By Susan Kreimer
April 7, 2022
Article In Brief
In a four-week clinical trial, those taking sulthiame experienced an apnea hypopnea index reduction equal to or greater than 50 percent. In addition, 40 percent of the patients on the drug had improved nocturnal oxygenation and sleep quality. Experts say that while some patients will benefit from the drug, they don’t believe that it will replace the current standard of care—CPAP.
Sulthiame had an acceptable safety and tolerability profile in patients with moderate-to-severe obstructive sleep apnea (OSA), according to a study published online on February 24 in the American Journal of Respiratory & Critical Care Medicine.
Sulthiame is a carbonic anhydrase inhibitor, which mitigates the ventilatory instability that appears to be an underlying mechanism in OSA. Initial randomized controlled studies on carbonic anhydrase inhibitors have yielded inconclusive results, however.
In the current four-week, randomized, placebo-controlled, double-blind trial, the investigators observed that those taking sulthiame experienced a clinically relevant OSA improvement—an apnea hypopnea index reduction equal to or greater than 50 percent. In addition, 40 percent of the patients on the drug had improved nocturnal oxygenation and sleep quality.
The trial demonstrates that “sleep apnea may be treated pharmacologically, and sulthiame provides a strategy to be further evaluated for this indication,” the study’s lead author, Jan Hedner MD, PhD, a professor of respiratory medicine at Sahlgrenska University Hospital, a part of the University of Gothenburg in Sweden, told Neurology Today.
Patients with OSA suffer from repetitive episodes of airway collapse, deranged blood gases, autonomic activation, and sleep fragmentation. Based on current diagnostic criteria, 425 million middle-aged people worldwide are estimated to have moderate-to-severe OSA.
The condition is linked to cardiometabolic diseases such as hypertension, in particular therapy-resistant hypertension, arrhythmia, stroke, myocardial infarction, dyslipidemia, and diabetes. OSA also can induce excessive sleepiness, heighten the risk of accidents, and decrease quality of life.
“Hence, the burden of illness and the health economic consequences of OSA are considerable,” the authors noted. “The mainstay therapy in OSA, continuous positive airway pressure (CPAP), is highly effective but limited by incomplete long-term compliance. Other therapies such as upper airway surgery, intraoral devices, position trainers, and implantable nerve/muscle stimulation systems have a less predictable efficacy. There is an unmet medical need for an effective drug therapy in OSA.”
Dr. Hedner told Neurology Today that the new study has multiple strengths. In addition to being a randomized controlled trial, its advantages included stringent evaluation using state-of-the-art analysis equipment, a dose-finding design, and therapeutic drug monitoring.
When asked about any concerns in prescribing this agent, Dr. Hedner acknowledged the potential for dose-dependent side effects but pointed out that the study adequately addressed safety.
The current study also did not document the positive outcomes on subjective daytime markers, most likely due to the poor sensitivity of questionnaires or the trial’s short duration. In this context, the markers refer to detectable daytime symptoms related to the disorder such as sleepiness, cognitive dysfunction, and reaction time, Dr. Hedner said.
The lack of a significant daytime effect possibly might be explained by side effects in the highest 400 mg group, Dr. Hedner said, confounded by the patient reports that masked potential changes. Alternatively, the questionnaires used were too insensitive and did not detect potential changes. It is also possible that duration of treatment in the study was too short to detect a change.
“A change in one or several of these means that the patient may trace a positive effect of intervention beyond the supposed immediate effect on health,” he said.
The study’s authors concluded that large-scale clinical studies of sulthiame in OSA are warranted. Dr. Hedner noted that the study’s positive findings have led to a continued multicentric larger scale efficacy trial, which was launched in December 2021.
For the study, investigators recruited male and female patients with OSA who had previously terminated CPAP therapy due to non-acceptance or lack of tolerability. To be eligible, participants had to be between 18 to 75 years old, have a body mass index of greater than or equal to 20 kg/m2 and less than or equal to 35 kg/m2, an apnea hypopnea index (AHI) of greater than or equal to 15, and an Epworth Sleepiness Scale score of greater than or equal to six.
The researchers excluded patients who had undergone OSA treatment within four weeks of the baseline visit as well as those with a central sleep apnea syndrome, dominant Cheyne-Stokes respiration, or a significant sleep disorder including periodic limb movements or parasomnia.
The investigators did report adverse events in the patients randomized to sulthiame. Seventy-nine percent of those assigned to the highest dose, 400 mg of sulthiame experienced intermittent paresthesia as did 67 percent of those taking the 200 mg dose—this compared with 18 percent of patients randomly assigned to placebo. Eighteen percent of patients receiving the 400 mg dose reported dyspnea. And six people in the higher-dose group withdrew from the trial due to adverse events. However, no serious adverse events occurred.
