Tell Them to Go Pound Salt: Ideology and the Campaign to Legislate Dietary Sodium Intake

In the March 28th, 2013 issue of the NEJM, a review of sorts entitled "Salt in Health and Disease - A Delicate Balance" by Kotchen et al can be found.  My interest in this topic stems from my interest in the question of association versus causation, my personal predilection for salt, my observation that I lose a good deal of sodium in outdoor activities in the American Southwest, and my concern for bias in the generation of and especially the implementation of evidence in medicine as public policy.

This is an important topic, especially because sweeping policy changes regarding the sodium content of food are proposed, but it is a nettlesome topic to study, rife with hobgoblins.  First we need a well-defined research question:  does reduction in dietary sodium intake:  a.) reduce blood pressure in hypertensive people?  in all people?  b.) does this reduction in hypertension lead to improved outcomes (hypertension is in some ways a surrogate marker)?  In a utopian world, we would randomize thousands of participants to diets low in sodium and "normal" in sodium, we would measure sodium intake carefully, and we would follow the participants for changes in blood pressure and clinical outcomes for a protracted period.  But alas, this has not been done, and it will not likely be done because of cost and logistics, among other obstacles (including ideology).

Even if we could conduct such a study, it may not be definitive because some of our unavoidable assumptions would be unfounded.  In almost all of the studies referenced in the NEJM review, sodium intake was inferred from sodium excretion in the urine, and this is a potentially highly flawed assumption.  Here's a thought experiment.  Suppose that a group of people enrolled in the utopian study are from Salt Lake City, Utah and they are avid bikers and backcountry skiers, and that they consume a good deal of salt, say 7 grams per day of sodium chloride.  Suppose also that they sweat out, during vigorous exercise, 3 grams per day.  Their urinary sodium excretion will show them to be low sodium consumers, but they are not.  The surrogate measure of sodium consumption has misclassified them.  Moreover, guess what their outcomes will be?  Presumably they will be good, but because of exercise and all the associated lifestyle choices - not because of low sodium intake.  Sodium intake is actually high!  But the conclusion will be that the (mistakenly) low  sodium intake was associated with the good outcomes (which were actually due to exercise.)  So, in my opinion, all of these studies are fundamentally and fatally flawed because of inability to measure sweat sodium losses, which means that vigorous exercise confounds the proper classification of sodium intake and at the same time influences outcomes of interest.   Moreover, almost all (all?) of the cited studies used sodium excretion at a single point or at intervals as the surrogate for sodium intake.  This carries the obvious assumption that the surrogate was stable over time.

With that in mind, I'll guide us through the review to see if other premises, taken for granted, are vulnerable to challenge.

The authors state (page 1229, paragraph 4) that "Studies across populations provide more convincing evidence than within-population studies of the association of salt intake with both blood pressure..."  Why might that be?  Several obvious explanations.  First, ecological fallacy.  The people consuming salt and driving up the population mean may not be the people having the events.  But there's a more compelling (and equally obvious) explanation - differences between populations have a good deal more to do with differences between populations in factors other than salt intake, which are not or cannot be measured.  The jewel of the references in this section of the review is reference 7, the Intersalt study, a herculean effort by investigators more than a quarter a century ago to catalog differences in sodium excretion and blood pressure in participants in 33 countries and 52 centers across the world.  The Intersalt report is rife with data, and one could spend hours poring over it (I did).  Suffice it to say that it is an observational dataset, and no matter how intriguing its findings, how prolific the data collected, it cannot answer the fundamental question of causation versus association.

In paragraph 5 which continues on page 1230, the authors emphasize several meta-analyses of studies of dietary sodium reduction on blood pressure measurements.  The most notable among these, the Midgley report in JAMA, 1996, (reference 10) found:  evidence of publication bias; that the regression analyses crossed the y-intercept suggesting that blood pressures declined after enrollment irrespective of sodium reduction; that the effect of sodium reduction on blood pressure was modest;  that trials generally were poor at reporting other variables known to affect blood pressure (with potential for confounding);  that the effect of sodium reduction on blood pressure was (much) greater in hypertensive participants; that trials involving "free range" participants (those not institutionalized or whose meals were prepared for them) showed no effect of sodium reduction on BP.  The authors concluded in the last sentence of their report:

This analysis, in part because of the large number of normotensive trials now published, does not support one of the goals of the Nutrition Labeling and Education Act (1990), that of lowering blood pressure in the normotensive population at large, and questions the wisdom of universal dietary sodium restriction  without better evidence of the long-term benefits  and safety of such an intervention.

