Potassium: To Add or to Replace…That is the Question

Hypertension is the leading cause of preventable death globally¹. Nearly 75% of adults with hypertension live in low- and middle-income countries where the prevalence of hypertension is rising². One major focus of public health efforts to lower blood pressure (BP) has been sodium reduction, as randomized trials demonstrated a consistent, linear decrease in BP with lower sodium intake, irrespective of baseline sodium intake³. However, effective strategies to reduce sodium intake have been elusive due to deep-rooted cultural practices related to meal preparation as well as high use of sodium by the food industry. The 2021 American Heart Association Dietary Guidance highlighted potassium-enriched salt (i.e., salt substitution) as “a promising alternative” to reduce sodium intake without altering behaviors around food choice or home preparation⁴. Indeed, previous studies have shown that salt substitution may serve as a strategy to lower BP⁵, but there had been limited evidence on the long-term cardiovascular benefits of such replacements.

The Salt Substitute and Stroke Study (SSaSS) was an open-label, cluster-randomized trial that involved 20,995 participants with a history of stroke (72.6%), or who were ≥60 years and had high BP (88.4%) from 600 villages in rural China. SSaSS demonstrated that replacing regular salt with a 75% potassium salt substitute reduced the rate of stroke by 14%, major cardiovascular events by 13%, and mortality by 12% over a ~5-year follow-up period⁶. However, it remained hotly debated how much of the reduction in risk was attributable to sodium reduction or increased potassium intake and what the estimated amount of potassium should be to achieve similar benefits for cardiovascular disease risk and mortality. One of the great enigmas of SSaSS pertained to the larger changes in urine potassium that were not commensurate with reductions in urine sodium.

In this issue of Hypertension, Yin et al. determined that the health benefits of SSaSS were achieved by consuming 8.8 g/d of potassium-enriched salt, which was equivalent to replacing 72% of the 12.2 g/d of regular salt consumption at baseline⁷. These numbers were estimated using the stored 24-hour urine samples from a subset of SSaSS participants (n = 4366) and were robust under varying assumptions about the proportions of urine potassium and sodium excretion. Of note, the predicted reduction in urinary sodium excretion between the potassium-enriched vs. regular salt groups was 0.79 g/d, higher than the observed reduction of 0.35 g/d. The authors attributed this difference to the incomplete replacement of regular salt with potassium-enriched salt, resulting in participants in this group also consuming 3.9 g/d of regular salt (e.g., from soy sauce, monosodium glutamate, or pickled vegetables). The authors ultimately concluded that even an incomplete replacement of regular salt with potassium-enriched salt could improve human health.

This finding has important implications for public health policies for low- and middle-income countries where most sodium is added during meal preparation at home. The INTERMAP (International Population Study on Macronutrients and BP) study estimated that 76% of dietary sodium is added during meal preparation at home in China⁸. It is estimated that an average of 9.3 g/d of salt is consumed from home cooking alone, double the recommended amount set by the World Health Organization⁹. Indeed, salt plays a critical role in Chinese cuisine and culture, as demonstrated by the Chinese idiom “chai mi you yan,” which literally translates as “firewood, rice, oil, and salt” and means “life’s essential.” Thus, salt substitution has the potential to tackle the epidemic of hypertension and cardiovascular diseases in China without significantly changing people’s eating habits. These findings align with a modeling study which estimated that a nationwide potassium-enriched salt substitution program in China could prevent ~450,000 net deaths per year from cardiovascular diseases¹⁰.

While SSaSS has been hailed as a public health victory for countries like China, it has raised questions about the translation of these findings to cultures where most sodium is primarily added to foods outside the home, such as restaurants and during food processing. The INTERMAP study found that in countries like the United States (U.S.), the United Kingdom, and Japan, the majority of sodium intake comes from commercially processed foods with discretionary salt accounting for only a small proportion of intake⁸. If little salt is added at home, there is little to substitute. While the use of potassium-enriched salt in processed foods and restaurant foods could circumvent this concern about substitution, it would require significant changes to the food industry.

