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Tirzepatide for the Treatment of OSA and Obesity
TAKE-HOME MESSAGE
- In two phase III, randomized, placebo-controlled trials involving 469 adults with obesity and moderate to severe obstructive sleep apnea, tirzepatide was associated with substantial improvements in apnea–hypopnea indices, hypoxic burden, body weight, blood pressure, hs-CRP concentrations, and sleep-related patient-reported outcomes compared with placebo. The findings were similar between the trials, regardless of background positive airway pressure therapy.
- These findings suggest that tirzepatide may be a valuable adjunctive treatment strategy for adults with obesity and obstructive sleep apnea.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.
METHODS
We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea–hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure.
RESULTS
At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was −25.3 events per hour (95% confidence interval [CI], −29.3 to −21.2) with tirzepatide and −5.3 events per hour (95% CI, −9.4 to −1.1) with placebo, for an estimated treatment difference of −20.0 events per hour (95% CI, −25.8 to −14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was −29.3 events per hour (95% CI, −33.2 to −25.4) with tirzepatide and −5.5 events per hour (95% CI, −9.9 to −1.2) with placebo, for an estimated treatment difference of −23.8 events per hour (95% CI, −29.6 to −17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity.
CONCLUSIONS
Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).
Additional Info
Disclosure statements are available on the authors' profiles:
Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity
N. Engl. J. Med 2024 Jun 21;[EPub Ahead of Print], A Malhotra, RR Grunstein, I Fietze, TE Weaver, S Redline, A Azarbarzin, SA Sands, RJ Schwab, JP Dunn, S Chakladar, MC Bunck, J BednarikFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
We conducted two phase III multinational randomized placebo-controlled studies. In study 1 we assessed patients with obstructive sleep apnea (OSA) not using positive airway pressure (PAP), whereas in study 2 we included OSA patients using PAP therapy. All patients had BMI >30 kg/m2, and we excluded people with diabetes mellitus and with mild sleep apnea. Both studies involved randomizing participants to either tirzepatide or placebo. All participants received standard of care, which included diet and exercise. The primary outcome was the standard metric of OSA severity, the apnea–hypopnea index, which did improve in both studies at 1 year. In addition, we examined secondary outcomes controlled for multiple comparisons and observed marked improvements in blood pressure, body weight, C-reactive protein, patient-reported outcomes, and hypoxic burden. Prior literature strongly suggests that treating both OSA and obesity is required to optimize cardiometabolic health. Thus, first-line treatment for OSA remains PAP therapy; but, in patients who do not use PAP therapy (as in study 1), tirzepatide may be considered, although not yet FDA-approved for this indication. Among OSA patients using PAP therapy, tirzepatide would yield improvement in cardiometabolic parameters based on the new data from SURMOUNT-OSA. Side effects from the tirzepatide were generally mild and self-limited but including nausea, vomiting, and diarrhea. In summary, the SURMOUNT-OSA trial showed major improvements with tirzepatide therapy compared with placebo in OSA severity with concomitant improvements in cardiometabolic health markers in patients with obesity.
Sleep and our health
Every so often, we see a collection of studies on one specific topic. In this case, it all had to do with sleep and our health. I know we have all told our patients that sleep is very important. This is when we do repair and maintenance. And yet, everyone, including ourselves, has sacrificed sleep for work, deadlines, or even binge-watching a show. Perhaps, we all need more data to show us why sleep is so important.
I will touch on the three papers that the editorial team thought were important to highlight. The first study1 is on sleep and pediatric hypertension. The second study2 showed that the lack of sleep or too much sleep can make cardiometabolic parameters worse, and, finally, the third study3 showed how using a dual GLP-1 RA and GIP agonist could help with sleep apnea. All three studies are very different, and, yet, they all focus on the importance of sleep.
Let's start off with the study on kids and hypertension. Usually, with this age group, most of us think that there must be some renal or adrenal cause for their hypertension. This paper1 looked at more than 500 kids who were referred to nephrology for hypertension. The researchers asked about when they went to bed and how long they slept. They found that having just one extra hour of sleep reduced the odds of having hypertension during the day by 12% (OR, 0.88; 95% CI, 0.79–0.99). Also, each additional hour of later sleep onset was associated with more hypertension. So, even in kids, sleep can affect hypertension. Therefore, the authors suggested that we should get kids to sleep earlier. This way, they will sleep longer, and we can reduce hypertension in some of our kids. So, sleep is now important in preventing hypertension, even in kids.
