Abstract
Background:
Obstructive sleep apnea (OSA) is a common disorder with major cardiometabolic and neurocognitive sequelae. It affects up to 1 billion people globally and is frequently attributable to excess weight [1]. Tirzepatide is a once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is FDA-approved for the treatment of moderate-to-severe OSA in adults with obesity.
Methods:
The SURMOUNT-OSA program included two 52-week, randomized, double-blind, placebo-controlled, Phase 3 studies (Study 1 and Study 2). The objective of these analyses was to assess time to treatment effects for improvements in apnea-hypopnea index (AHI) and sleep apnea-specific hypoxic burden (SASHB), and how these changes correspond with body weight reduction. We also aimed to investigate weight-dependent and weight-independent effects of tirzepatide treatment for OSA using linear regression analysis.
Results:
The results of peripheral AHI (pAHI) and SASHB measurements from WatchPAT 300 in Study 1 were consistent with the polysomnographic (PSG) findings. The tirzepatide-associated improvements in pAHI were significant vs baseline as early as Week 4. However, the estimated treatment difference compared to placebo was not significant until Week 20 for both pAHI and WatchPAT-based SASHB. The magnitude of changes in AHI and SASHB were associated with achieved weight reduction in both studies.
Conclusions:
The results from these post hoc analyses provide details regarding the time course of resolution and insights regarding the impact of weight reduction on OSA improvements. Additional research is needed to determine the impact of body weight reduction versus other effects of tirzepatide on the improvements in OSA measures.
Keywords: Obstructive sleep apnea, Apnea-hypopnea index, Sleep apnea-specific hypoxic burden, SURMOUNT-OSA
1. Introduction
Obstructive sleep apnea (OSA) is a common disorder with major cardiometabolic and neurocognitive sequelae [2]. OSA is estimated to affect up to 1 billion people worldwide, with more than half of adults with moderate-to-severe OSA having the disease, attributable to excess weight [1].
Tirzepatide is a once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that has demonstrated clinically relevant weight reduction in adults with obesity [3,4], and is FDA-approved for obesity, type 2 diabetes mellitus, and moderate-to-severe OSA in people with obesity [5,6]. The SURMOUNT-OSA program comprised 2 randomized, placebo-controlled Phase 3 studies of tirzepatide in participants with moderate-to-severe OSA and obesity [7]. These studies showed clinically relevant improvements in the apnea-hypopnea index (AHI) as a marker of sleep apnea severity, with concomitant improvements in sleep apnea-specific hypoxic burden (SASHB), systolic blood pressure, body weight, high-sensitivity C-reactive protein, as well as self-reported daily functioning [8]. However, there is interest to better understand the weight-dependent vs weight-independent proportions of the observed effects. Time to benefit is important for clinical decision making, and the time course of the changes observed in the program has not been fully reported yet.
An important question in the OSA/obesity literature is regarding the level of weight reduction required to obtain clinically important improvements. We have recently reported a meta-analysis showing a relationship between improvements in OSA severity with reported reduction of BMI [9]. Data from the SURMOUNT-OSA program reported in this paper gives more insight into the question.
The objective of the current analyses was to assess time to treatment effects for improvements in AHI and SASHB, and how these changes correspond with body weight reduction. We also aimed to investigate weight-dependent and weight-independent effects of tirzepatide treatment for OSA.
2. Methods
2.1. Study design, procedures, and participants
The SURMOUNT-OSA program comprised two 52-week, randomized, placebo-controlled Phase 3 studies to evaluate the efficacy and safety of the maximum tolerated dose (MTD) of tirzepatide (TZP, 10 mg or 15 mg) once weekly (QW) in adults with moderate-to-severe OSA (AHI ≥15 events per hour) and obesity (body mass index, BMI, of ≥30 [≥27 in Japan]). Participants were assigned to either Study 1 or Study 2, for participants who at screening reported not using, or using, positive airway pressure (PAP) therapy, respectively. The master protocol rationale, study design, eligibility criteria, participant disposition, and pre-specified efficacy and safety results have been published previously [7,8]. The trial was conducted in accordance with good clinical practice guidelines and the principles of the Declaration of Helsinki. Independent ethics committee or institutional review board approvals were received for each participating site. All participants provided written informed consent before trial participation.
