ABSTRACT
Background
Obstructive sleep apnea (OSA) is a common condition affecting around one billion people worldwide. Emerging evidence from recent studies suggests that Glucagon-like peptide 1 receptor (GLP-1) agonists may reduce OSA severity. Hence, this meta-analysis aims to evaluate the efficacy and safety of GLP-1 agonists in patients with OSA.
Methods
Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science) to identify eligible studies reported up to 24 June 2024. Using Review Manager software, we reported outcomes as risk ratios (RRs) or mean difference (MD) and confidence intervals (CIs). The protocol for this review has been registered and published in PROSPERO with the ID (CRD42024562853).
Results
The meta-analysis included three randomized controlled trials with 828 patients. Pooled analysis of patients administered GLP-1 agonists or tirzepatide showed improvement in Apnea/Hypopnea Index (MD −16.57 events per hour, 95% CI [−27.41, −5.73], p = 0.003), weight reduction (MD −12.71%, 95% CI [−21.38, −4.03], p = 0.004), and systolic blood pressure (MD −4.93 mmHg,95% CI [−7.67, −2.19], p = 0.0004). Tirzepatide showed a reduction in high-sensitivity C-reactive protein (MD −0.89 mg/dl, 95% CI [−1.25, −0.54], p < 0.0001) and sleep apnea-specific hypoxic burden (MD −66.21%/min, 95% CI [−81.75, −50.67], p < 0.0001). Despite the heterogeneity observed in the AHI and weight, it was resolved, and the results were consistent. GLP-1 agonists/tirzepatide showed comparable outcomes concerning diastolic blood pressure (MD −1.34 mmHg, 95% CI [−2.80, 0.12], p = 0.07). No significant serious adverse events were observed for GLP-1 agonists/tirzepatide, but it was associated with a higher incidence of gastrointestinal adverse events.
Conclusion
GLP-1 agonists, including tirzepatide, improved Apnea/Hypopnea Index, weight, and systolic blood pressure in adults with moderate-to-severe OSA. However, the evidence remains limited to two published studies comprising three randomized controlled trials using different pharmacological agents. Consequently, further research is needed before firm conclusions can be drawn.
KEYWORDS: Glucagon-like peptide-1 receptor agonist, GLP-1, sleep apnea, review, meta-analysis
Introduction
Obstructive sleep apnea (OSA) is a common condition affecting around one billion people worldwide [1]. It is characterized by recurrent pharyngeal collapse during sleep, which could be complete or partial, leading to apnea or hypopnea [2]. The interruption of airflow results in low oxygen and high carbon dioxide levels in the blood. This often contributes to the metabolic, cardiovascular, and neurocognitive disorders associated with OSA [3]. Patients with OSA suffer from various symptoms, including excessive sleepiness during the day, headache, and nocturia [3]. Additionally, OSA is associated with an approximately 2-fold increase in the risk of cardiovascular mortality. Therefore, the management of OSA is crucial to improve survival and quality of life [2,3]
The current treatment options for OSA include continuous positive air pressure (CPAP), airway surgery, oral appliances, and weight reduction [3]. CPAP is considered the gold standard for managing OSA, and it prevents airway collapse by applying positive pressure through the nasal route [3]. Recent review articles by Javaheri et al. showed that CPAP improved disease severity, sleepiness, and sleep-related quality of life in adults [2,3]. Also, these updates indicated that CPAP therapy is the most effective treatment for OSA, particularly in comparison to anti-obesity medications [2,3]. While anti-obesity treatments are a prominent topic of discussion, their role in OSA management should not overshadow or diminish the well-established efficacy of CPAP. For instance, evidence from meta-analysis highlighted that CPAP use of at least 4 hours/day in addition to usual care was associated with a decrease in major adverse cerebrovascular and cardiovascular events in patients with OSA [4]. Also, CPAP therapy might prevent subsequent major cardiovascular events and all-cause death among patients with moderate to severe obstructive sleep apnea and concomitant coronary artery disease [5]. Notably, the effectiveness of CPAP is limited by patients’ non-compliance [6]. As for the other approaches, oral airways have limited effectiveness, and invasive surgeries could have serious side effects [7]. Therefore, research into alternative treatment options remains ongoing.