Rather than substitute salt, an alternate solution may be to simply increase potassium intake. Yin et al. found that even partial replacement of regular salt with potassium-enriched salt yielded substantial benefits. Consistent with these findings, Messerli et al. compared the 24-hour sodium and potassium excretion in SSaSS to the U.S. National Health and Nutrition Examination Survey data and found that most benefits observed in SSaSS were likely due to the increase in potassium intake¹¹. Potassium intake reduces salt sensitivity and increases sodium excretion by inhibiting a cascade involving basolateral potassium channels, WNK4 (with-no-lysine [K]) kinase, and STE20/SPS1-related proline/alanine-rich kinase, and suppressing sodium chloride absorption in the distal convoluted tubule¹². This implies that even in places where commercially processed food is a major source of sodium intake, adopting a healthy potassium-rich diet such as a Dietary Approaches to Stop Hypertension (DASH) diet may produce similar benefits as salt substitution. However, these diets can be more expensive and less accessible to historically marginalized communities; this highlights a critical need for targeted interventions to eliminate barriers in these communities to increase access to healthy diets and achieve health equity.

Potassium supplementation may also be a viable population-wide approach, but it may not be applicable in all settings. In a dose-response meta-analysis of 32 potassium supplementation trials, Filippini et al. observed that the greatest BP-lowering effects occurred among adults with a higher baseline urine sodium excretion and a lower potassium excretion¹³. These conditions exist globally, irrespective of whether sodium is added during the process of cooking (e.g., in China) or outside of the home through restaurants or food processing (e.g., in the U.S.). However, these trials investigated potassium supplementation on short-term BP changes (study durations ranged from 4 to 15 weeks), and efficacy data with respect to long-term cardiovascular outcomes are lacking but represent a promising opportunity for future trials.

Concerns remain about the potential risks of hyperkalemia, particularly among adults with chronic kidney diseases (CKD) or those who are on medications that impair potassium excretion⁵. SSaSS did not observe an increased risk of hyperkalemia in the potassium-enriched salt group, but the trial had already excluded people at higher risk of this condition⁶. The modeling study mentioned above also estimated that a China nationwide potassium-enriched salt substitution program could result in ~11,000 hyperkalemia-related deaths in people with CKD (although the net benefit prevents ~450,000 deaths)¹⁰. Yin et al. stated that individuals at a higher risk for hyperkalemia are already recommended to avoid any dietary salt, but it is uncertain if this applies to the population level due to the under-diagnosis of CKD in China and a potential lack of understanding of potassium-related risks among those susceptible to hyperkalemia. In one small feeding study of higher dietary potassium among adults with CKD, there were more cases of hyperkalemia from the high potassium assignment short-term, but no adverse events¹⁴. More research is needed on the population level to evaluate the safety and efficacy of potassium supplementation or fortification strategies with respect to long-term outcomes. Additionally, the cost of potassium-enriched salt is higher compared to that of regular salt, and many people are unaware of its availability and health benefits. Future research needs to determine the best approach to making potassium-enriched salt accessible and cost-effective if it is proven to be beneficial.

In summary, this report by Yin et al. addresses an important question of why urine sodium reduction was not commensurate with increases in urine potassium and the potential implications for potassium as the primary driver of the cardiovascular health benefits found in SSaSS. This study offers crucial insights for shaping public health policies and dietary guidelines aimed at reducing BP and improving cardiovascular health, especially in countries where discretionary salt is widely used. It also brings us closer to understanding the optimal intervention strategy to improve cardiovascular health in diverse cultural settings: salt substitution, potassium supplementation, or a combination of both (Figure 1). Ultimately, the question is not related to the need for more potassium intake, but how best to achieve it at the population level.

Figure 1.

Strategies to increase population-wide potassium consumption. Abbreviations: RCT indicates randomized controlled trial; SSaSS, Salt Substitute and Stroke Study; BP, blood pressure; CVD, cardiovascular disease; K⁺, potassium; Na⁺, sodium; NaCl, sodium chloride; KCl, potassium chloride; and LDL, low-density lipoprotein. Created with BioRender.com.

Abbreviations:

BP

Blood pressure

CKD

Chronic kidney disease

DASH

Dietary Approaches to Stop Hypertension

INTERMAP

International Population Study on Macronutrients and Blood Pressure

SSaSS

Salt Substitute and Stroke Study

U.S.

United States