2.2. WatchPAT300
The WatchPAT300 is a noninvasive device consisting of multiple biosensors, including a proprietary technology known as peripheral arterial tone (PAT), pulse oximetry, an accelerometer, and an acoustic sensor for detecting chest position and snoring. It has been cleared as a diagnostic aid for the detection of sleep-related breathing disorders by the FDA. WatchPAT300 measures the number of apneas and hypopneas per hour of sleep (peripheral apnea-hypopnea index, pAHI) and allows the analysis of SASHB.
2.3. Apnea-hypopnea index (AHI) measurements
AHI was measured by laboratory polysomnography at screening, Week 20, and Week 52 in both studies. pAHI was measured at Weeks 0, 4, 12, 20, and 52 by WatchPAT 300 in participants from Study 1 (n = 117 at baseline, n = 59 assigned to tirzepatide, and n = 58 on placebo).
2.4. Sleep apnea-specific hypoxic burden (SASHB) measurements
The respiratory event-related hypoxic burden (%.min/hr) [10] was calculated from a polysomnographic study (Weeks 0, 20, and 52) in both studies. The sleep apnea-specific hypoxic burden (%.min/hr) is defined as the total area under the respiratory event-related desaturation curve and is expressed as the time (in minutes) spent in oxygen desaturation (%) per hour of sleep [10]. This was also calculated from WatchPAT 300 data (Weeks 0, 4, 12, 20, and 52) in Study 1 participants (n = 118 at baseline, n = 60 assigned to tirzepatide, and n = 58 on placebo).
Association of AHI or SASHB (measured with polysomnography) with body weight was also assessed in both studies.
2.5. Statistical analysis
Changes in AHI, SASHB, and body weight from SURMOUNT-OSA have already been reported [8]. Data from all the participants who received at least 1 dose of tirzepatide or placebo (the intention-to-treat population) were used to analyze the efficacy and safety endpoints.
The current analysis was guided by the “efficacy” estimand; it included data collected prior to permanent discontinuation of the study intervention and was conducted using the efficacy analysis set (EAS). No explicit imputations for missing data were performed for these analyses.
Unless otherwise noted, all tests of treatment effects were conducted at a 2-sided alpha level of 0.05, and the confidence intervals were calculated at 95 %. In statistical summaries and analyses, participants were analyzed as randomized.
The mixed model repeated measures (MMRM) analysis, a restricted-maximum-likelihood-based model, was used to analyze continuous longitudinal variables by treatment and visit from baseline to Week 52. The model includes the fixed class effects of treatment, strata (pooled country/geographic region, baseline OSA severity, and sex), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of the baseline value. Significance tests were based on least-squares means and Type III tests. The MMRM statistical analysis was conducted on WatchPAT 300 data based on the data points from modified intent-to-treat (mITT) participants, collected on treatment and not on PAP for Study 1. Log transformation was used for SASHB data.
Participants in each study and each treatment arm were also divided into 3 approximately equal groups based on the percentage of weight reduction (Lower, Middle, and Upper). Tertiles were chosen as the grouping method to ensure that each group contained a sufficient number of participants for analysis. AHI and SASHB changes were calculated within each of these tertiles, and the mean percentage changes within each group, along with their standard deviations, are reported. These analyses help in identifying trends in sleep parameter changes with differing amounts of weight reduction.
Scatterplots were created to visualize the relationship between percentage change in AHI and percentage change in weight, percentage change in SASHB and percentage change in weight, and percentage change in AHI and percentage change in SASHB. Separate linear regression lines were fitted for the placebo group, treatment group, and the combined data to assess and compare trends within each group and overall. Regression lines were computed using the method of ordinary least squares. For each response variable, 3 models were fit, 1 only on the participants treated with tirzepatide, 1 only on the participants treated with placebo, and 1 on the data combined across the two treatment arms. The models analyzing the relationship between weight change and changes in AHI/SASHB use percentage change in AHI and percentage change in SASHB as the response variables, and percentage change in weight as the independent variable. The model analyzing the relationship between AHI and SASHB uses percentage change in SASHB as the response variable, and percentage change in AHI as the independent variable. For the model fitted across the combined data over the two treatment arms, a treatment term was also added to the model.
3. Results
3.1. Trial participants
In the SURMOUNT-OSA program, a total of 469 participants were randomized to receive either tirzepatide or placebo across Study 1 (234 participants; tirzepatide n = 114, placebo n = 120) and Study 2 (235 participants; tirzepatide n = 120, placebo n = 115) [8]. Results are presented under the efficacy estimand. Participants’ sleep disordered breathing (SDB)-related baseline characteristics, previously reported by Malhotra et al. (2024), are shown in Table 1 [8].
