August 13th, 2014

Two New Studies Fuel the Debate Over Sodium

Three papers and an editorial in the New England Journal of Medicine are sure to throw fresh fuel on the ongoing fiery debate over sodium recommendations. Current guidelines recommend that people should limit their intake of sodium to 1.5  to 2.4 grams per day, but these recommendations are based on projections and have never been tested in clinical trials or other large studies.

Two papers from the  ongoing Prospective Urban Rural Epidemiology (PURE) study offer fresh evidence against the low-sodium recommendations. The PURE investigators estimated sodium and potassium intake based on a single fasting morning urine specimen in more than 100,000 adults from 18 countries. They then followed the participants for 3.7 years. In two separate papers, they report the relationship between estimated sodium and potassium levels on blood pressure levels and on death and cardiovascular events.

In the first PURE paper, blood pressure, as expected, increased along with sodium excretion. For each additional 1-g/day increase in sodium, systolic and diastolic blood pressure increased by 2.11 mm Hg and 0.78 mm Hg, respectively. However, the investigators reported that the association was most pronounced at the higher levels of sodium excretion: a 2.58-mm Hg increment in systolic blood pressure per gram for those with sodium excretion >5 g per day versus a 0.74-mm Hg increment per gram for those with sodium excretion <3 g per day. Sodium excretion also had a larger effect on blood pressure in people with hypertension than in people without hypertension and in older people compared with younger people. A similar but inverse pattern emerged with potassium.

The second paper reported the cardiovascular outcomes of the PURE participants after 3.7 years of follow-up. People who had the highest levels of sodium excretion (7 or more g/day) had a 15% increase in the risk for death or major cardiovascular event (OR 1.15, CI 1.02 – 1.30). The highest risk was seen in people with hypertension. Of particular note, there was a 27% increase in risk in people with sodium excretion levels below 3 g/day (OR 1.27, CI 1.12 – 1.44). The increased risk in the high-sodium group was closely linked to the increase in blood pressure. By contrast, the increased risk in the low sodium group was not linked to blood pressure. Again, an inverse pattern was observed for potassium.

In the third NEJM paper, researchers in the Global Burden of Diseases Nutrition and Chronic Diseases Expert  (NUTRICODE) Group, led by Dariush Mozaffarian, performed a systematic analysis of published studies and combined the data to estimate global sodium consumption. They calculated the  global mean level of sodium consumption as 3.95 g/day. They then calculated the effect of the sodium on blood pressure and then estimated that the increase in blood pressure from sodium consumption greater than 2 g/day resulted in 1.65 million cardiovascular deaths annually, accounting for 9.5% of all deaths from cardiovascular causes.

The American Heart Association, which has been a strong proponent of low-sodium guidelines, released a statement discounting the findings of the PURE study as “an observational study that attempts to link dietary sodium intake with subsequent cardiovascular diseases.” AHA president Elliott Antman said, “Interpreting the results of these types of studies was particularly challenging because results can be highly dependent on the types of data collected (and not collected) and the types of analyses performed.”

By contrast, Antman said the findings of NUTRICODE were “staggering”: “About 1 in 10 cardiovascular deaths were estimated to be attributed to sodium intake of greater than 2,000 milligrams per day. This is a level exceeded by 99.2 percent of the world’s adults, on average. In the U.S. alone, almost 57,600 annual cardiovascular deaths are attributed to sodium intake at this level.”

But the AHA party line is not followed by Suzanne Oparil, herself a former president of the AHA as well as the American Society of Hypertension, in the accompanying NEJM editorial. Her editorial is noteworthy for its reluctance to endorse low-sodium recommendations. Oparil notes that a recent report from the Institute of Medicine concluded that the evidence was unclear whether the low currently recommended sodium levels were linked with better or worse cardiovascular outcomes.

Her evaluation of the two studies differs significantly from the AHA position. She notes the limitations of PURE and calls for a randomized trial to test the effects of low sodium levels, but writes that “in the absence of such a trial, the results argue against reduction of dietary sodium as an isolated public health recommendation.”

Similarly, she applauds the NUTRICODE investigators for their “herculean effort in synthesizing a large body of data regarding the potential harm of excess salt consumption” but writes that “given the numerous assumptions necessitated by the lack of high-quality data, caution should be taken in interpreting the findings of the study.”

In a response to the AHA statement, the first two authors of the PURE papers, Andrew Mente and Martin O’Donnell, tried to emphasize their points of agreement with the AHA. They said that PURE “confirms the association between sodium intake and blood pressure,” and also does not question “the association between excess sodium intake and health risks.” They disagree with the AHA, however, on “whether moderate or low sodium intake is optimal.”

“As a community of researchers, we should strive for guidelines to be based on robust evidence from large clinical trials evaluating clinical events, which is essential in areas of uncertainty. At present, there is just too much uncertainty about the cardiovascular health effects of low sodium intake. If low sodium intake were a medicinal product, there would be widespread consensus on the need for a definitive clinical trial. A first step is to acknowledge the uncertainty, and then work together to complete a definitive randomized controlled trial, so we can be confident in making recommendations to our patients and the general public.”

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