CV Events Increase Only With High Levels of Sodium Intake: PURE

Batya Swift Yasgur, MA, LSW

August 17, 2018

Increased risks for stroke or cardiovascular disease (CVD) are seen only in communities where mean sodium intake exceeds 5 g per day, new research from the Prospective Urban Rural Epidemiology (PURE) study shows.  

Investigators measured blood pressure (BP) in almost 96,000 adults in 300 communities across18 countries and assessed almost 83,000 adults for cardiovascular outcomes over an 8-year period.

They analyzed participants' urine to determine sodium intake and found that higher sodium intake was associated with increased BP and incidence of stroke, but this association was found only in communities with very high sodium intake, almost all of which were located in China.

On the other hand, higher sodium intake was actually associated with lower rates of myocardial infarction (MI) and total mortality.

"Sodium has always been a 'holy grail' nutrient for CVD prevention, going back to the 1970s, but sodium is an essential nutrient and lowering too much can actually increase mortality," lead author Andrew Mente, PhD, associate professor, Department of health Research Methodology, Evidence, and Impact, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, told | Medscape Cardiology.

"A number of studies have found a U-shaped relationship between sodium and cardiovascular events, with a 'sweet spot' in the middle — between 3 and 5 g per day — associated with the lowest risk," he said.

The study was published online August 11 in The Lancet.

Unproven Assumptions

The World Health Organization recommends reduction of sodium intake as a population-level intervention to reduce CVD and mortality, the authors write.

The rationale is based on the association between sodium intake and BP and is predicated on the assumption that "any approach to reducing BP will translate into fewer clinical cardiovascular outcomes," they state.

However, the claim that the effects of salt on CVD are "exclusively mediated through its effects on BP has never been proven," they point out.

Moreover, "no study has reported on the association between community-level sodium intake and CVD or mortality."

"There is data in the general population, in people with vascular disease, in people with and without hypertension, and people with and without diabetes, showing low sodium to be associated with harm," Mente said.

"We wanted to look at the sodium issue at a community level across communities and spanning countries across the world, ranging from low to high," he said.

To investigate the question, the researchers designed the PURE study, consisting of 95,767 participants (aged 35 - 70 years) in 369 communities across 18 countries whose BP was analyzed.

The researchers also analyzed cardiovascular events in 82,544 participants in 255 communities.

A morning fasting midstream urine sample collected from every participant was used to calculate 24-hour urinary sodium and potassium excretion, and these values were used as surrogates of intake.

Participants were followed at 3, 6, and 9 years (median, 8.1 years), when information was gathered about selected risk factors (eg, weight, height, and BP), health outcomes, and community.

When Is Sodium Consumption "Fine"?

During the follow-up period, 3695 people died: 3543 had major cardiovascular events (MI [n = 1372], stroke [n = 1965], heart failure [n = 343], and cardiovascular death [n = 914]).

At least one follow-up visit was completed for 89,659 (95%) participants. The mean sodium intake across all 369 communities was 4.77 g/day (range, 3.22 to 7.52 g/day).

However, at the individual level, sodium intake varied much more (from a fifth percentile value of 2.53 g/day to a 95th percentile value of 7.97 g/day [range, 1.92 - 19.2 g/day] after correction for regression dilution bias).

Sodium intake was "substantially higher" in communities from China than in other countries (5.58 g/day vs 4.45 g/day), with a mean intake greater than 5 g/day in 82 (80%) of 103 Chinese communities.

By contrast, in other countries, 224 (84%) of 266 communities had a mean intake of 3 to 5 g/day.

Mean systolic BP increased by 2.86 mm Hg per 1-g increase in mean sodium intake; however, positive associations were found only among the communities in the highest tertile of sodium intake (95% confidence interval [CI], 2.12 - 3.60; P < .0001).

The slope estimates in group-level analyses were stronger than those in individual-level analyses, even after adjustment for regression dilution bias (change in systolic BP per 1-g increase in sodium intake [2.86 mm Hg vs 2.10 mm Hg]).

The associations between community-level systolic BP and sodium intake were "positive, large, and significant in communities in the highest sodium intake tertile," but there was "an inverse and non-significant association" in the communities with sodium intakes in the middle and lower tertiles (P < .0001 for heterogeneity).

Results were similar for diastolic BP.

The researchers found a positive association in 255 communities (P < .0001) between mean sodium intake and the mean overall cardiovascular event rate (0.66; 95% CI, 0.46 - 0.87) events per 1000 years per 1-g increase in sodium intake.