Obesity is a major risk factor for OSA; around 70% of patients with morbid obesity have OSA [7]. The main mechanism could be the increased deposition of peripharyngeal fat, which could impair the ability of dilator muscles to maintain airway patency [7]. It has been shown that around 5–10% weight loss improves OSA severity. Glucagon-like peptide 1 receptor (GLP-1) agonists could be a promising therapy for patients with OSA. They have the potential to manage diabetes, obesity, and cardiometabolic disorders associated with OSA [8]. The FDA has approved liraglutide and semaglutide for weight loss in patients with a BMI ≥27 kg/m2 and associated comorbidities [9]. Moreover, they reduced the incidence of cardiovascular mortality among patients with type 2 diabetes [10].
Studies have shown that GLP-1 agonists significantly improve apnea-hypopnea index (AHI), body weight, and systolic blood pressure (SBP) in patients with OSA [11–13]. Given the importance of OSA management, we conducted this systematic review and meta-analysis to summarize and analyze the evidence on the efficacy and safety of GLP-1 agonists for patients with OSA.
Methodology
Protocol registration
This systematic review and meta-analysis followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [14] and the Cochrane Handbook for Systematic Reviews and Meta-Analyses guidelines [15]. The protocol for this review has been registered and published in PROSPERO with the ID (CRD42024562853).
Data sources & search strategy
We searched the following databases until 24 June 2024: PubMed (MEDLINE), Web of Science (WoS), SCOPUS, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). (Table S1) reveals the results of each database’s search phrases and keywords.
Eligibility criteria
We used the Population, Intervention, Comparison, and Outcomes (PICO) criteria to select eligible studies: population (non-diabetic patients with OSA); intervention (GLP-1 agonist); comparison (placebo); and outcomes (efficacy outcomes, including change in AHI, SBP, diastolic blood pressure (DBP), and body weight). The safety outcomes were any adverse event, any serious adverse event, death, nausea, vomiting, nasopharyngitis, gastroesophageal reflux, dyspepsia, diarrhea, constipation, upper respiratory tract infection, injection-site reaction, and research design was randomized controlled trials (RCTs). We excluded any study design other than RCTs, non-human and in vitro experiments, and studies not published in English.
Study selection
The online Covidence tool was used to conduct the review. After removing duplicates, the two authors (O.A. and M.T.) independently assessed every record they retrieved. For the first full-text screening for eligibility requirements, the entire text of the records was examined by two authors (O.A. and M.T.). Any disagreements were resolved by consensus and discussion with the senior author (M.A.).
Data extraction
The two authors, O.A. and M.T., exported the baseline characteristics and data to Microsoft Excel, and author M.A. resolved any disagreement. The order of these data was as follows [1]: Study characteristics including study ID, study design, country of study, number of centers, NCT number, blinding status, total participants, intervention and control with the description, main inclusion criteria, primary outcome, and follow-up duration [2]. Baseline patient characteristics, including number of patients in each group, age, gender, smoking status, weight, waist circumference, neck circumference, body mass index (BMI), BMI categories, AHI events, OSA severity, SBP, DBP, comorbidities (hypertension, prediabetes, diabetes mellitus, and dyslipidemia), race (White, black or African American, Asian, and Hispanic/Latino) [3]. Outcome measures, as previously described. The disagreements were settled through conversation with the senior author (M.A.).
Risk of bias and certainty of evidence
The authors O.A. and M.T. used the Cochrane Risk of Bias 2 (RoB 2) tool [16] to evaluate the quality of included RCTs. The six domains that comprise the complete RoB 2 tool are each dedicated to a particular facet of trial design, conduct, and reporting. The mentioned domains include the following [1]: Randomization process [2]; Deviations from intended interventions [3]; Missing outcome data [4]; Outcome measurement [5]; Reporting result selection; and [6] Overall bias. Discussions with the senior author (M.A.) settled any conflicts.
