October 1, 2016Journal of the American College of Cardiology
Sodium Intake and All-Cause Mortality Over 20 Years in the Trials of Hypertension Prevention
Key result
Higher sodium intake linked to ~12% higher all-cause mortality per 1000 mg/day increase.
- HR 1.12
- 95% CI 1.00-1.26
- P=0.05
- n=2,974
Why the study?
The relationship between lower sodium intake and total mortality remains controversial, with reported J-shaped curves potentially reflecting poor measurement quality or confounding bias.
Does higher usual dietary sodium intake (or a randomized sodium reduction intervention) affect long-term all-cause mortality over 20+ years in pre-hypertensive adults?
Key Points
- To evaluate the association between accurately measured sodium intake via multiple 24-hour urine collections and long-term all-cause mortality over more than two decades.
- Follow-up of pre-hypertensive adults aged 30 to 54 years enrolled in two randomized trials (TOHP Phase I, 18 months, and Phase II, 36 months) testing dietary sodium reduction interventions.
- Sodium exposure was estimated from multiple scheduled 24-hour urine collections (average 4.4 in Phase I and 3.5 in Phase II) during the trials.
- Post-trial mortality was tracked over a median follow-up of 24 years through December 31, 2013, using the National Death Index.
- Among 744 Phase I and 2,382 Phase II participants randomized to sodium reduction versus control, 251 deaths occurred, showing a nonsignificant reduction in mortality risk with the intervention (HR = 0.85, 95% CI = 0.66–1.09, p = 0.19).
- Among 2,974 participants not assigned to an active intervention (272 deaths), average sodium intake showed a direct linear association with mortality (HR = 1.12 per 1,000 mg/24hr, 95% CI = 1.00–1.26, p = 0.05) with no evidence of a J-shaped or nonlinear curve.
- Each unit increase in the urinary sodium-to-potassium ratio was associated with higher mortality risk (HR = 1.13, 95% CI = 1.01–1.27, p = 0.04).
Study Design
Type
Cohort (n=2,974)
Randomization
Randomized in original TOHP I and II trials (including factorial design in Phase II); this study is a long-term observational post-trial follow-up
Multicenter
Yes
Structured PICO
Does higher usual dietary sodium intake (or a randomized sodium reduction intervention) affect long-term all-cause mortality over 20+ years in pre-hypertensive adults?
P
Population
2,974 pre-hypertensive adults aged 30-54 years (mean age 43, 32% female) not assigned to active sodium reduction (plus 3,126 in the randomized comparison), followed for a median of 24 years for all-cause mortality.
E
Exposure
Observational exposure: Usual dietary sodium intake and sodium/potassium ratio, estimated from the mean of 3 to 7 scheduled 24-hour urinary excretions collected over 18 months (TOHP I) or 3-4 years (TOHP II). Randomized intervention: Active lifestyle sodium reduction intervention over 18 months (TOHP I) or 36 months (TOHP II).
C
Comparator
Observational comparator: Reference sodium excretion category of 3600 to <4800 mg/24hr (or continuous per 1000 mg/24hr increase). Randomized comparator: Usual care / sodium control group.
O
Outcome
All-cause mortality ascertained over a median follow-up of 24 years (total 23-26 years through December 31, 2013) using the National Death Index.hard clinical
Main Result
Hazard Ratio: 1.12 (95% CI 1–1.26)
p-value: p=0.05
Using gold-standard repeated 24-hour urine collections over 20+ years of follow-up, this study demonstrates a direct linear relationship between dietary sodium intake and all-cause mortality without a J-shaped curve, supporting public health guidelines to reduce sodium consumption.
