A recent study published in the Mayo Clinic Proceedings has shed light on a concerning trend among patients with narcolepsy. Researchers found an increased risk of new-onset hypertension in normotensive patients who initiated sodium oxybate (Xyrem; Jazz Pharmaceuticals), a medication commonly used to treat narcolepsy. This risk was observed even in patients without a prior history of cardiovascular disease. The findings suggest that clinicians should consider the cardiovascular risks associated with sodium oxybate, particularly in patients who are normotensive.

The study, a retrospective cohort analysis, involved 954 patients who started sodium oxybate and 1,908 propensity score-matched control patients without prior hypertension or antihypertensive medication use. The primary outcome, a composite of hypertension diagnosis or antihypertensive medication initiation, occurred at a rate of 6.60 per 100 patients in the sodium oxybate group compared to 4.20 per 100 patients in the control group (OR, 1.61; 95% CI, 1.15-2.27). A secondary outcome assessing hypertension diagnosis alone was also elevated among sodium oxybate users (0.94 vs 0.52 per 100 patients; OR, 1.81; 95% CI, 0.73-4.46), though this result was not statistically significant.

The Mechanism Behind the Risk

The high sodium content in sodium oxybate is thought to be the primary contributor to the increased risk of hypertension. As senior author William B. White, MD, explained, “The high sodium content of this medication, rather than the active ingredient, is mechanistically plausible to contribute increased risk of hypertension. ‘Increases in sodium results in an increase in plasma volume/cardiac output which is a major contributor to the arterial pressure.”

Key Findings and Implications

The study utilized MarketScan claims data from January 2014 to February 2020, focusing on patients aged 18 years or older with at least 180 days of continuous insurance enrollment before and after treatment initiation. Patients with prior hypertension, antihypertensive medication use, or sodium oxybate exposure in the previous 13 months were excluded. The mean age in the sodium oxybate group was 34.9 years, with 35.1 years in the control group, and a predominance of female patients (67.2% vs 66.5%).

“To my knowledge, no prior studies have evaluated the association between oxybate and risk of hypertension; however, our findings are in line with the extensive scientific literature on the association between excess sodium and increased risk of hypertension and cardiovascular disease.”

— William B. White, MD

Salt Sensitivity and Cardiovascular Health

White also noted that people with controlled or uncontrolled hypertension are more susceptible to blood pressure increases due to the excessive sodium burden. “As people with narcolepsy have a higher prevalence and risk of cardiovascular disease (including hypertension as a risk factor), and because most people in the US already consume too much salt, I think there is a need to monitor all patients treated with sodium oxybate, particularly those known to be at increased CV risk. The alternative treatment right now is a low-sodium oxybate treatment, which has a similar oxybate content but only a small fraction of the sodium content compared to the drug studied in our paper.”

Further Research and Practical Applications

The authors highlight the need for future research to investigate the differential impact of low- vs. high-sodium oxybate on blood pressure and cardiovascular outcomes. Additionally, they suggest studying the impact of sodium oxybate on blood pressure by age, gender, baseline BP levels, and narcolepsy type in a large observational database. White mentioned, “Potential future research will be oriented towards investigation of differences in the impact of low vs. high sodium oxybate on blood pressure (I prefer that this will be studied with 24-hour BP monitoring and 24-hour sodium excretion in a clinical trial).”

Implications for Clinical Practice

The study’s reliance on administrative claims data limited its ability to capture detailed clinical characteristics, and potential unmeasured confounding could exist. Future studies with larger cohorts and more detailed clinical assessments are warranted. Practitioners should remain vigilant in monitoring patients on sodium oxybate, especially given the high prevalence of salt sensitivity. The use of low-sodium oxybate as an alternative could be a prudent approach for managing patients with a higher risk of cardiovascular disease. “In addition, referring back to your question about subgroups, it will be of interest to study high sodium oxybate BP impact by age, gender, baseline BP levels and narcolepsy type in a large observational database than our present study. Ideally, we’d like to evaluate the association with longer-term outcomes such as cardiovascular disease but that is difficult as it requires large patient populations,” said White.