The degree of evidence’s certainty was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines [17,18]. We considered publication bias, risk of bias, indirectness, inconsistency, and imprecision. Every result was evaluated, and the choices were supported by evidence and recorded.
Statistical analysis
We used RevMan Manager (RevMan Computer program Version 5.4, The Cochrane Collaboration, 2020) to conduct the meta-analysis [19]. We pooled continuous outcomes using mean difference (MD) and 95% confidence interval (CI), and for the dichotomous outcomes, we used risk ratio (RR) along the corresponding 95% confidence interval (CI) for the pooled analysis. We did the pooled analysis using the fixed-effects model; however, if significant heterogeneity was detected, we shifted to the DerSimonian Laird method. By allocating a greater standard error to the pooled estimate, this random model accounts for disparate effect sizes by favoring studies with small samples over those with large samples. Consequently, we must account for these potential discrepancies in our estimates. We assessed the heterogeneity using the Cochran Q (Chi-square) test and measured it using the Higgins and Thompson I-squared test, indicating the proportion of the variation in effect estimate caused by heterogeneity instead of chance [20,21]. We considered a significant Chi-square test at an alpha level of below 0.1, and we considered significant heterogeneity if the I-square was > 50% [21]. We conducted a sensitivity analysis on significant heterogeneity in multiple scenarios, excluding one study in each scenario, and rerun the analysis to explore the source of heterogeneity. To assess how GLP-1 agonists differ from placebo in their effects on AHI according to adjuvant therapy with CPAP, we performed subgroup analysis where the included studies were divided into two subgroups: one for those who received CPAP and one for those who did not receive. We also did a subgroup analysis to identify any differences between pure GLP-1 agonists and combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonists regarding their effects on AHI, finally, in agreement with Egger et al. Publication bias assessment was inapplicable as the included studies were fewer than 10 RCTs [22].
Results
Search results and study selection
By searching databases, we retrieved 1113 records, and 384 references were excluded by Covidence, leaving 729 references for primary screening by title and abstract. After screening by title and abstract, 17 articles were available to be assessed for our eligibility criteria. Finally, we included two studies [11,13] describing three RCTs in this systematic review and meta-analysis. The PRISMA selection process flow chart is shown in (Figure 1).
Figure 1.
PRISMA flow chart of the screening process.
Characteristics of included studies
We included three RCTs: two involved tirzepatide (a combined GLP-1 and GIP agonist) and one involved a GLP-1 agonist (liraglutide). Therefore, for clarity, in the pooled analysis, the intervention group was referred to as the GLP-1/tirzepatide group.
The final analysis included 828 patients: 414 in the GLP-1/tirzepatide group and 414 in the control group. Blackman et al. 2016 (The SCALE) [11] was a double-blinded RCT clinical trial where non-diabetic patients with obesity and moderate (AHI 15–29.9 events h − 1) to severe (AHI > 30 events h − 1) OSP without treatment with continuous positive airway pressure at baseline were allocated to receive either 32-week liraglutide 3.0 mg or placebo. Malhorta et al. 2024 study was a two-phase three, multicenter, double-blinded RCT (Trial 1 and 2) involving non-diabetic patients with obesity with moderate to severe OSP [13]. Patients who did not receive positive airway therapy at baseline were enrolled in Trial 1, and patients who received positive airway therapy were enrolled in Trial 2. Patients in both trials were allocated in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide10 mg or 15 mg subcutaneously once weekly or placebo for 52 weeks. Finally, each trial in the Malohorta et al. study has its distinct, independent control group, so there was no fear of potential unit of analysis errors [23]. Summary of included studies and baseline characteristics are presented in (Tables 1 and 2), respectively.
Table 1.