The second study looked at adults and the effects of sleep on cardiometabolic parameters — not just hypertension but other factors like triglyceride levels, metabolic syndrome, high-density lipoprotein cholesterol levels, fasting glucose levels, and waist circumference. This study looked at 6696 adult participants from the National Health and Nutrition Examination Survey study, which has been collecting data on patients by doing surveys on their health since 1960. The authors found that patients aged between 40 and 59 years who went to sleep past midnight and had less than 7 hours of sleep did worse in their metabolic parameters. Their odds of having metabolic syndrome were up by 46% (OR, 1.46; 95% CI, 1.03–2.06).
Interestingly, too much sleep was not good either. Participants who slept for more than 9 hours also showed a worsening of metabolic parameters. In particular, hypertension was increased by 66% (OR, 1.66; 95% CI, 1.14–2.44). The odds of having hypertriglyceridemia were up by 168% (OR, 2.68; 95% CI, 1.02–7.05) for “over-sleepers.” No one knows exactly what the mechanism is. Perhaps, their repair and maintenance system is not working well, and, hence, they need longer time to do the work; so, they need to sleep longer. And, if those systems are not working well, then the other metabolic systems may not be working well either. Whatever the mechanism, too much or too little sleep is not good. So, let' aim for the normal amount of sleep. So, sleep before midnight, and sleep for 7 to 9 hours.
Now, the final study3 is about treatment for obstructive sleep apnea. It is a condition where the airway is blocked, usually, by the tongue falling backward, and there is no airflow; so, the patient effectively stops breathing. Basically, the patient is having “choking” spells throughout the night. This is associated with disrupted sleep and many cardiovascular (CV) complications. The standard treatment is to blow air with a continuous positive airway pressure (CPAP) machine in order to keep the airways open.
Now, we know that obesity can cause fat to accumulate in the pharynx and, hence, make the passages narrower; so, obstruction is easier.
In this study, the authors used tirzepatide, which is a dual GLP-1 RA and GIP agonist, to see whether weight reduction in patients with moderate to severe sleep apnea would help their sleep apnea. They performed two trials: trial 1 was for patients not on CPAP, and trial 2 was for patients on CPAP. Each trial included just over 230 patients. They measured the Apnea–Hypopnea Index (AHI), which is the number of apneas and hypopneas that occurred during 1 hour of sleep. At the baseline, the non-CPAP group experienced 51.5 events per hour and the CPAP group experienced 49.5 events per hour. Imagine having 50 choking events every hour. No wonder these patients have more CV events.
Half the patients in each trial got a once-weekly injection of tirzepatide, and the other half got a placebo. After 1 year, in both trials, patient weight was reduced by around 17 kg in the tirzepatide group. The AHI number was reduced dramatically as well.
For the non-CPAP group, patients on tirzepatide had 20.0 events per hour less than those in the placebo group (95% CI, −25.8 to −14.2; P < .001). In patients on CPAP, one would not expect much benefit because patients are already on the proper therapy. However, the tirzepatide group still had 23.8 events per hour less than those in the placebo group (95% CI, −29.6 to −17.9; P < .001). In both studies, the AHI numbers were reduced by more than 50%, and they were both statistically significant.
So, this means that, for patients with obstructive sleep apnea, tirzepatide is a good option whether they are using CPAP or not. Now, this study is not long enough in duration nor powered to look for CV event reductions. However, if I were to speculate, I would think that a patient who had 50% fewer “choking events” would have a bright future.
So, with this trilogy on sleep, it is clear that sleep is very important for our health. Let's start by making sure that our kids grow up with good sleep habits, and, hopefully, their path will be a healthier one. For adults, especially those aged between 40 and 59 years, let’s encourage them to get to sleep before midnight and aim for 7 to 9 hours of sleep. And, finally, tirzepatide, with its weight-reduction ability, was able to reduce the number of “choking” episodes by more than 50%, regardless of whether the patients were on CPAP or not.
So, let us take our own advice — protect our sleep and keep it as regular as possible. Boring is good when it comes to our sleep.
References