Table 1.
Baseline clinical characteristics of the SURMOUNT-OSA participants (total randomized population).
| Characteristic | Study 1 |
Study 2 |
||||
|---|---|---|---|---|---|---|
| Tirzepatide MTD (n = 114) | Placebo (n = 120) | Total (n = 234) | Tirzepatide MTD (n = 120) | Placebo (n = 115) | Total (n = 235) | |
|
| ||||||
| BMI - kg/m2 | 39.7 ± 7.3 | 38.6 ± 6.7 | 39.1 ± 7.0 | 38.6 ± 6.1 | 38.7 ± 6.0 | 38.7 ± 6.0 |
| AHI - events/hr | 52.9 ± 30.5 | 50.1 ± 31.5 | 51.5 ± 31.0 | 46.1 ± 22.4 | 53.1 ± 30.2 | 49.5 ± 26.7 |
| OSA severity - n (%) | ||||||
| No Apnea | 0 (0.0 | 1 (0.8) | 1 (0.4) | – | – | – |
| Mild | 1 (0.9) | 2 (1.7) | 3 (1.3) | 0 (0.0) | 2 (1.8) | 2 (0.9) |
| Moderate | 39 (34.2) | 43 (36.1) | 82 (35.2) | 35 (29.4) | 37 (32.5) | 72 (30.9) |
| Severe | 74 (64.9) | 73 (61.3) | 147 (63.1) | 84 (70.6) | 75 (65.8) | 159 (68.2) |
| SASHB - %.min/hr (CV [%])a | 153.6 (102.7) | 137.8 (104.1) | 145.3 (103.4) | 132.2 (83.4) | 142.1 (112.5) | 137.0 (97.5) |
Data are for the total randomized population (as previously presented in Malhotra et al. (2024) [8].
Data are mean ± SD unless otherwise specified.
AHI = apnea-hypopnea index; BMI = body mass index; CV = coefficient of variation; OSA = obstructive sleep apnea; SASHB = sleep apnea-specific hypoxic burden; SD = standard deviation.
Data are geometric means (coefficient of variation, %).
3.2. Changes in sleep-disordered breathing-related measures
In Study 1, the change in AHI from baseline was −21.1 ± 1.9 events/hr at Week 20 and −27.4 ± 2.1 events/hr at Week 52 in participants treated with tirzepatide (with a reduction from 54.3 ± 2.95 to 25.1 ± 2.14 events/hr from baseline to Week 52), and −4.8 ± 2.0 events/hr at Week 20 and −4.8 ± 2.3 events/hr at Week 52 with placebo (from 50.9 ± 3.07 events/hr at baseline to 47.6 ± 2.28 events/hr at Week 52). The estimated treatment difference (ETD) was −16.3 (95 % confidence interval [CI] −21.8, −10.8; p < 0.001) at Week 20, and −22.5 (95 % CI −28.7, −16.4; p < 0.001) at Week 52 (Fig. 1A), as previously reported [8]. The change in pAHI in Study 1 from baseline was −18.7 ± 1.8 events/hr at Week 20 and −21.9 ± 2.6 events/hr at Week 52 in participants treated with tirzepatide (from 45.4 ± 3.35 events/hr at baseline to 23.3 ± 2.59 events/hr at Week 52), and −7.8 ± 1.7 events/hr at Week 20 and −6.7 ± 2.6 events/hr at Week 52 with placebo (from 45.4 ± 3.38 events/hr at baseline to 38.5 ± 2.56 events/hr at Week 52), for an ETD of −10.8 (95 % CI −15.8, −5.9; p < 0.001) at Week 20, and −15.1 (95 % CI −22.4, −7.9; p <0.001) at Week 52 (Fig. 1A). In Study 2, the change in AHI from baseline was −22.6 ± 2.0 events/hr at Week 20 and −30.4 ± 2.0 events/hr at Week 52 with tirzepatide (with a reduction from 45.8 ± 2.42 events/hr at baseline to 18.7 ± 1.98 events/hr at Week 52), and −5.4 ± 2.1 events/hr at Week 20 and −6.0 ± 2.2 events/hr at Week 52 with placebo (from 53.1 ± 2.62 events/hr at baseline to 43.2 ± 2.19 events/hr at Week 52) for an ETD of −17.2 (95 % CI −23.0, −11.4; p < 0.001) at Week 20, and −24.4 (95 % CI −30.3, −18.6; p < 0.001) at Week 52 (Fig. 1B), as previously reported [8]. Changes from baseline to each time point for both studies for this post-hoc analysis are also presented in Table 2. The oxygen desaturation index (ODI), defined as desaturation per hour ≥4 % in Total Sleep Time (TST), is included in Supplement Table 1.