Summary characteristics of the included RCTs.
| Study ID | Study Design | Country | Number of centers | Total Participants† | Intervention |
Control | Main Inclusion Criteria | Primary Outcome | Follow-up duration | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Drug | Dose | Frequency of administration | Route of administration | Treatment duration | |||||||||
| Blackman et al. [11] | A randomized, double-blind, placebo-controlled parallel-group trial | United States and Canada | 40 | 359 | Liraglutide | 3.0 mg | Once daily | Subcutaneously | 32 weeks | Participants will receive dose-volume equivalent placebo | BMI ≥30 kg/m2, age 18 − 64 years, diagnosis of moderate or severe OSA, unwilling or unable to use CPAP or other positive airway pressure) treatment | Change from Baseline in AHI | 2 weeks |
| Malhorta et al. (Trial 1) [13] | Two phase 3, double-blind, randomized, controlled trials | United States, Australia, Brazil, China, Czechia, Germany, Japan, Mexico, Puerto Rico, and Taiwan | 60 | 234 | Tirzepatide | 10 mg/15 mg | Once weekly | Subcutaneously | 52 weeks | Participants will receive placebo subcutaneously, and are unwilling or unable to use PAP therapy | BMI ≥30 kg/m2, unable or unwilling to use PAP therapy, must not have used PAP for at least 4 weeks prior to screening | Change from Baseline in AHI | 4 weeks |
| Malhorta et al. (Trial 2) [13] | 235 | Participants will receive placebo subcutaneously, and are on PAP therapy | BMI ≥30 kg/m2, have been on PAP therapy for at least 3 consecutive months prior to screening and plan to continue PAP therapy during the study | ||||||||||
†A total of 743 patients were studied (354 patients from the Blackman paper and 389 in the Malhotra since there were some who did not complete the tests).
NA, not available; BMI, body mass index; OSA, obstructive sleep apnea; AHI, apnea – hypopnea index; CPAP, continuous positive air pressure; PAP, positive air pressure.
Table 2.
Baseline characteristics of the participants.
| Study ID | Blackman et al. [11] | Malhorta et al. (Trial 1) [13] | Malhorta et al. (Trial 2) [13] | ||
|---|---|---|---|---|---|
| Number of patients in each group | GLP-1/tirzepatide | 180 | 114 | 120 | |
| Placebo | 179 | 120 | 115 | ||
| Age (years), mean (SD) | GLP-1/tirzepatide | 48.6 (9.9) | 47.3 (11.0) | 50.8 (10.7) | |
| Placebo | 48.4 (9.5) | 48.4 (11.9) | 52.7 (11.3) | ||
| Male, N (%) | GLP-1/tirzepatide | 129 (71.7) | 78 (68.4) | 87 (72.5) | |
| Placebo | 129 (72.1) | 79 (65.8) | 83 (72.2) | ||
| Smoking, N (%) | GLP-1/tirzepatide | NA | NA | NA | |
| Placebo | NA | NA | NA | ||
| weight (kg), mean (SD) | GLP-1/tirzepatide | NA | 116.7 (24.6) | 115.8 (21.5) | |
| Placebo | NA | 112.8 (22.6) | 115.1 (22.7) | ||
| Waist circumference (cm), mean (SD) | GLP-1/tirzepatide | 122.3 (14.5) | 122.6 (16.6) | 120.7 (13.1) | |
| Placebo | 122.7 (14.9) | 119.8 (14.8) | 121.0 (14.0) | ||
| Neck circumference (cm), mean (SD) | GLP-1/tirzepatide | 44.5 (4.5) | NA | NA | |
| Placebo | 44.2 (4.6) | NA | NA | ||
| BMI, mean (SD) | GLP-1/tirzepatide | 38.9 (6.4) | 39.7 (7.3) | 38.6 (6.1) | |