Limitations
- Unclear how well participants in the randomized comparison maintained the sodium reduction intervention over more than 20 years of follow-up
- No subsequent measures of sodium intake were collected after the initial trial periods during the long-term observational follow-up
- Inability to fully control for other dietary factors such as fruit, vegetable, and saturated fat intake due to limited dietary data in TOHP II
- Limited statistical power to estimate effects at the extreme tails of the sodium distribution
- Unclear maintenance of the randomized sodium reduction intervention over more than 20 years of post-trial follow-up
- Lack of repeated urinary sodium intake measurements after the initial trial periods during long-term follow-up
- Inability to control for other dietary factors (e.g., fruit, vegetable, and saturated fat intake) with sufficient power because dietary data were only collected in a small subset of TOHP II
- Limited statistical power to estimate mortality effects at the tails of the sodium distribution
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Sodium is an essential nutrient. It's not tobacco. Without sodium, you die. The body needs sodium. The optimal level of tobacco is zero, but with sodium, it's not zero. The question is, how much sodium? Every essential nutrient in the body tends to have the so-called U-shaped relationship with mortality—calcium, magnesium, vitamin D, and so on and so forth. Why would sodium be any different? The researchers are making it seem like there's a linear relationship when in fact it violates the laws of biology. It doesn't make any sense.”
“I think sodium levels should be less than 2,300 mg per day. I would be a little bit hesitant to suggest less than 1,500 mg per day as this is very difficult to achieve. There are few people and very few studies with sodium intakes that low—you'd really have to work at it. It does look like there might be benefit if you could do it, such as in patients with cardiovascular disease, but it's a special population. It's not a wide public health recommendation.”
“Our results are not that surprising because we know that sodium increases blood pressure, and we have found that it increases risk of cardiovascular disease also. We found a direct linear association, such that those with the lowest sodium levels had the lowest mortality rates.”
Implication
Linear sodium-mortality link supports current intake targets; leaves open whether reduction interventions improve survival in prehypertension.
Abstract
Background While several studies suggest beneficial effects of lower sodium on cardiovascular disease, the relationship with total mortality remains controversial. Some have reported a J-shaped curve, but this may be due to poor quality measurement of sodium or confounding bias. Objective To examine the relationship of well-characterized measures of sodium intake, estimated from urinary sodium excretion, with long-term mortality. Methods Two trials [Phase I (1987-90) over 18 month and Phase II (1990-5) over 36 months in the Trials of Hypertension Prevention] implemented sodium reduction interventions. Multiple 24-hour urines were collected from pre-hypertensive adults aged 30-54 during these trial periods. Post-trial deaths were ascertained over a median 24 years through December 31, 2013 using the National Death Index. The association of mortality with both the randomized intervention and average sodium intake was examined. Results Among 744 Phase I and 2382 Phase II participants randomized to sodium reduction or control, 251 deaths occurred, with a nonsignificant 15% lower risk in the active intervention (hazard ratio (HR)=0.85, 95% CI=0.66-1.09, p=0.19). Among 2,974 participants not assigned to an active sodium intervention, 272 deaths occurred. There was a direct linear association of average sodium intake with mortality, with HR=0.75, 0.95, 1.00 (reference), and 1.07 (p-trend = 0.30) for <2300, 2300-<3600, 3600-<4800, and >=4800 mg/24hr, respectively, with HR=1.12 per 1000 mg/24hr (95% CI = 1.00-1.26, p=0.05) and no evidence of a J-shape or nonlinear relation. The HR per unit increase in sodium/potassium ratio was 1.13 (95% CI = 1.01-1.27, p=0.04). Conclusions This study, with carefully characterized measures of sodium intake, found an increased risk at high sodium intake and a direct relation with total mortality even at the lowest levels of sodium intake. Overall, these results are consistent with a benefit of reduced sodium and sodium/potassium on total mortality over a period of over 20 years.
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Cite This Study
Cook et al. (2016) conducted a cohort in Pre-hypertension (high normal blood pressure) (n=2,974). Usual dietary sodium intake (measured by multiple 24-hour urinary sodium excretions per 1000 mg/24hr increase) vs. Lower urinary sodium excretion levels (or reference category 3600 to <4800 mg/24hr; usual care in the randomized analysis) was evaluated on All-cause mortality (HR 1.12, 95% CI 1.00-1.26, p=0.05). Higher usual sodium intake showed a direct linear association with all-cause mortality over 24 years (HR 1.12 per 1000 mg/24hr, 95% CI 1.00-1.26, p=0.05), with no evidence of a J-shaped curve.