Multiple 24-hour urine samples plot a linear trend

It’s hardly news that excess salt consumption is a driver of hypertension and a major contributor to cardiovascular mortality, yet it is a message that remains a hard sell in countries like the U.S. where processed foods have become a dietary staple. But that “sell” may become easier for clinicians armed with results from a new study that puts a number on just how great that sodium-driven cardiovascular risk is.

Moreover, in terms of cardiovascular risk, the worst combination is high sodium and low potassium, according to results from a study by a team of Harvard researchers that used individual-participant data from six prospective cohort studies to assess 24-hour urinary sodium and potassium excretion.

“Each daily increment of 1,000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1,000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94),” Yuan Ma, PhD, of the department of epidemiology at the Harvard T.H. Chan School of Public Health and the Channing Division of Network Medicine, reported at the virtual American Heart Association’s 2021 Scientific Sessions.

The findings were simultaneously published online by The New England Journal of Medicine.

“Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1,000 person-years). The median 24-hour urinary sodium excretion was 3,270 mg (10th to 90th percentile, 2099 to 4899),” Ma and colleagues wrote. “Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratios.”

The researchers added that they did not find evidence of an association between sodium excretion and death from non-cardiovascular causes.

Eugene Yang, MD, who chairs the American College of Cardiology’s Prevention Section and Leadership Council, told BreakingMED that the study confirms again “what we believed, which was that sodium intake has a negative effect on potential mortality.”

Yang, a professor of medicine at the University of Washington School of Medicine in Seattle, added that this is the second major study reported in recent months that provides compelling evidence of the sodium risk.

The SSaSS trial, reported at the European Society of Cardiology’s virtual meeting in August 2021 and simultaneously published online by The New England Journal of Medicine, found that high risk patients who switched out table salt for a salt substitute significantly reduced their risk of stroke and other cardiovascular events. At the time SSaSS was reported, ACC spokesperson Erin Donnelly Michose, MD, MHS, told BreakingMED that although the SSaSS study was conducted among high-risk individuals in rural China, the findings were likely be generalizable, because “anyone can benefit from reducing salt. These are really definitive data. It’s a low-cost intervention, and in underserved areas it can have such a meaningful impact.”

The take-home message from the analysis by Ma et al “is a simple one: eat more fruits and vegetables, which are naturally low in sodium and high in potassium, and reduce the intake of processed foods,” said Yang, who added that while the message is simple, delivering it can be difficult.

“We have shifted from eating things that we grow and become a society characterized by a high intake of processed food… that is why the FDA recently announced guidance asking restaurants and manufacturers of frozen foods to reduce the amount of sodium in products,” Yang added. He noted that “sodium intake today is not all that different from what it was 10 years ago or 20 years ago, when the amount of sodium intake that was projected was about 3,500 mg, very similar to today’s estimates.”

Asked about using the findings by Ma et al to bolster messaging to patients, Yang said the study findings are helpful, especially since they used multiple 24-hour urine samples, “a gold standard;” however, he also cautioned the cohort studies included are not representative of the diverse U.S. population.

The studies included—the Health Professionals Follow-Up Study, the Nurses’ Health Study, the Nurses’ Health Study II, the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, and the Trials of Hypertension Prevention (TOHP I and TOHPII)— “enrolled mostly White women, who were well-educated, healthy, middle- to upper-middle income individuals. Blacks, who are known to have greater salt sensitivity, represent only 4% of the study population, so I’m not sure how generalizable these results will be,” Yang said in a phone interview.

Nonetheless, Ma and colleagues did avoid an issue found with previous studies.

“A key limitation of previous studies is the assessment of sodium intake by methods that are prone to measurement errors, such as questionnaires, spot urine samples, and single 24-hour urine samples. The J-shaped association is probably due to confounding variables that were used in the equations to estimate the 24-hour urinary sodium excretion from spot urine samples (e.g., age, sex, body weight, and urinary creatinine concentration), all of which are related to cardiovascular risk and may contribute in part to the increased cardiovascular risk that has been associated with lower sodium intake in observational studies. Another methodologic issue of previous studies is the inclusion of participants with existing chronic diseases such as heart failure, which resulted in the potential for reverse-causation bias,” they wrote.

The researchers did, however, echo the concern about the generalizability of the findings. Other limitations included the observational nature of the study, which raises the possibility of residual confounding, “such as dietary factors, energy intake, and socioeconomic status, for which data were available in only some of the included studies.”

Ma and colleagues concluded that the study demonstrated “a significant linear association between sodium intake, as measured with the use of multiple 24-hour urine samples, and cardiovascular risk in a dose–response manner with a daily sodium intake of approximately 2,000 to 6,000 mg. Higher potassium intake was associated with a lower cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels.”

  1. Be aware that an analysis of multiple 24-hour urine samples found a linear relationship between increased sodium excretion and increased risk of cardiovascular events, as well as an inverse relationship between increased potassium excretion and risk of cardiovascular events.

  2. Note that the study populations in this analysis were overwhelmingly White and well-educated, so the findings may not be generalizable to a diverse population.

Peggy Peck, Editor-in-Chief, BreakingMED™

Ma reported grants from the American Heart Association and the National Institutes of Health.

Cat ID: 232

Topic ID: 74,232,730,232,358,5,6,127,410,192,925,231