| Placebo | 39.4 (7.4) | 38.6 (6.7) | 38.7 (6.0) | ||
| Body-mass index categories, N (%) | <35 | GLP-1/tirzepatide | 58 (32.2) | 33 (28.9) | 33 (27.7) |
| Placebo | 52 (29) | 44 (36.7) | 33 (28.9) | ||
| 35–39.9 | GLP-1/tirzepatide | 59 (32.8) | 39 (34.2) | 47 (39.5) | |
| Placebo | 62 (34.6) | 35 (29.2) | 41 (36.0) | ||
| ≥40 | GLP-1/tirzepatide | 63 (35.0) | 42 (36.8) | 39 (32.8) | |
| Placebo | 65 (36.3) | 41 (34.2) | 40 (35.1) | ||
| AHI events/h, mean (SD) | GLP-1/tirzepatide | 49.0 (27.5) | 52.9 (30.5) | 46.1 (22.4) | |
| Placebo | 49.3 (27.5) | 50.1 (31.5) | 53.1 (30.2) | ||
| Obstructive sleep apnea severity, N (%) | Mild: AHI < 15 events/hr | GLP-1/tirzepatide | 0 | 1 (0.9) | 0 |
| Placebo | 0 | 2 (1.7) | 2 (1.8) | ||
| Moderate: AHI 15–29 events/hr | GLP-1/tirzepatide | 60 (33.3) | 39 (34.2) | 35 (29.4) | |
| Placebo | 58 (32.4) | 43 (36.1) | 37 (32.5) | ||
| Severe: AHI ≥ 30 events/hr | GLP-1/tirzepatide | 120 (66.7) | 74 (64.9) | 84 (70.6) | |
| Placebo | 121 (67.6) | 73 (61.3) | 75 (65.8) | ||
| Blood pressure (mmHg), mean (SD) | Systolic blood pressure | GLP-1/tirzepatide | NA | 128.4 (12.2) | 130.5 (14.3) |
| Placebo | NA | 130.3 (10.7) | 130.5 (12.8) | ||
| Diastolic blood pressure | GLP-1/tirzepatide | NA | 83.7 (8.9) | 83.2 (8.2) | |
| Placebo | NA | 84.0 (8.6) | 80.5 (8.6) | ||
| Comorbidities, N (%) | Hypertension | GLP-1/tirzepatide | 75 (41.7) | 84 (73.7) | 91 (75.8) |
| Placebo | 77 (43.0) | 93 (77.5) | 91 (79.1) | ||
| Prediabetes | GLP-1/tirzepatide | 115 (63.9) | NA | NA | |
| Placebo | 112 (62.6) | NA | NA | ||
| Diabetes mellitus | GLP-1/tirzepatide | 0 | 0 | 0 | |
| Placebo | 0 | 0 | 0 | ||
| Dyslipidemia | GLP-1/tirzepatide | 65 (36.1) | NA | NA | |
| Placebo | 55 (30.7) | NA | NA | ||
| Race, N (%) | White | GLP-1/tirzepatide | 130 (72.2) | 74 (64.9) | 85 (70.8) |
| Placebo | 135 (75.4) | 80 (66.7) | 86 (75.4) | ||
| Black or African American | GLP-1/tirzepatide | 33 (18.3) | 6 (5.3) | 8 (6.7) | |
| Placebo | 36 (20.1) | 7 (5.8) | 3 (2.6) | ||
| Asian | GLP-1/tirzepatide | 13 (7.2) | 23 (20.2) | 17 (14.2) | |
| Placebo | 3 (1.7) | 24 (20.0) | 16 (14.0) | ||
| Hispanic/Latino | GLP-1/tirzepatide | 19 (10.6) | 51 (44.7) | 38 (31.7) | |
| Placebo | 24 (13.4) | 47 (39.2) | 38 (33.0) | ||
NA, not available; SD, standard deviation; AHI, apnea – hypopnea index.
Risk of bias and certainty of evidence
The findings of the risk bias assessment revealed that the included studies were of high quality in all domains. The risk of bias summary and risk of bias graph are shown in (Figure 2). No biases were detected regarding the selection (randomization) process, such as random sequence generation and concealment of allocators. All studies included double-blinding for both patient treatment and assessment. No study has limited the reporting of any key outcomes like AHI. All trials analyzed patients using intention-to-treat analysis to deal with lacking outcome data. Regarding the certainty of evidence, all outcomes had a moderate overall certainty of evidence, except for changes in AHI and changes in body weight. Full details are shown in Table 3.
Figure 2.
