A Letter to the Editor Commenting On the Recent Publication By AY Avidan and Ca Kushida

Keywords:

• blood pressure
• cardiovascular disease
• hypertension
• oxybate
• sodium

Dear Editor,

We wish to comment on the misinterpretation contained in the publication “Is the sodium in sodium oxybate a risk for heart health? A plain language summary” by Avidan and Kushida, which was published in the May 2022 issue of Future Cardiology [1]. Plain language summaries are intended for a lay audience and to help patients better understand scientific information. Urgent clarification or correction is warranted based on the authors’ misinterpretation of the science and data related to the cardiovascular risks associated with excessive daily sodium intake. The authors’ presentation of the data is made irrespective of medical and regulatory authorities’ recommendations and guidelines on sodium intake, and it is with great concern that we believe patients, caregivers and healthcare professionals must be made aware of these discrepancies.

First, the authors describe that there is a ‘debate’ about appropriate sodium intake levels because of the differences in recommendations from the American Heart Association (AHA) and the European Society of Cardiology (ESC). Notably, the authors write that the ESC recommendation is <5000 mg of sodium per day. In fact, the ESC does not recommend an upper daily limit of 5000 mg of sodium; rather, the ESC recommends an upper daily limit of 5000 mg of salt [2]. The difference between salt and sodium is critical. The US FDA has communicated, “The words ‘table salt’ and ‘sodium’ are often used interchangeably, but they do not mean the same thing” [3]. According to the European Commission, “Salt or sodium chloride (NaCl) is a crystalline compound consisting of sodium (Na) and chloride (Cl). 1 g of salt contains about 0.4 g of sodium and 0.6 g of chloride. Likewise, in the context of salt content or intake, 1 gram of sodium equals approximately 2.5 g salt” [4]. Because the authors failed to perform this adjustment between salt and sodium, they misstate the ESC recommendation. The correct dietary recommendations from the AHA and ESC, expressed for convenience in both sodium and salt levels, are reflected in Table 1 below.

Table 1. Comparison of dietary sodium recommendations.

	Upper limit	Ideal	Ref.
AHA	<2300 mg of sodium per day <5.8 g of salt per day	<1500 mg of sodium per day <3.8 g of salt per day	[5]
ESC	<2000 mg of sodium per day <5 g of salt per day	≈1200 mg of sodium per day ≈3 g of salt per day	[2]

The AHA and the ESC present their dietary recommendations in different units because food in the USA is labeled in milligrams of sodium, whereas food labeling in Europe uses salt equivalents. To compare salt/sodium recommendations across jurisdictions, one must adjust using the formulas: salt in g = sodium in mg × 2.5 divided by 1000 and sodium in mg = salt in g × 0.4 × 1000. Here, the actual recommendations from the AHA and ESC are expressed in terms of both sodium and salt.

AHA: American Heart Association; ESC: European Society of Cardiology.

The differences in upper limits among countries are not debatable, as the goal is to minimize the risk of developing cardiovascular conditions. The AHA recommends that “even cutting back by 1000 mg a day can significantly improve blood pressure and heart health” [5]. Similarly, the National Academy of Sciences, Engineering, and Medicine concludes that reducing sodium intake by 1000 mg/day can reduce the risk of cardiovascular disease and hypertension by 27 and 20%, respectively [6]. Moreover, the FDA has made reducing daily sodium intake a key public health priority, stating “Reducing sodium intake has the potential to prevent hundreds of thousands of premature deaths and illnesses in the coming years” [7].

Second, at the time of the article publication and the submission of this letter, the sodium oxybate (SXB; Xyrem^®) oral solution US prescribing information contains an explicit warning regarding daily sodium intake in patients sensitive to high sodium intake [8]. SXB contains 1100–1640 mg of total sodium at the recommended nightly dosage range of 6–9 g [8]. This same warning is not included in the prescribing information for lower-sodium oxybate (LXB; Xywav^® [calcium, magnesium, potassium and sodium oxybates] oral solution), which contains 92% less sodium than SXB [9]. Moreover, the FDA granted LXB orphan drug exclusivity [10]. The FDA’s Office of Orphan Products Development determined that LXB is clinically superior to Xyrem in narcolepsy based on the greater cardiovascular safety provided by its reduced sodium burden [11]. The FDA stated in their summary: “Xywav (calcium, magnesium, potassium and sodium oxybates) is clinically superior to Xyrem by means of greater safety because Xywav provides a greatly reduced chronic sodium burden…,” and the reduced sodium burden between the two products “…will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated” [11].

Third, the authors assert that the sodium in SXB ‘should not be a cause for concern’ for most patients with narcolepsy and that most current patients ‘do not need to change their sodium oxybate medicine.’ The authors fail to disclose any data to support these claims, thus misinforming the reader by contradicting ‘the enormous body of evidence supporting recommendations to reduce dietary sodium intake [12]’, including recommendations in the range of the sodium burden associated with regular SXB use.

Finally, the authors overstate the quality and utility of the available data regarding the relationship between SXB and the risk of cardiovascular disease. The studies cited in the article were neither designed nor intended to assess the cardiovascular impact of lifelong exposure to 1000–1600 mg/day of additional sodium. The limited data generated by those studies cannot support a conclusion that the sodium content in SXB should not be a concern. Moreover, such a conclusion would contradict the safety concerns of the FDA [11].

We describe the risk this article conveys to the reader as it directly opposes health authorities and has the potential to misinform the patient population at large. It is our hope that these corrections are received in the spirit of educating patients, caregivers and healthcare providers on the importance of sodium and cardiovascular health concerns with the therapeutic use of oxybates.

Financial & competing interests disclosure

This work was sponsored by Jazz Pharmaceuticals. W Macfadden, A Wilhelm, S Candler and S Mettam are full-time employees of Jazz Pharmaceuticals who, in the course of this employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals, plc. At the time of this submission, Jazz Pharmaceuticals is in litigation with Avadel Pharmaceuticals related to intellectual property claims. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Under the direction of the authors, Peloton Advantage, LLC, an OPEN Health company, provided editorial support, which was funded by Jazz Pharmaceuticals.