More on dissidents and dietary sodium

There is a lack of clarity in the response from O’Donnell et al. to concerns about their commentary on current dietary sodium recommendations.1,2 The lack of clarity may lead readers to misunderstand the scientific evidence behind current dietary guidelines for sodium. O’Donnell et al. imply that current guideline recommendations do not account for new evidence.1 Yet critical appraisals of the evidence to create dietary sodium recommendations have been and continue to be regularly conducted by highly esteemed national and international health and scientific organizations and include new evidence. The latest major recommendations were the Dietary Guidelines for Americans, which included an assessment of the Prospective Urban Rural Epidemiology (PURE) study results.3 The guidelines state: ‘Consume no more than 2,400 mg of sodium/day … Further reduction of sodium intake to 1,500 mg/day can result in even greater reduction in blood pressure’ and ‘A reduction in sodium intake by approximately 1,000 mg/day reduces CVD [cardiovascular disease] events by about 30 percent’. The multi-year evidence review process to update the American and Canadian dietary reference intakes for sodium is under way.4 Supported by international health organizations, there is a weekly Medline update of the science related to dietary sodium [http://www.hypertensiontalk.com/science-of-salt-weekly/)]], and updated critical appraisals of the literature on dietary sodium and outcomes were published annually and are now published every few months.5–8 The evidence base and recommendations on dietary sodium continue to be kept up to date. The updated evidence reviews and the recommendations of national and international health and scientific organizations do not support the recommendations on dietary sodium proposed by O’Donnell et al. O’Donnell et al. imply that there is no primary evidence to support current dietary sodium recommendations; yet meta-analysis of quality cohort studies shows associations of dietary sodium and CVD, and a meta-analysis of randomized controlled trials of sodium reduction (with and without added potassium) shows reduced cardiovascular events in the intervention arm.9,10 The primary studies in the meta-analyses were conducted on populations consuming a range of dietary sodium intakes (above and within current recommendations) and show higher rates of adverse outcomes with higher intakes of dietary sodium. In the study that most rigorously assessed sodium intake (using multiple days of complete 24-h urine collections), lower cardiovascular event rates were observed in those consuming less than 2300 mg/day,11 and there was a linear relationship with total mortality.12 Studies with serious design flaws and of low quality do not affect the conclusions of high quality evidence reviews conducted by expert governmental and non-governmental organizations; rather, such studies are a threat to scientific integrity and public health.13–15 J, U or inverse relationships between sodium intake and health outcomes generated in studies that use inappropriate or low quality methods can be explained by artefacts of the research methodology and, in several instances, studies with ‘controversial’ J, U or inverse results have not been reproduced on subsequent re-analysis of the same databases.16–21 It is unusual for higher quality studies to not show a direct relationship between sodium intake and a major health outcome.7,8 Low quality research on dietary sodium has generated an unusual call by major national and international health and scientific organizations to develop minimum standards for the conduct of research.13 O’Donnell et al. infer that a credible scientific organization supports their views regarding dietary sodium intake, by referring to a 2013 Institute of Medicine report.22 The Institute of Medicine continues to recommend that middle-aged adults consume less than 2300 mg sodium/day, with an adequate intake level of 1500 mg/day, and that other age groups should have a lower intake.23 The 2013 Institute of Medicine report expressed concern about the quality of research examining dietary sodium intake below 2300 mg/day, but did not apply quality criteria in assessing studies, such as those used in the World Health Organization review.9 The committee mandate was to assess research conducted over the 8 years between 2005 and 2012.9,22 More recently, a World Heart Federation committee, formed under Dr Yusuf’s presidency and with a former Salt Institute consultant as Co-Chair and Dr O’Donnell as a member, expressed concern about the quality of research supporting current dietary sodium recommendations. Nevertheless, the World Heart Federation continues to align with WHO Global Action Plan Targets that include a 30% reduction in dietary salt by 2025.24 O’Donnell et al. have claimed that sodium reduction in the context of public health interventions is associated with marked increases in renin aldosterone axis (RAS) and refute that there is ‘little impact’ on the RAS of reducing dietary sodium to recommended levels, citing a meta-analysis published in 2013.25,26 Yet