Quality assessment of risk of bias in the included trials. The upper panel presents a schematic representation of risks (low = green, unclear = yellow, and high = red) for specific types of biases of each of the studies in the review. The lower panel presents risks (low = green, unclear = yellow, and high = red) for the subtypes of biases of the combination of studies included in this review.
Table 3.
GRADE evidence profile.
| Certainty assessment |
Summary of findings |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Participants (studies) Follow-up |
Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Overall certainty of evidence | Study event rates (%) |
Relative effect (95% CI) |
Anticipated absolute effects |
||
| With [GLP-1/tirzepatide] | With [placebo] | Risk with [GLP-1/tirzepatide] | Risk difference with [placebo] | ||||||||
| Change in Apnea/Hypopnea Index (AHI) | |||||||||||
| 803 (3 RCTs) |
not serious | very seriousa | not serious | seriousb | none | ⊕◯◯◯ Very low |
402 | 401 | – | The mean change in AHI was 0 events per hour | MD 16.57 lower (27.41 lower to 5.73 lower) |
| ≥50% reduction in AHI at week 52 | |||||||||||
| 469 (2 RCTs) |
not serious | not serious | not serious | seriousc | none | ⊕⊕⊕◯ Moderate |
156/234 (66.7%) | 50/235 (21.3%) | RR 3.12 (2.4 to 4.1) |
667 per 1,000 | 1413 more per 1,000 (from 933 more to 2033 more) |
| AHI of < 5 (no sleep apnea) or AHI of 5 to 14 (Mild sleep apnea) with Epworth Sleepiness Scale (ESS) ≤ 10 at week 52 | |||||||||||
| 469 (2 RCTs) |
not serious | not serious | not serious | seriousc | none | ⊕⊕⊕◯ Moderate |
108/234 (46.2%) | 35/235 (14.9%) | RR 3.07 (2.2 to 4.3) |
462 per 1,000 | 955 more per 1,000 (from 549 more to 1523 more) |
| Change Sleep apnea-specific hypoxic burden (SASHB, %/min). | |||||||||||
| 469 (2 RCTs) |
not serious | not serious | not serious | seriousc | None | ⊕⊕⊕◯ Moderate |
234 | 235 | – | The mean change sleep apnea-specific hypoxic burden was 0%/min | MD 66.2 lower (81.75 lower to 50.67 lower) |
| Change in body weight (%). | |||||||||||
| 822 (3 RCTs) |
not serious | very seriousa | not serious | seriousb | None | ⊕◯◯◯ Very low |
409 | 413 | – | The mean change in body weight was 0% | MD 12.7 lower (21.4 lower to 4.0 lower) |
| Change in SBP at 48 week | |||||||||||
| 826 (3 RCTs) |
not serious | seriousd | not serious | not serious | None | ⊕⊕⊕◯ Moderate |
412 | 414 | – | The mean change in SBP at 48 weak was 0 mmHg | MD 4.9 lower (7.7 lower to 2.2 lower) |
| Change in DBP at 48 week. | |||||||||||
| 826 (3 RCTs) |
not serious | not serious | not serious | seriousb | None | ⊕⊕⊕◯ Moderate |
412 | 414 | – | The mean change in DBP at 48 weak was 0 mmHg | MD 1.3 lower (2.8 lower to 0.1 higher) |
| Change in level of hsCRP (mg/dl) at 52 weeks | |||||||||||
| 469 (2 RCTs) |
not serious | not serious | not serious | seriousc | None | ⊕⊕⊕◯ Moderate |
234 | 235 | – | The mean change in level of hsCRP at 52 weeks was 0 mg/dl | MD 0.89 lower (1.25 lower to 0.5 lower) |
CI: confidence interval; MD: mean difference; RR: risk ratio.
a - I2 > 90%, b - A wide confidence interval that does not exclude the appreciable harm/benefit, c - Low number of events (<300 events), and d - I2 > 50%.