Fig. 1.
Change in AHI, pAHI, and body weight. Change from baseline in AHI (number of apneas and hypopneas events per hour of sleep) and percent change from baseline in body weight. Study 1 also includes pAHI measurements carried out with WatchPAT 300. Data points from baseline to Week 52 for Study 1 and Study 2 are shown according to the weeks since randomization, derived from a mixed-model-for-repeated-measures analysis for the efficacy estimand. Data points are LSMean ± SE. ***p < 0.001 versus placebo. AHI = apnea-hypopnea index; LSMean = least-squares mean; PBO = placebo; SE = standard error; TZP = tirzepatide maximum tolerated dose (MTD, 10 mg or 15 mg once weekly).
Table 2.
Change in AHI, pAHI, body weight, and SASHB from baseline to Week 52 in this post-hoc analysis population.
| Study 1 |
Study 2 |
|||
|---|---|---|---|---|
| Tirzepatide | Placebo | Tirzepatide | Placebo | |
|
| ||||
| AHI (events/hr) at | ||||
| Baseline | 54.3 ± 2.95 | 50.9 ± 3.07 | 45.8 ± 2.42 | 53.1 ± 2.62 |
| Week 20 | 31.4 ± 1.94 | 47.6 ± 2.00 | 26.5 ± 1.97 | 43.7 ± 2.14 |
| Week 52 | 25.1 ± 2.14 | 47.6 ± 2.28 | 18.7 ± 1.98 | 43.2 ± 2.19 |
| Change in AHI (events/hr) from baseline at | ||||
| Week 20 | −21.10 ± 1.94 *** | −4.80 ± 2.00 * | −22.60 ± 1.97 *** | −5.40 ± 2.14 * |
| Week 52 | −27.40 ± 2 14 *** | −4.80 ± 2.28 * | −30.40 ± 1.98 *** | −6.00 ± 2.19 ** |
| pAHI (events/hr) at | ||||
| Baseline | 45.4 ± 3.35 | 45.4 ± 3.38 | − | − |
| Week 4 | 39.1 ± 2.02 | 41.3 ± 2.11 | − | − |
| Week 12 | 33.4 ± 2.41 | 39.9 ± 2.51 | − | − |
| Week 20 | 26.5 ± 1.76 | 37.4 ± 1.73 | − | − |
| Week 52 | 23.3 ± 2.59 | 38.5 ± 2.56 | − | − |
| Change in pAHI (events/hr) from baseline at | ||||
| Week 4 | −6.10 ± 2.02 ** | −3.90 ± 2.11 n.s. | − | − |
| Week 12 | −11.80 ± 2 41 *** | −5.30 ± 2.51 * | − | − |
| Week 20 | −18.70 ± 1 76 *** | −7.80 ± 1.73 | − | − |
| Week 52 | −21.90 ± 2.59 *** | −6.70 ± 2.56 * | − | − |
| Percent change in body weight from baseline at | ||||
| Week 4 | −2.40 ± 0 17 *** | −0.80 ± 0.16 | −3.20 ± 0.19 *** | −0.8 ± 0.19 *** |
| Week 8 | −4.80 ± 0.26 *** | −0.80 ± 0.26 | −5.80 ± 0.24 *** | −1.30 ± 0.25 *** |
| Week 12 | −7.00 ± 0.32 *** | −1.4 ± 0.32 *** | −8.30 ± 0.31 *** | −1.70 ± 0.32 *** |
| Week 16 | −9.00 ± 0 39 *** | −1.70 ± 0.39 | −10.40 ± 0.37 *** | −2.10 ± 0.39 *** |
| Week 20 | −11.00 ± 0.44 *** | −2.20 ± 0.45 | −12.60 ± 0.44 *** | −2.60 ± 0.46 *** |
| Week 24 | −12.80 ± 0.49 *** | −2.30 ± 0.50 | −14.50 ± 0.49 *** | −2.30 ± 0.52 *** |
| Week 36 | −15.90 ± 0.59 *** | −2.20 ± 0.61 | −17.80 ± 0.64 *** | −2.50 ± 0.68 *** |
| Week 48 | −17.60 ± 0.68 *** | −1.90 ± 0.71 * | −19.40 ± 0.72 *** | −2.30 ± 0.77 ** |
| Week 52 | −18.10 ± 0 71 *** | −1.30 ± 0.73 n.s. | −20.10 ± 0.73 *** | −2.30 ± 0.78 ** |
| Percent change in SASHB from baseline at | ||||
| Week 20 | −49.80 ± 3.02 *** | −13.70 ± 5.36 * | −57.30 ± 3.65 *** | −25.70 ± 6.90 ** |
| Week 52 | −67.60 ± 2.76 *** | −13.80 ± 7.88 n.s. | −76.90 ± 2.71 *** | −30.40 ± 9.04 ** |
| Percent change in WatchPAT SASHB from baseline at | ||||
| Week 4 | −6.90 ± 6.92 n.s. | −12.50 ± 6.79 n.s. | − | − |