A similar conclusion was reached by the authors of reference 12 (Graudal et al, JAMA, 1998): 

"These results do not support a general recommendation to reduce sodium intake.  Reduced sodium intake may be used as a supplementary treatment in hypertension.  Further long-term studies of the effects of high reduction of sodium intake on blood pressure and metabolic variables may clarify the disagreements as to the role of reduced sodium intake, but ideally trials with hard end points such as morbidity and survival should end the controversy."

It seems odd that these two studies should figure so prominently as part of the basis of the authors' arguments (and in Table 1).  They state (paragraph 5) that "clinical trials provide definitive evidence of a direct cause-and-effect relationship between salt consumption and blood pressure."  Not so, says Dr. Scott.  A utopian clinical trial would provide definitive evidence, but these trials are not utopian and thus not definitive.  (They don't control all the variables [diet, exercise], they don't account for all the variables, their surrogate for sodium intake is flawed, etc.)   If they were, we would not be combining them into a meta-analysis, and we would not have the authors of the meta-analyses hedging their conclusions as they do.  The use of references 10 and 12 to support this statement is duplicitous.

A subsequent premise described in the review, namely that sodium reduction on the population level will reduce clinical disease on the population level, is quite curiously attempted to be supported by a 2010 NEJM article (Reference 31:  Bibbins-Domingo et al, NEJM, 2010) using complex modeling to estimate the reduction in cardiovascular disease events that might  be achieved, (with all the assumptions inherent in the model) if sodium intake were reduced by certain levels.  Their optimistic estimate, reduction in salt by 3 grams per day (which equates to 1.2 grams of sodium or about 52 mmol), is greater than what was achieved in a strictly controlled, monitoring-intensive study of fewer than 1000 hypertensive subjects followed for a relatively short 30 months (see Whelton et al, JAMA, 1998).  To expect that results superior to that may be achieved on the level of the entire population for extended periods is optimistic indeed.  In any case, projections based on premises do not support the premises themselves.  The next reference in support of this premise is the meta-analysis by Strazullo (reference 32) which did show that among  observational  studies, cardiovascular events, especially stroke, were associated with  lower sodium intake.  So we've advanced the association from sodium and hypertension to sodium and clinical events, but we still don't have evidence of causality and all the associational caveats of observational studies apply (also the GIGO - "garbage in, garbage out" - caveat of meta-analyses).

Enter the clinical trials references (39-41).  (Unfortunately, because I don't have an academic affiliation, I cannot access many of the studies in journals to which I do not subscribe.  I'm a victim of academia's proprietary monopoly on [mostly] publicly funded data.  That's right, the taxpayer pays for it, but can't access it.  Even when it's used to promote a public health agenda in which the taxpayer is a major stakeholder.  But that's a story for another post.)  Reference 39 (Cook et al, BMJ, 2007) is not really a clinical trial after all.  It's a long[er]-term observational follow-up of patients enrolled in sodium reduction trials, and the results showing improved cardiovascular outcomes with sodium reduction were barely statistically significant, and then only after statistical adjustment.  Technically, a it's a "FAIL" by rigorous standards, and certainly not a "long-term, prospective, randomized clinical trial" as touted by Kotchen et al.  Reference 41 (Whelton et al, JAMA, 1998) is indeed an RCT of sodium reduction in elderly hypertensive patients that shows a statistically significant reduction in a composite outcome with sodium reduction as the intervention.  A careful look at Table 3 (page 845 of the article) shows that all of the benefit of sodium reduction on the composite outcome had to do with the ability to withdraw antihypertensive medications, and there were no reductions in cardiovascular events in the sodium reduction group.  If you want to show that sodium reduction does something to "clinical outcomes", this is a very clever design indeed.  But for patients, the operative question remains:  would I rather restrict my sodium intake, or take an antihypertensive medication?