the meta-analysis they cite in their letter found that ‘salt reduction is associated with a small physiological increase in plasma renin activity, and aldosterone’. O’Donnell et al. ignore a recent meta-analysis that showed a diminishing effect of sodium reduction on the RAS over time, no changes in RAS in studies lasting more than 5–6 weeks, and no association of sodium intake and RAS activity in the general population.27 Studies that have markedly altered sodium intake over hours to a few days increase RAS, but are not relevant to public health interventions to reduce dietary sodium.28 O’Donnell et al. continue to defend their PURE study validation of spot urine samples relative to 24-h urine samples, citing their dependent correlation coefficient. In a seminal publication in 1986, Bland and Altman state: ‘In clinical measurement comparison of a new measurement technique with an established one it is often needed to see whether they agree sufficiently for the new to replace the old. Such investigations are often analyzed inappropriately, notably by using correlation coefficients. The use of correlation is misleading.’29 Subsequently, Bland–Altman plots have been used to assess agreement between measurement methods. The Bland–Altman plot in the PURE validation of spot vs 24-h urine, as in other similar validation studies, shows that a single spot urine test is not a valid method to assess 24-h urine sodium.30 Spot samples systematically overestimate 24-h urine sodium at low 24-h urine sodium, and systematically underestimate 24-h urine sodium at high 24-h urine sodium.31 The systematic error will influence the association of sodium intake assessed by spot urine samples with blood pressure and CVD outcomes, potentially creating relationships that curve or have differing slopes. A systematic review found the Kawasaki equation (which was used in the PURE study) standing out ‘as a poor performer’, markedly overestimating mean consumption.31 Newer research continues to demonstrate the lack of validity of using single spot urine samples to assess an individual’s sodium consumption.32 For example, single spot urine estimates for salt intake were recently calculated to be inaccurate by more than 3 g in 75% of individuals, compared with a single 24-h urine sodium value (noting that multiple 24-h urine sodium values were required to accurately classify an individual’s sodium intake).33 Further, the formulas used to estimate 24-h urine sodium from spot samples contain many of the same variables as used in cardiovascular risk calculations and are strong predictors of total mortality and cardiovascular events. Hence, it is inappropriate to use output from such formulas to assess the associations of dietary sodium with outcomes, as the associations are likely to be related to the known risk factors (e.g. age, sex, creatinine level) in the formula. Perhaps the area of O’Donnell et al.’s response that is most likely to be misunderstood by readers is the section on potential conflicts of interest. Commercial interests in pharmaceutical management of CVD compete with public health policies that could prevent or control CVD. In fact, much of the current epidemic of CVD is attributed to unhealthy diets, and much of the pharmaceutical industry’s profits come from treating diet-related disease and risks.34 Disclosures are required to assess bias that might influence research findings or their interpretation. O’Donnell et al. imply that giving talks at commercially supported meetings does not require disclosure,1 and defend a lack of disclosure of a patent and patent applications relating to pharmaceutical treatments held by Dr Yusuf. O’Donnell et al. claim that the group has not received funding from the food industry, whereas a recent publication on which they were prominent authors indicated funding from the Unilever Health Institute and the Sugar Institute of South Africa,35 and Mente and Yusuf were on the organizing committee of a meeting that received funding from multiple food-related companies.2 Specifically, the International Committee of Medical Journal Editors has a standard for disclosing potential conflicts.36 The letter from O’Donnell et al. justifies their having conflicts of interest but leaves uncertainty as to whether they have disclosed their conflicts of interest (honoraria, research grants, patents and their applications, travel support etc.) from commercial sources that could bias their perspective. I hope O’Donnell et al. will provide clarity in addressing my concerns, a complete disclosure of their conflicts of interest and the full analysis of the PURE validation study, including the examination of independent spot and 24-h urine samples, and/or allow open access to the data. Conflict of interest: Since writing my first letter, I have become a paid consultant to the Novartis Foundation to support their programme to improve hypertension control in low- to middle-income countries, which includes travel support for site visits and a contract to develop a survey. I am an unpaid member of World Action on Salt and Health (WASH).

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