| Week 12 | −14.10 ± 6.70 n.s. | −14.50 ± 7.03 n.s. | − | − |
| Week 20 | −33.00 ± 4.35 *** | −9.00 ± 5.84 n.s. | − | − |
| Week 52 | −41.10 ± 5.05 *** | −18.90 ± 6.90 * | − | − |
AHI, change from baseline in AHI, and percent change from baseline in body weight and in SASHB are included for this post-hoc analysis population from the SURMOUNT-OSA Study 1 and Study 2. Study 1 also includes the change from baseline in pAHI and SASHB, carried out with WatchPAT 300.
Data are LSMean ± SE for AHI, pAHI, and body weight, and Estimate ± SE for SASHB, and WatchPAT SASHB.
Data are derived from a mixed-model-for-repeated-measures analysis aligned with the efficacy estimand.
p < 0.05
p ≤ 0.010
p ≤ 0.001 represent significant changes from baseline. N.s. = not statistically significant.
AHI = number of apnea and hypopnea events during an hour of sleep; LSMean = least-squares mean; pAHI = peripheral apnea-hypopnea index; SASHB = sleep apnea-specific hypoxic burden; SE = standard error.
In Study 1, the percent change in body weight from baseline was −11.0 ± 0.4 % at Week 20 and −18.1 ± 0.7 % at Week 52 in participants treated with tirzepatide, and −2.2 ± 0.5 % at Week 20 and −1.3 ± 0.7 % at Week 52 with placebo, as previously reported [8], for an ETD of −8.8 (95 % CI −10.1, −7.6; p < 0.001) at Week 20 and −16.8 (95 % CI −18.8, −14.7; p < 0.001) at Week 52 (Fig. 1A). In Study 2, the change in body weight from baseline was −12.6 ± 0.4 % at Week 20 and −20.1 ± 0.7 % at Week 52 with tirzepatide, and −2.6 ± 0.5 % at Week 20 and −2.3 ± 0.8 % at week 52 with placebo, as previously reported [8], for an ETD of −10.0 (95 % CI −11.3, −8.8; p < 0.001) at Week 20 and −17.8 (95 % CI −19.9, −15.7; p < 0.001) at Week 52 (Fig. 1B). Participants in both studies who received tirzepatide had significant ETD versus placebo in body weight from Week 4 to Week 52; the results are reported in Fig. 1A and B and in Table 2.
In Study 1, the percent change in SASHB (% min/hr) from baseline was −49.8 ± 3.0 % at Week 20 and −67.6 ± 2.8 % at Week 52 in participants treated with tirzepatide, and −13.7 ± 5.4 % at Week 20 and −13.8 ± 7.9 % at Week 52 with placebo, for an ETD of −41.8 (95 % CI −51.0, −31.0; p < 0.001) at Week 20, and −62.4 (95 % CI −70.6, −51.9; p < 0.001) at Week 52 (Fig. 2A). In Study 1, the percent change in WatchPAT SASHB from baseline was −33.0 ± 4.4 % at Week 20 and −41.1 ± 5.1 % at Week 52 with tirzepatide, and −9.0 ± 5.8 % at Week 20 and −18.9 ± 6.9 % at Week 52 with placebo, for an ETD of −26.3 (95 % CI −38.6, −11.6; p = 0.001) at Week 20, and −27.3 (95 % CI −42.9, −7.5; p = 0.010) at Week 52 (Fig. 2A). In Study 2, the change in SASHB from baseline was −57.3 ± 3.7 % at Week 20 and −76.9 ± 2.7 % at Week 52 with tirzepatide, and −25.7 ± 6.9 % at Week 20 and −30.4 ± 9.0 % at Week 52 with placebo for an ETD of −42.5 (95 % CI −55.2, −26.2; p < 0.001) at Week 20, and −66.8 (95 % CI −76.5, −53.1; p < 0.001) at Week 52 (Fig. 2B). Changes from baseline to each time point for both studies for this post-hoc analysis are also presented in Table 2.