The review goes on, and so could this post, but I'll stop here to spare the reader the drivel.  (Nor will I attempt to entertain the reader with links to pages all over the web where proponents and detractors of sodium reduction battle furiously over their positions, along with the evidence of bias and conspiracy alleged by both sides.)  The above paragraphs summarize the main data upon which the purported benefits of sodium reduction are predicated.  A perusal of these data shows that the premises, the very foundations of the arguments proffered, are precarious.  Here's what we can say with some confidence:

• Most people consume far more sodium than is necessary for survival.
• All studies of sodium consumption and reduction thereof are subject to severe methodological and logistical limitations.
• There are associations between sodium intake and blood pressure, and between blood pressure and clinical outcomes of interest.
• Reduction of sodium intake in patients with hypertension lowers blood pressure.
• None of this establishes a causal link between sodium intake or reduction thereof and clinical outcomes of interest other than hypertension in hypertensive persons.

So, what does this mean for patients and public policy?  For patients, if you don't have hypertension, you probably don't need to worry about sodium intake - for now.  If you do have hypertension, you can consider sodium intake reduction among several alternative options for reducing your blood pressure.  Some may prefer to take a pill, some may prefer to limit sodium intake, some may decide to lose weight or exercise or reduce alcohol consumption (or initiate it - it's Mediterranean!), some may elect to (or be forced to) do a combination of these things.

As for public policy (the nuances and philosophy and ethics and morals and politics thereof are far too many to discuss in this post), for me it's clear.  Before the true-believers (that is, those guided by faith rather than by reason; the devout; the ideological - as opposed to the reasoned; the scientific; the logical) - before they begin to tinker with the food that people eat, they had better have robust data of causation as the logical foundation of their enterprise, lest they rush us headlong into another ill-begotten catastrophe like hormone replacement therapy.  Behold how quickly the lessons of history are forgotten, especially by the zealous.

I don't like feeling that somebody is trying to hoodwink me (or tell me what to eat). So the true-believers and public-policy-tinkerers can go pound salt.  The rest of us can keep eating it.

Added 6/7/2013:  See this NYT article about the recent IOM report on reducing sodium intake.

Added 2/10/15:   The PURE study was published in the NEJM in August, 2014.  I wrote this letter to the editor, which I thought had a high likelihood of publication, but alas it did not.  Suffice it to say that the PURE study suffers from some of the same limitations described above:

Two important limitations could have profound implications for the interpretation of the PURE Investigators' results [1, 2].  Firstly, the use of a single urinary sodium measurement assumes that sodium balance is in a steady state at the time of measurement.   This assumption may be false if a sodium retaining  state such as heart failure is developing.  This would lead to misclassification of a person with incident cardiovascular disease as having lower than actual sodium intake.  Secondly, the urinary sodium surrogate ignores the substantial sodium lost in sweat (on the order of 1 gram sodium per liter sweat)[3].  This will lead to misclassification of lower sodium intake in those who exercise vigorously.  If they also have low blood pressure and low mortality, it will be attributed to the spuriously low sodium excretion rather than vigorous exercise.  The analysis included self-reported physical activity but perceptions of physical activity are known to be inaccurate and the temperature and humidity in which the activity takes place affect the amount of sweat and its sodium content [3, 4].

Reference List

    1.    Mente A, O'Donnell MJ, Rangarajan S, McQueen MJ, Poirier P, Wielgosz A, et al. Association of Urinary Sodium and Potassium Excretion with Blood Pressure. New England Journal of Medicine 2014; 371(7):601-611.

    2.    O'Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events. New England Journal of Medicine 2014; 371(7):612-623.

    3.    Bates G, Miller V. Sweat rate and sodium loss during work in the heat. Journal of Occupational Medicine and Toxicology 2008; 3(1):4.

    4.    Canning KL, Brown RE, Jamnik VK, Salmon A, Ardern CI, Kuk JL. Individuals Underestimate Moderate and Vigorous Intensity Physical Activity. PLoS ONE 2014; 9(5):e97927.