SAN ANTONIO — While obstructive sleep apnea is closely associated with obesity, not all the drugs being developed for the treatment of OSA are based upon weight loss as their mechanism of benefit.

For example, acetazolamide addresses ventilatory instability, which has emerged as a potential novel therapeutic target in OSA.

Another early study suggests the sedative eszopiclone (Lunesta) reduces sleep apnea severity and increases sleep duration by raising the respiratory arousal threshold, investigators reported at the meeting.

Still, weight loss is the classic source of pharmacologic improvement in OSA. The first drug shown to be of benefit in patients with OSA was sibutramine (Meridia), a serotonin and noradrenaline reuptake inhibitor, noted Dr. Ronald R. Grunstein, professor of sleep medicine at the University of Sydney.

He was lead investigator in a study that showed 6 months of sibutramine plus a 600-kcal-deficit diet and exercise not only resulted in significant weight loss, it also brought marked improvement in OSA, reduced insulin resistance, a rise in high-density lipoprotein cholesterol, and decreased visceral, subcutaneous, and hepatic fat, with no change in blood pressure (J. Clin. Sleep Med. 2009;5:416-21).

At the sleep disorders meeting, audiences learned of another weight-loss drug with evidence of efficacy for OSA: Qnexa, an investigational once-daily proprietary combination of phentermine and controlled-release topiramate.

Dr. David H. Winslow presented a double-blind, single-center trial in which 45 obese patients with OSA were randomized to once-daily Qnexa at 15-mg phentermine/92-mg topiramate CR or to placebo for 28 weeks.

All participants were either noncompliant with or disinterested in continuous positive airway pressure (CPAP) therapy, and all were provided with a structured lifestyle modification program.

At week 8, the mean apnea-hypopnea index (AHI) in the Qnexa group had dropped from a baseline of 45.5 to 19.1 events per hour.

By week 28, their mean AHI had fallen to 13.5, as compared with 27.2 in the placebo arm, reported Dr. Winslow, a chest physician and president of the Kentucky Research Group, Lexington.

The Qnexa group experienced a mean 11% reduction in body weight over the 28 weeks, twice that of the placebo group.

Other statistically significant and clinically meaningful changes in the Qnexa group included a mean 15–mm Hg drop in systolic blood pressure from a baseline of 138 mm Hg, as compared with a 7.3–mm Hg drop in controls, along with polysomnographic improvements in arousal index and mean and minimum overnight oxygen saturation.

The most common adverse events were mild to moderate dry mouth and altered taste. There were no serious adverse events in the study.

“I think we may be looking at a new paradigm in the treatment of OSA,” Dr. Winslow said in an interview.

Qnexa is under Food and Drug Administration review for a proposed indication as a treatment for obesity; a regulatory decision is expected later this year. While the results in the 45-patient OSA study are quite encouraging, getting an additional indication as a therapy for OSA will require much larger clinical trials, he noted.

Danny J. Eckert, Ph.D., of Brigham and Women's Hospital, Boston, presented a double-blind, randomized, crossover trial in which 17 untreated OSA patients received 3 mg of eszopiclone or placebo immediately prior to going to sleep during overnight polysomnography on two occasions in the sleep lab.

The patients' mean AHI was 24 events per hour on eszopiclone, compared with 31 per hour with placebo.

The seven patients with a low baseline respiratory arousal threshold, defined as less than 15 cm H₂O, had a mean 42% improvement in AHI on active therapy, and all seven of them had at least a 20% improvement.

Patients on eszopiclone also had a marked increase in total sleep time, from 5.3 hours on placebo to 6.8 hours, along with fewer arousals per hour and improved sleep quality, he reported.

Dr. Bradley A. Edwards, also of Brigham and Women's Hospital, presented a preliminary physiologic study in which six CPAP-treated patients with OSA underwent 2 nights of baseline polysomnography, and then took acetazolamide SR 500 mg twice daily for a week.

This was followed by another 2 nights of polysomnography in which CPAP was intermittently turned down to subtherapeutic levels in order to see whether acetazolamide reduced ventilatory control instability. This indeed proved to be the case in all six patients.

Moreover, five of the six patients experienced an associated reduction in AHI.

Dr. Grunstein said other drugs being explored as possible OSA therapies include lorcaserin, now under FDA review as a potential antiobesity drug, and testosterone.

Disclosures: Dr. Winslow disclosed that he serves as a consultant to Vivus Inc., which is developing Qnexa. Dr. Eckert's study was partially funded by a research grant from Sepracor Inc. Dr. Grunstein's sibutramine study was supported by Abbott Laboratories. Dr. Edwards reported no financial conflicts.

70793_fx1.sml

'I think we may be looking at a new paradigm in the treatment of OSA.'

Source DR. WINSLOW

OSA Drugs No Longer Aim Only at Weight Loss