Fig. 2.
Sleep Apnea-Specific Hypoxic Burden (SASHB). Percentage change from baseline in SASHB. Data are geometric means (coefficient of variation, %) expressed as the time spent in event-related oxygen desaturation per hour of sleep (% min/hr). Data points from baseline to Week 52 for Study 1 and Study 2 are shown according to the weeks since randomization, derived from a mixed-model-for-repeated-measures analysis for the efficacy estimand, using Log transformation. Data points are LSMean ± SE. **p ≤ 0.010; ***p ≤ 0.001 versus placebo. LSMean = least-squares mean; PBO = placebo; SASHB = Sleep Apnea-Specific Hypoxic Burden; SE = standard error; TZP = tirzepatide maximum tolerated dose (MTD, 10 mg or 15 mg once weekly).
3.3. Analysis by weight change tertiles
Participants were categorized into tertiles by percent weight change at Week 52, with participants in the upper tertile having the greatest weight reduction and participants in the lower tertile having the least weight reduction (Fig. 3 for the tirzepatide group, and Supplement Fig. 1 for the placebo group). In the participants treated with tirzepatide, the percent body weight reduction was ≥22.33 % in the upper tertile, <22.33 % to ≥15.65 % in the middle tertile, and <15.65 % in the lower tertile for Study 1, and ≥23.42 % in the upper tertile, <23.08 % to ≥16.23 % in the middle tertile, and <16.23 % in the lower tertile for Study 2.
Fig. 3.
Percent change in AHI and SASHB by tertile analysis based on percent body weight change in participants treated with tirzepatide. Data are mean ± SD unless otherwise specified. Tertiles were based on percent body weight reduction, which was ≥22.33 % in the Upper, <22.33 % to ≥15.65 % in the Middle, and <15.65 % in the Lower for Study 1, and ≥23.42 % in the Upper, <23.42 % to ≥16.23 % in the Middle, and <16.23 % in the Lower for Study 2. AHI = apnea-hypopnea index; SASHB = sleep apnea-specific hypoxic burden; SD = standard deviation; TZP = tirzepatide maximum tolerated dose (MTD, 10 mg or 15 mg once weekly).
The greater weight reduction was consistently accompanied by the greater mean percent AHI change in both studies. In the participants treated with tirzepatide, the mean percentage change in AHI was −70.58 ± 26.10 %, −53.07 ± 33.89 %, and −42.48 ± 48.02 % for Upper, Middle, and Lower tertile, respectively, for Study 1 (Fig. 3A), and −81.60 ± 30.01 %, −62.70 ± 25.55 %, and −41.78 ± 56.31 % for Upper, Middle, and Lower tertile, respectively, for Study 2 (Fig. 3B).
The greater weight reduction was consistently accompanied by the greater mean percent SASHB change in both studies. In the participants treated with tirzepatide, the percentage change in SASHB was −67.20 ± 25.82 %, −55.02 ± 31.20 %, and −41.94 ± 50.86 % for Upper, Middle, and Lower tertile, respectively for Study 1 (Fig. 3C), and −76.98 ± 39.77 %, −59.32 ± 27.95 %, and −41.42 ± 51.83 % for Upper, Middle, and Lower tertile, respectively for Study 2 (Fig. 3D).
3.4. Linear regression analysis
Linear regression analyses were performed for each of the two studies. Based on the linear models depicted in Fig. 4, percentage change in AHI and percentage change in SASHB seem to have a strong linear relationship with percentage change in weight, and percentage change in SASHB seems to have a strong linear relationship with percentage change in AHI, as evidenced by significant p-values corresponding to the independent variables of all linear models. All the p-values for the parameters corresponding to the percentage change in weight term, or AHI term respectively, for all the fitted models were less than 0.05, except in percentage change in weight vs percentage change in SASHB in Study 1 for the model for placebo only (p = 0.163) (Fig. 4B), and the model for the combined treatment arms (p = 0.067) (Fig. 4B).
