium consumption70 and that such levels are not associated with increased CVD events and mortality. Population salt intake for communities with diets that do not have added salt are nearly all below 1 g of sodium (2.5 g of salt) per day.71-73 So, although sodium is required for proper bodily function, the minimum physiological amount required is <1 g of sodium per day.70 Very few populations are currently consuming such low amounts, but in the few remaining hunter-gatherer populations where they do, BP does not rise with age and hypertension and CVD are uncommon.37, 74, 75 Reliable vital statistics are unavailable in these isolated populations, but mortality appears to be related to infectious diseases and other problems of economically developing regions that are unrelated to salt intake. While some of the studies that suggest lower amounts of dietary salt are associated with increased CVD events and mortality are based on very large numbers of participants, the methodologies are seriously flawed. Hence, their findings should be interpreted with caution and are not appropriate to guide policy. Systematic reviews of cohort studies that have criteria to exclude lower-quality studies, as well as systematic reviews of RCTs, have found that CVD is reduced (not increased) with lower intakes of dietary sodium.21-23, 51, 67 7. Why can't untimed collections (eg, spot samples) such as those used in the PURE study and others, which show a J-shaped curve, accurately reflect the usual long-term salt intake of individuals? Response: Spot urine samples are an unreliable measure of individual salt intake and should not be used as the basis for correlating salt intake with health outcomes, such as BP or CVD.78, 85-87 There is ongoing research to examine the potential for use of spot urine samples from a large sample of the population to estimate mean population salt intake.88 However, spot urine samples do not provide an accurate assessment of an individual's intake. The reasons are as follows: Public health policy regarding nutritional exposures and chronic disease outcomes (including CVD and cancer), where diseases develop over decades, is seldom based solely on evidence from RCTs.94 Although RCTs are widely regarded as the best evidence to test the effects of a medical therapy, they are often impractical in the context of long-term public health interventions on outcomes that may have multifactorial influences over time. They may also be unethical, particularly if there is already a substantial body of evidence from epidemiological studies and/or intervention studies using intermediate end points, such as BP in the case of salt reduction.94 To delay implementation of public health policy, in the absence of RCT data providing "direct" evidence, may convey considerable harm to the population, especially if such RCT evidence is unlikely to be forthcoming.95 For this reason, authoritative bodies have developed tools for systematically appraising the totality of scientific evidence (including experimental, epidemiological, and RCT evidence) in order to develop recommendations aimed at individuals and populations.96 Despite this, vested interests (including the food industry) may exaggerate any uncertainties that this situation offers in order to prevent or delay government action or regulation.12, 13, 97 The evidence regarding the harms of diets high in salt is sufficient to justify recommendations from the WHO and other governmental and health-related organizations to reduce population salt intake.16, 20, 61 For example, there is a "substantial amount of evidence" of a dose-response relationship that dietary salt and salted foods are positively associated with stomach cancer,28 leading the World Cancer Research Fund and WHO to conclude that dietary salt and salted foods are a probable cause of this cancer.20, 96 There is a much larger body of evidence that supports an association between high intake of dietary salt and elevated BP45 and CVDs, such as myocardial infarction and stroke.21 On the other hand, the premise that reducing salt intake in populations could cause harm is not supported by a strict application of the criteria used to demonstrate cause and effect.8 The WHO target to implement population-level interventions to lower dietary salt intake by 30% by 2025 was agreed on by its 194 member states in 2013.98 The WHO and regional offices have developed a number of different tools to support member states to achieve this target.99, 100 A 2014 review highlighted the fact that 75 countries already had national programs in place to reduce population salt intake.101 There is growing evidence of the efficacy of such programs.102 Evaluations of the more established interventions have also shown that population-level reductions in salt intake have been associated with declines in CVD rates in those populations.42, 103 The recent publication of paradoxical studies with low-quality methodology should not delay implementation of public health interventions. The attention given to such studies in comparison to the critique of them8, 63, 104, 105 is completely unwarranted. The call for further research106 is also not a reason to delay such implementation. There are numerous examples where the conduct of further research has not added to knowledge but merely delayed implementation of policies based on findings that would have been apparent if systematic synthesis of existing study results had been available or undertaken. To document contemporary evidence on the science of salt, the World Hypertension League and other organizations support a regular (every few months) updated review. Over the past 3 years (2013–2015), having screened for inclusion based on minimum methodologic criteria set a priori, this approach found 14 studies that supported and no studies that countered the evidence for the beneficial impact of salt reduction on disease.22, 23, 107 International organizations have published a statement of concern about the impact of research studies that do not meet quality criteria (including the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET], the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease [TRANSCEND], Diabetes REduction Assessment with ramipril and rosiglitazone Medication [EpiDREAM], and PURE).10 An international expert group (the TRUE consortium) has been established and will soon be publishing the criteria that need to be met in order for studies of salt reduction to be reliable. Current recommendations to reduce population sodium intake20 are based on sound scientific evidence. The recent publication of a few paradoxical studies of questionable scientific merit should not delay implementation of salt reduction initiatives worldwide. Governments and health organization should continue to implement programs to reduce salt in line with the WHO Global Action Plan for the prevention and control of noncommunicable diseases.108 The authors wish to thank Mary E Cogswell, Dr. P.H (Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, CDC) for her advice and support. TW, JA, KT, LJA, and RM have no conflicts of interest to declare. JW is Director of the WHO Collaborating Centre on Population Salt Reduction and is supported by a National Health and Medical Research Council/National Heart Foundation Career Development Fellowship on International strategies to reduce salt. JW has funding from WHO, VicHealth, and the Australian National Health and Medical Research Council of Australia for research on salt reduction. FPC is Director of the WHO Collaborating Centre for Nutrition, Vice-President and Trustee of the British and Irish Hypertension Society, Technical Advisor to the WHO, and unpaid member of CASH, WASH, and the UK Health Forum, all Registered Charities in the United Kingdom. MW is a consultant for Amgen. NC has a contract with Novartis Foundation to assist in hypertension control interventions in low-resource settings and is a member of World Action on Salt and Health (a dietary salt reduction organization). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.