Sulthiame decreased the apnea-hypopnea index (AHI) from 55.3 to 33.1 events per hour (-41.0 percent) in the 400 mg group and from 61.2 to 40.7 events per hour (-32.1 percent) after 200 mg (p<0.001, respectively). Corresponding placebo values were 53.9 and 50.9 events per hour (-5.4 percent). The AHI reduction threshold of greater than or equal to 50 percent was reached in 40 percent of those taking 400 mg, 25 percent on 200 mg, and 5 percent, following placebo. Mean overnight oxygen saturation improved by 1.1 percent after 400 mg and 200 mg (p<0.001 and p=0.034, respectively).
On average, sulthiame lowered OSA by more than 20 events per hour, one of the most notable declines observed in a drug trial for OSA. As a result, larger scale clinical studies of this pharmacological agent are justified, the authors wrote.
Considering that some patients are reluctant or find it difficult to use CPAP for OSA, additional pharmacological options would be an important development, said Karin Johnson, MD, FAAN, FAASM, associate professor at UMass Chan School of Medicine-Baystate and medical director of the Baystate Health regional sleep medicine program in Springfield, MA.
“Ventilatory instability is seen quite commonly in patients with OSA and tends to lead to a higher number of events and more difficulty treating some patients with CPAP therapy who develop treatment-emergent central sleep apnea,” she said.
Dr. Johnson added that it’s worthwhile to consider referring these patients to a sleep specialist, who can discuss other treatment options including medications. However, she advised that clinicians caution patients about the likelihood that a medication alone may not work as well as PAP therapy or other treatment options that also address anatomical obstruction.
The study’s results are not surprising, she said. The reduction in AHI with sulthiame mirrors the outcomes with another carbonic anhydrase inhibitor, acetazolamide, which she has used successfully in some patients who have high loop-gain and a tendency toward a periodic breathing pattern.
Nonetheless, as this trial suggests, the reduction in AHI does not always correlate well with clinical outcomes such as reduction in sleepiness or improved sleep quality, Dr. Johnson pointed out. Sleepiness and quality-of-life scales did not improve in this study, probably due to the fact that OSA stems from a combination of both structural and ventilatory instability causes, she said. Sulthiame targets the instability component alone and does not improve breathing adequately enough to make a clinically significant difference in most patients, Dr. Johnson explained.
In many patients in this study, the residual AHI ranged between 20 and 60 events per hour on treatment, which still represents a high degree of residual obstruction.
“There are likely to be some patients who will benefit from sulthiame alone if other treatments are not a possibility,” she said. “Most likely, it will be best to use in combination with CPAP therapy or with other alternative treatments that help the obstructive component, such as lateral sleeping, nasal congestion treatments, mandibular advancement devices, or newer treatments like nasal expiratory positive airway pressure, oral negative pressure, or daytime tongue stimulation.”
Logan Schneider, MD, a consultant neurologist at the Stanford/VA Alzheimer’s Center in Palo Alto, CA, echoed similar sentiments, welcoming a pharmacological agent to the arsenal of treatments for OSA.
“At first blush, from a general perspective, obviously this is what everybody wants for sleep apnea—a pill to treat it instead of the standard CPAP devices,” said Dr. Schneider, who is also a clinical assistant professor affiliated with the Stanford Sleep Center at the Stanford University School of Medicine.
“While this is a good treatment, particularly for people who cant tolerate the standard-of-care therapy, which is the CPAP device, its certainly not a replacement for it in the average person.”—DR. LOGAN SCHNEIDER
However, most people in the study—even those receiving the highest dose of the medication—still experienced severe OSA. “While this is a good treatment, particularly for people who can’t tolerate the standard-of-care therapy, which is the CPAP device, it’s certainly not a replacement for it in the average person,” he said.
Neurologists acknowledge that OSA is more complicated than they initially thought, with multiple contributing factors, Dr. Schneider said, adding that “each person is a mix of what you call underlying pathophysiology—causes for a disease state.”
The researchers randomly selected patients, without any particular inclusion criteria pertaining to OSA endotypes such as loop-gain—the way that the body manages carbon dioxide and oxygen in the blood through communication between the lungs and brainstem. The other endotypes believed to contribute to OSA are Pcrit, arousal threshold, and muscle tone in the tongue. However, the study didn’t distinguish between the factors specifically at play in relation to therapeutic response, so that should be investigated in future trials to determine the appropriate patient population for this medication, Dr. Schneider noted.
“Sulthiame is not a silver bullet,” he said. “You don’t use it indiscriminately in all sleep apnea patients.” Instead, he described it as “possibly another option, which obviously needs to go through more rigorous validation.”
He added that this small study “highlights that some patients might benefit from this therapy if they can’t tolerate the primary gold standard therapy, or if we find better ways to categorize obstructive sleep apnea based on what causes it.”
Link Up for More Information
• Hedner J, Stemlof K, Zou D, et al. A randomized controlled trial exploring safety and tolerability of sulthiame in sleep apnea https://www.atsjournals.org/doi/10.1164/rccm.202109-2043OC. Am J Respir Crit Care Med 2022: Epub 2022 Feb 24.