Fig. 4.
Linear regression analysis. Linear regression analysis demonstrating associations (A) between percent change in weight and percent change in AHI; (B) between percent change in weight and percent change in SASHB; and (C) between percent change in AHI and percent change in SASHB. For each response variable, 3 models were fit, 1 only on the participants treated with TZP, 1 only on the participants treated with placebo, and 1 on the data combined across the two treatment arms. AHI = apnea-hypopnea index; SASHB = sleep apnea-specific hypoxic burden; TZP = tirzepatide maximum tolerated dose (MTD, 10 mg or 15 mg once weekly).
4. Discussion
The presented findings provide insights into the time course of tirzepatide treatment-related OSA severity improvements and their relationship with observed weight reduction. These findings are important as they add to the already published data from SURMOUNT-OSA regarding the first pharmacotherapy for treating moderate-to-severe OSA in adults with obesity [8]. First, we have observed that the AHI and SASHB improvements with tirzepatide therapy were associated with weight reduction over time. There has been postulation regarding weight-independent effects of incretin-based medications [11], and the presented data may suggest a larger effect of tirzepatide per reported weight reduction in comparison with placebo. Second, the improvements in AHI and SASHB were present in the placebo arms, suggesting that the lifestyle intervention delivered by experienced personnel was moderately effective. The initial improvement in AHI with lifestyle intervention seems larger than expected in relation to observed weight reduction. This is consistent with prior reports that exercise may have independent effects from weight reduction, potentially via training of upper airway muscles [12–14]. Third, there has been debate about the relationship between weight reduction and AHI improvement with different weight interventions [15]. We have observed a quadratic relationship between BMI and AHI changes across various interventions in our recent meta-analysis [9], but the data presented here for pharmacotherapy with tirzepatide suggest a linear dose-response relationship (Fig. 4A), suggesting incremental weight reduction will lead to similar incremental AHI improvement. In aggregate, our new findings are clinically important and may help tailor the management of adults with moderate-to-severe OSA and obesity.
The GLP-1 and GIP/GLP-1 receptor agonist medications such as tirzepatide have pleotropic effects. The mechanism of weight reduction has been debated but may be largely attributable to reduced energy intake [11]. In addition, tirzepatide has reported additional effects, including reductions in alcohol and tobacco intake, perhaps via the dopamine reward pathways in the brain [16,17]. Reduced alcohol and tobacco intake could feasibly improve OSA and OSA-related cardiometabolic health. The carotid body also has GLP-1 receptors, which may be involved in mitigating the sympathetic activation associated with hyperglycemia [18]; dampening sympathetic drive could feasibly reduce overreactive chemoreflexes and promote OSA severity improvements [19]. The analysis of the study data did not confirm TZP effects on sleep-disordered breathing that would not be attributable to weight reduction.
The information regarding the time course of resolution of OSA presented in Table 2 is important since it may inform clinical care. A rapid resolution of OSA may obviate the need for other OSA therapies, whereas a delayed response may point to the need for additional therapies while weight reduction is occurring. We observed early improvements of AHI and SASHB in both the tirzepatide and placebo arms, with tirzepatide significantly differentiating from placebo from Week 20. These results may suggest that the lifestyle intervention was having an impact early on. With tirzepatide but not placebo, we did observe significant improvements vs. baseline by 4 weeks of treatment, suggesting an early effect of the medication on top of lifestyle intervention. With SASHB, we did not observe significant improvements vs. baseline until Week 20, either in the placebo or tirzepatide group, suggesting that more time will be required to realize the benefits of interventions on SASHB than on AHI. Further research will be required to determine whether there is a dissociation of these observed improvements over time.
We did observe considerable improvements in SURMOUNT-OSA in the control group. Several potential explanations are possible. The impact of structured lifestyle intervention may well be meaningful [20]. In addition, it has been reported that placebo injections can produce a therapeutic effect [21]. Furthermore, Hawthorne effect has been reported whereby participants in a study may improve over time, simply by being carefully observed in the context of a rigorous clinical trial [22]. Participation bias may also be important since perhaps the people who consented for SURMOUNT-OSA were motivated to lose weight and were thus receptive to instructions provided during the studies. However, consistent with clinical experience, adherence to lifestyle intervention can be transient and unlikely to be sustained over long periods of time.
