Letter in Reply: A Letter to the Editor Commenting on the Recent Publication By AY Avidan and CA Kushida

Keywords: :

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

We reviewed the letter by employees of Jazz Pharmaceuticals, ‘A letter to the editor commenting on the recent publication by AY Avidan and CA Kushida’ [1], and respond to clarify that the Plain Language Summary of Publication (PLSP), ‘Is the sodium in sodium oxybate a risk for heart health? A plain language summary of publication’ [2], did not contain the misinterpretation they assert to have occurred. The crux of these authors’ criticism is that ‘salt’ and ‘sodium’ were incorrectly interchanged; however, this is not the case.

This PLSP referenced a 2020 publication by O'Donnell et al. in European Heart Journal, ‘Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake’ [3]. The initial submission of our PLSP to Future Cardiology included reference citations. Peer reviewers who are experts in PLSPs advised that references were not appropriate for the intended patient audience and asked for the reference citations to be removed. Given the lack of transparency regarding the O'Donnell reference, it is instructive for readers to review the abstract from this publication:

Several blood pressure guidelines recommend low sodium intake (<2.3 g/day, 100 mmol, 5.8 g/day of salt) for the entire population, on the premise that reductions in sodium intake, irrespective of the levels, will lower blood pressure, and, in turn, reduce cardiovascular disease occurrence…Our review provides a counterpoint to the current recommendation for low sodium intake and suggests that a specific low sodium intake target (e.g., <2.3 g/day) for individuals may be unfeasible, of uncertain effect on other dietary factors and of unproven effectiveness in reducing cardiovascular disease. We contend that current evidence, despite methodological limitations, suggests that most of the world's population consume a moderate range of dietary sodium (2.3–4.6 g/day; 1–2 teaspoons of salt) that is not associated with increased cardiovascular risk, and that the risk of cardiovascular disease increases when sodium intakes exceed 5 g/day. While current evidence has limitations, and there are differences of opinion in interpretation of existing evidence, it is reasonable, based upon observational studies, to suggest a population-level mean target of <5 g/day in populations with mean sodium intake of >5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality (emboldened emphasis added to clarify the differences in ‘sodium’ and ‘salt’).

The expert opinion from O'Donnell et al., which included authors from around the globe, was unintentionally attributed to the European Society of Cardiology, the publisher of the Eur. Heart J. As O'Donnell et al. describe further in their comprehensive review:

Guideline recommendations for low sodium intake were first introduced at a time when there was limited evidence on the association of sodium intake and cardiovascular events. As evidence has evolved, most guideline panels have been reluctant to incorporate the findings from these. In 2013, an independent review of the evidence by the National Academy of Medicine (NAM) concluded there to be insufficient evidence to support a recommendation of low sodium intake for cardiovascular prevention. However, in 2019, a re-constituted panel provided a strong recommendation for low sodium intake, despite the absence of any new evidence to support low sodium intake for cardiovascular prevention, and substantially more data, eg on 100,000 people from Prospective Urban Rural Epidemiology (PURE) study and 300,000 people from the UK-Biobank study, suggesting that the range of sodium intake between 2.3 and 4.6 g/day is more likely to be optimal.

Since the 2020 publication by O'Donnell et al. [3], additional publications have continued to challenge the status quo recommendations for sodium intake by citing the divergent data [4–6] and recognizing that “an increasing number of studies regarding sodium impact on health do not support the general benefits associated with salt restriction upon [cardiovascular disease] CVD and related events” [6]. Specific to heart failure, Patel and Joseph [7] recently published a review, recognizing that the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to prevent and manage heart failure, but “the evidence behind such recommendations is unclear”; further there “appears to be no effect or slightly higher risk in mortality compared to no sodium restriction” in heart failure patients. In 2022, Ezekowitz et al. published a randomized controlled trial of 806 patients with heart failure, which ultimately concluded that dietary intervention to reduce sodium intake did not reduce cardiovascular events [8]. In 2023, Zhou et al. [9] published a study of more than 2600 participants randomized to a 7-day diet of low sodium (50 mmol sodium chloride [1150 mg sodium]) and high sodium (250 mmol sodium chloride [5750 mg sodium]), showing no significant change in the mean difference in 24 h systolic and diastolic blood pressure variability between the diets. Clearly, the debate of appropriate sodium intake exists. The central thesis of the PLSP, however, was not about sodium intake in the general population; it specifically sought to understand if, after 2 decades of sodium oxybate utilization, any signal for cardiovascular risk had been identified.

MacFadden et al. highlight a warning/precaution in product labeling for Xyrem^® (Jazz Pharmaceuticals, CA, USA), an immediate release form of sodium oxybate, which has been approved by the US FDA since 2002 and approved in Europe since 2005. However, they do not excerpt the warning, which states:

Xyrem has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension or renal impairment), consider the amount of daily sodium intake in each dose of Xyrem [10].

