Article Digest: Treatment of Narcolepsy in Patients with Cardiometabolic Risk

The current treatment landscape for narcolepsy includes several nonpharmacologic and pharmacologic options (Table 1.  

Circadian rhythm alignment (exercise, regular nighttime sleep, scheduled daytime naps)Psychosocial supportSchool and work accommodationsWeight lossAddressing EDSPsychostimulants (amphetamines, methylphenidate)Wake-promoting agents (arodafinil, modafinil, pitolisant, solriamfetol)Sodium oxybate (SXB) and lower-sodium oxybate
Anticataleptic agentsNRIs*, SNRIs*, SSRIs*, SXB, TCAs**do not have an FDA indication for cataplexy
Table 1. Treatment landscape for narcolepsy. EDS = excessive daytime sleepiness; NRIs = norepinephrine reuptake inhibitors; SNRIs = serotonin and norepinephrine reuptake inhibitors; TCAs = tricyclic antidepressants

Some of these medications may have potential negative effects on cardiovascular health, and in their chronic, long-term use in NT1 can exacerbate cardiovascular risk.  Certain wake-promoting agents, such as modafinil, solriamfetol, and pitolisant are associated with increases in the usage of antihypertensive medications or slight increases in blood pressure (for the first two), and slight QT interval prolongations (for the latter).  The concurrent use of modafinil and solriamfetol is contraindicated in patients with unstable cardiovascular disease, serious heart arrhythmias, and other serious heart problems.  Furthermore, many antidepressants that are often used off-label for narcolepsy have significant cardiometabolic concerns, including increased blood pressure, tachycardia, ECG abnormalities, myocardial infarction, weight gain, and more.    

The current first-line therapy for narcolepsy, which treats cataplexy and EDS is sodium oxybate (SXB).  This drug is gamma-hydroxybutyrate, which is a prodrug of GABA and is a central nervous system depressant. It is hypothesized that it works by acting as a neurotransmitter and neuromodulator acting at noradrenergic, dopaminergic, and thalamocortical neurons.  A potential concern with this therapy is that it contains high amounts of sodium (the estimated daily sodium content ranges from 550-160 mg at 3-9g dose), which can increase blood pressure and risk for cardiovascular events, and SXB prescribing information highlights that patients who are sensitive to sodium intake (such as those with heart failure, hypertension, or chronic kidney disease) should be monitored.  The sodium levels in SXB may be a potential cause of concern, especially when taking into account that patients with HTN/HF/CKD may exceed the daily dietary sodium intake levels needed to keep CV risk in check.

Another formulation of SXB, which contains 92% less sodium than the existing formulation, was approved in July 2020 in the US for the treatment of EDS or cataplexy in patients ≥7 years of age with narcolepsy. This lower-sodium formulation can be potentially beneficial in helping narcolepsy patients with cardiovascular risk better meet the American Heart Association’s recommendation of lowering sodium intake, in order to help decrease CV risk.  In the phase 3 trials which lead to its approval, lower-sodium oxybate was as effective as SXB for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy patients (Bogan 2021).

Additionally, another formulation of SBX called FT218, a once-nightly formulation, is currently under investigation and has been given orphan drug designation from the FDA following a double-blind, randomized, placebo-controlled Phase 3 trial in patients 16 years of age and older (Seiden 2020).  Results of the phase 3 REST-ON study with this agent were announced, showing that this agent significantly improved narcolepsy symptoms across the narcolepsy spectrum, including clinical and patient-focused endpoints. Recently, positive secondary endpoint data were declared, which showed a clinically meaningful improvement in the assessment of disrupted nighttime sleep compared to placebo in adults with narcolepsy. As such, this agent can potentially address challenges with adherence to conventional SBX formulations, since at present the only approved formulations of sodium oxybate in the US and Europe require twice-nightly dosing.  Additionally, other one-nightly sodium oxybate formulations are in early clinical development, including JZP-324, a low sodium, extended-release formulation.

Future research into other possible novel therapies for narcolepsy is needed and ongoing, such as in gene therapy, immunologically-based therapy, cell transplantation, and hypocretin peptide replacement. Further research is also indicated to show how nonpharmacologic interventions can impact treatment and work synergistically with pharmacologic agents.   


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