Despite our study’s strengths, we acknowledge a number of limitations. First, we acquired WatchPAT data for participants not using PAP in Study 1 but not for participants using PAP in Study 2. Thus, our analyses regarding the time course of resolution of OSA may be somewhat underpowered to detect small changes that may have occurred following initiation of therapy. Moreover, while WatchPAT is currently approved as a diagnostic device [23], its utility in monitoring therapeutic responses in OSA is less well established. Second, although we provided structured standard of care lifestyle intervention in all arms of the 2 studies, we did not acquire detailed assessments of calorie intake, food composition, or physical activity. Thus, we are unable to determine to what extent the reduced calorie recommendations were actually implemented, or to what extent physical activity was changing over time during the study. Third, the SURMOUNT-OSA studies involved 52 weeks of treatment intervention with tirzepatide or placebo. Thus, we are unable to draw conclusions regarding long-term follow-up beyond the course of the study. However, the recent report by Jastreboff et al. [4], with >3-year (176 weeks) follow-up of tirzepatide therapy, showing a 93 % sustained reduction in incident diabetes mellitus as well as sustained reduction in body weight, is strongly suggestive that our observed benefits in SURMOUNT-OSA may be sustained over time. Despite these limitations, we view our new findings as clinically important.
5. Conclusions
Tirzepatide is the first FDA-approved pharmacotherapy for moderate-to-severe OSA in people with obesity. The new findings provide details regarding the time course of disease improvement and provide mechanistic insight regarding the impact of weight reduction on OSA improvements. The effect of tirzepatide on AHI and SASHB was larger in greater weight reduction tertiles, and statistically significant differences compared to placebo were detected from Week 20 in both AHI and SASHB. Further research is required to determine which of the observed improvements are attributable to OSA resolution improvement in body weight vs. direct effects of tirzepatide per se vs. standard of care lifestyle intervention provided in the trial.
Supplementary Material
Acknowledgments
The authors thank the participants, the study teams, and the investigators.
The authors would like to thank Roberta Angoi, PhD (Eli Lilly and Company) for editorial assistance.
Funding information
This study was funded by Eli Lilly and Company.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.sleep.2025.106853.
Footnotes
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Atul Malhotra is funded by the National Institutes of Health (NIH). He reports income from Eli Lilly and Company, LivaNova, Zoll Medical, and Powell Mansfield. ResMed provided a philanthropic donation to the employer of AM (University of California San Diego).
Ron Grunstein reports income from serving on the advisory board for Apnimed, the steering committee for SURMOUNT-OSA, Eli Lilly and Company, and lecture fees from Somnomed Department. He conducts sponsored studies with Eli Lilly and Company, Alkermes, Takeda, and Bod Science: Lambert Initiative.
Ali Azarbarzin serves as a consultant for Respicardia, Eli Lilly and Company, Inspire, Amgen, and Apnimed. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. AA’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. AA also serves on the advisory board for Incannex. He is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping, also via his Institution.
Scott A. Sands received grant support from Apnimed, ProSomnus, DynaFlex, and Inspire Medial Systems, and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly and Company, Respicardia, LinguaFlex, Incannix, and Achaemenid. He receives royalties for intellectual property pertaining to combination pharmacotherapy for sleep apnea via his Institution. He is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping also via his Institution. He has received equity in Achaemenid, a company commercializing biosensor technology for monitoring oral appliance treatment efficacy. He is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping, also via his Institution. His industry interactions are actively managed by his Institution.
XD, SC, JPD and BF are employees of Eli Lilly and Company.
JB contributed to the manuscript as an employee of Eli Lilly and Company.
CRediT authorship contribution statement
Atul Malhotra: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Ronald R. Grunstein: Writing – review & editing. Ali Azarbarzin: Writing – review & editing, Conceptualization. Scott A. Sands: Writing – review & editing. Xiangnan Dang: Writing – review & editing, Formal analysis. Sujatro Chakladar: Writing – review & editing, Formal analysis. Julia P. Dunn: Writing – review & editing, Conceptualization. Beverly Falcon: Writing – review & editing. Josef Bednarik: Writing – review & editing, Writing – original draft, Methodology, Conceptualization.
SURMOUNT-OSA ClinicalTrials.gov number NCT05412004.
Data availability
Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.