For 20 years, clinicians heeded this warning/precaution and prescribed Xyrem in appropriate patients. As the PLSP stated, postmarketing safety surveillance data were published by authors employed by Jazz Pharmaceuticals [11,12], which did not identify a risk of CVD or events in patients taking their product. Further, our comprehensive review of cardiovascular adverse events reported in published literature of patients treated with sodium oxybate for narcolepsy did not identify an association between sodium oxybate treatment and cardiovascular risk [2,13]. As Macfadden et al. noted, these studies were not designed, nor were they powered to measure cardiovascular outcomes. A definitive conclusion cannot be drawn without long-term studies specifically designed for this purpose. However, with more than 20 years of real-world experience with sodium oxybate, if the manufacturer is aware of previously undisclosed risks, this should be brought to public attention.

In 2020, Jazz Pharmaceuticals introduced Xywav^® (calcium/magnesium/potassium/sodium oxybate) or ‘mixed salt’ oxybates, which is also immediate release, meaning that both medications require patients to take one dose at bedtime and awaken between 2.5 and 4 h later to take their second dose [10,14]. Narcolepsy, a chronic neurological disorder in which the brain cannot regulate the sleep–wake cycle, typically requires lifelong pharmacotherapy. Chronic sleep disruption required to take a middle-of-the-night dose has been the only oxybate option for patients with narcolepsy since 2002. The timing of introducing the mixed salt oxybates and a heavy marketing message to warn of sodium risks, coincided with the expected timing for when an extended-release sodium oxybate, requiring only a single bedtime dose, as well as generics to Xyrem, were expected to enter the market.

A recently presented poster based on claims data sponsored by Jazz Pharmaceuticals, ‘Hypertension Onset Among Narcolepsy Patients Newly Treated With Sodium Oxybate’, showed a nonsignificant increase in hypertension (OR: 1.81; 95% CI: 0.73–4.46) [15]. Although the authors included covariates such as age, gender, various comorbidities, use of wake-promoting agents or stimulants, additional confounders recognized to contribute to hypertension risk (e.g., BMI, lifestyle factors) were not included [16–18].

The pivotal trial that was the basis of FDA approval for mixed salt oxybates was a randomized withdrawal design; nearly 40% of the subjects switched from Xyrem [19]. Among those participants, the publication described a higher mean systolic blood pressure (SBP) of 126.2–129.5 mm Hg compared with those not taking Xyrem who had a mean SBP of 122.3–123.3 mm Hg. The mean diastolic blood pressure was 80.6–82.4 mm Hg in those taking Xyrem compared with 78.8–80.1 mm Hg in those not taking Xyrem. The authors did not note any reduction in blood pressure after switching to mixed salt oxybates for a period of 14 weeks. Whereas some may believe that a reduction in blood pressure would only occur over a longer duration, that is not the case: a meta-analysis of 6376 nonacutely ill patients showed that reduced sodium resulted in decreased SBP and DBP of approximately 4.1 and 1.7 mm Hg, respectively, for studies less than 12 weeks in duration [20]. Studies of greater than 6 months of duration showed that the decreases in SBP and DBP were 0.88 and 0.45 mm Hg, respectively.

While MacFadden et al. extol the ‘risks’ associated with Xyrem, this product remains available for prescribing in the US and constitutes nearly half of all oxybate prescriptions [21]. Moreover, the mixed salt oxybates has not been introduced in Europe, where Xyrem remains the only oxybate option, and a presumably different marketing message exists there.

It is established that patients who have compromised renal function and are not able to regulate sodium excretion through homeostatic mechanisms should be judicious about sodium intake with similar restrictions for patients with salt-sensitive hypertension or heart failure. The warning/precaution in the product labeling for Xyrem for sodium will be included in future generics to Xyrem and for an extended-release formulation of sodium oxybate (LUMRYZ™, Avadel Pharmaceuticals, MO, USA), that is now approved by the FDA [22]. In the approval, FDA recognized that LUMRYZ is clinically superior to the twice-nightly oxybates products, as LUMRYZ provides a ‘major contribution to patient care’ with the single bedtime dose ‘that does not involve disrupting or fragmenting sleep’ [23]. We maintain the conclusion from our published comprehensive review of the literature that there is a lack of evidence to suggest that sodium oxybate confers increased cardiovascular risk in patients appropriately prescribed the medication to treat narcolepsy.

Author contributions

The authors analyzed and interpreted the data and directed the writing of the manuscript. All authors read and approved the final manuscript.

Financial & competing interests disclosure

AY has received honoraria from or served on advisory boards for Avadel Pharmaceuticals, Jazz Pharmaceuticals, Eisai Pharma, Harmony Biosciences, Merck & Co., Inc, and Idorsia. CAK is a consultant of Avadel Pharmaceuticals and XW Pharma, has served on speakers bureaus for Avadel Pharmaceuticals and Jazz Pharmaceuticals, and has received research grant funding from Avadel Pharmaceuticals and Jazz Pharmaceuticals. At the time of this submission, Jazz Pharmaceuticals is in patent-related litigation with Avadel Pharmaceuticals. 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.

The Curry Rockefeller Group LLC (Tarrytown, NY, USA) provided editorial support to the authors, which was funded by Avadel Pharmaceuticals (Chesterfield, MO, USA).