The association was primarily driven by stroke.

The positive association between sodium intake and major cardiovascular events remained similar across communities (0.73; 95% CI, 0.53 - 0.93; P < .0001), even after the researchers adjusted for known confounders.

There was a significant inverse association in the lowest tertile between sodium intake and major cardiovascular events but no association in the multivariable adjustment (1.01; 95% CI, 0.86 - 1.17; P < .0001).

Similarly, a positive association was found in communities with the highest tertile of sodium intake (>5.08), but not in the middle or lowest tertiles (P = .3437 for heterogeneity of slopes estimates; P < .0001 for deviation from linearity).

After multivariable adjustment, the researchers found inverse associations between each 1-g increase in sodium intake and MI (–0.15; 95% CI, –0.26 to –0.04; P = .0030) and total mortality (–0.66; 95% CI, –1.04 to –0.29; P = .0006), but no significant association with the composite outcome (0.09; 95% CI, –0.29 to 0.46; P = .65).

When the researchers adjusted the associations between sodium intake and cardiovascular events for age, sex, and BP, there was no change, suggesting "that the effects of sodium intake on cardiovascular events is largely unrelated to the effects of sodium intake on BP."

"The current analysis found that sodium consumption was fine, up to 5 g per day," Mente commented.

Increase Potassium

The researchers also investigated the role of potassium in CVD and found that the potassium intake was 2.16 g/day (range, 1.25 - 3.11 g/day) across 369 communities and 2.12 g/day (range, 0.90 - 7.69 g/day) in individuals, after correction for regression dilution bias.

Mean potassium intake did not differ between communities inside and outside China.

There was no significant association between potassium and systolic or diastolic BP. However, all major cardiovascular outcomes decreased with increasing potassium intake in all countries.

"We found that higher potassium intake was associated with lower risk of stroke and MI mortality" Mente reported.

He emphasized that sodium is an "essential nutrient" and, as with other essential nutrients, "high levels lead to toxicity and low levels lead to deficiency, so people's consumption should remain within the 'sweet spot' of optimal levels."

An additional take-home message for clinicians is "rather than focusing on reducing sodium to low levels, encourage patients to increase their potassium levels by eating more fruit, vegetables, dairy foods, and nuts, which will have a protective effect."

Relax the Guidelines

Commenting on the study for | Medscape Cardiology, David A. McCarron, MD, past head of nephrology at the Oregon Health and Sciences University, Portland, and a recent research associate at UC Davis Department of Nutrition, California, who was not involved with the study, noted that it was "an observational study, with all the imitations of an observational study."

Nevertheless, "it was about as well-executed a study as possible," since the researchers "have used the best way to collect a lot of urine around the world in a precise manner, using midstream collections in the morning."

He noted that previous research, conducted across 45 societies and 5 decades, found that humans consume a reproducible, narrow range of sodium: of roughly 2600 to 4800 mg/day.

"This range is independent of the food supply, verifiable in randomized controlled trials, consistent with the physiologic regulators of sodium intake and is not modifiable by public policy interventions," he emphasized.

Also commenting on the study for | Medscape Cardiology, Franz H. Messerli, MD, professor of medicine and cardiology, University of Bern, Switzerland, Mount Sinai Icahn School of Medicine, New York City, and Jagiellonian University, Krakow, Poland, who was not involved with the study, called it "solid and well-done, showing still that BP and stroke increase with salt intake, but heart attack and mortality do not."

He does not regard the study as providing sufficient evidence for "people to not worry about their salt intake if they have high BP."

But "if their BP is normal, there seems little reason to restrict salt intake," said Messerli, who is the coauthor of an  accompanying editorial.

He added that "the current salt intake in the US population seems acceptable, unless you have hypertension."

Moreover, "foods with high potassium, such as fruits, vegetables, and nuts, were protective, even in those with high salt intake."

Mente added, "We need to bring sodium consumptions to moderate levels and to relax the old recommendations, to be more consistent with data and science."

The PURE Study is an investigator-led study funded by the Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research's Strategy for Patient Oriented Research, through the Ontario SPOR Support Unit, and the European Research Council. Additional sources of funding are listed on the original paper. The study authors have disclosed no relevant financial relationships. McCarron is a consultant to Conagra Foods and Grocery Manufacturers Association. Messerli has received grants, advisory board and speaking honoraria from Menarini, Servier, Pfizer, Novartis, Medscape, and Medtronic. Disclosures for the other editorialists are listed on the original editorial.

Lancet. Published online August 11, 2018. Abstract, Editorial

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