Primary outcomes
Change in Apnea/Hypopnea Index (AHI, events per hour)
The overall mean change in AHI favored the GLP-1/tirzepatide group over the placebo group, showing a significantly greater mean reduction in AHI in the GLP-1/tirzepatide (MD −16.57 events per hour, 95% CI [−27.41, −5.73], p = 0.003,3 RCTs,803 patients, with very low certainty evidence, (Figure 3). The pooled studies in AHI change were significantly heterogeneous (I2 = 91%). To investigate the source of this heterogeneity, we performed a sensitivity analysis and found that excluding the Blackman 2016 study [11] showed a significant reduction in heterogeneity I2 = 0%. Excluding the Blackman study, the overall mean change remained to favor the GLP-1/tirzepatide over the placebo group (MD −21.89 events per hour,95% CI [−26.00, −17.77], p < 0.00001) (Figure S1).
Figure 3.
Forest plot of the primary outcome (change in Apnea/Hypopnea Index (AHI, events per hour), RR: Risk ratio, CI: Confidence interval.
Subgroup Analysis
Adjuvant CPAP
In the subgroup of patients receiving CPAP, there was no significant difference between the GLP-1/tirzepatide group and placebo in reducing AHI (MD −14.90 events per hour, 95% CI [−32.25, 2.44], p = 0.09). However, in the subgroup of patients not receiving CPAP, the results significantly favored the GLP-1/tirzepatide group over placebo (MD −20 events per hour, 95% CI [−25.80, −14.20], p < 0.00001). Despite these variations in response based on CPAP status, the test for subgroup differences showed that these differences were not statistically significant (p = 0.58) (Figure S2).
GLP-1 agonist versus combined GLP-1 & GIP agonist
Liraglutide and tirzepatide remained to be superior to placebo in terms of reducing AHI (MD −6.1 events per hour, 95% CI [−11.37, −0.83], p = 0.02) and (MD −21.89, 95% CI [−26.00, −17.77], p = 0.003), respectively. However, tirzepatide achieved a significantly greater AHI reduction than the GLP-1 subgroup (p < 0.00001) (Figure S4).
Secondary outcomes
≥50% reduction in AHI at week 52
Enrolling homogenous studies (I2 = 0%) in this pooled analysis, patients who used tirzepatide compared to the placebo group had a significantly greater rate of achieving ≥ 50% reduction in AHI at week 52 (RR 3.12,95% CI [2.40, 4.05], p < 0.00001, 469 patients, 2 RCTs, with moderate certainty evidence (Figure S4).
AHI of < 5 (no sleep apnea) or AHI of 5 to 14 (mild sleep apnea) with Epworth sleepiness scale (ESS) ≤ 10 at week 52
In this pooled analysis, which included homogenous studies (I2 = 0%), patients in the tirzepatide group had a significantly higher rate of achieving AHI of < 5 or AHI of 5 to 14 with ESS ≤ 10 at week 52 (RR 3.07,95% CI [2.19, 4.30], p < 0.00001, 469 patients, 2RCTs, with moderate certainty evidence] (Figure S5).
Change sleep apnea-specific hypoxic burden (SASHB, %/min)
In a polled analysis of homogenous studies (I2 = 0%) compared to the placebo group, the tirzepatide group achieved a significantly greater reduction in sleep apnea-specific hypoxic burden (MD −66.21%/min, 95% CI [−81.75, −50.67], p < 0.00001,2RCTs,469 patients, with moderate certainty evidence (Figure S6).
Change in body weight (%)
The studies enrolled in the pooled analysis for change in body weight were substantially heterogeneous (I2 = 99%). The GLP-1/tirzepatide group showed a significant reduction in body weight (%) compared to the placebo group (MD −12.71%, 95% CI [−21.38, −4.03], p = 0.004, 3 RCTs, 822 patients, with very low certainty evidence (Figure S7). Heterogeneity significantly reduced (I2 = 0%) when we excluded the Blackman et al. 2016 study in a sensitivity analysis maintaining the significant benefit of body weight reduction (MD −12.71%, 95% CI [−21.38, −4.03], p = 0.00001, (Figure S8).
Change in blood pressure (mmHg)
Change in SBP at 48 weak
The pooled analysis significantly favored the GLP-1/tirzepatide group over the placebo group in terms of change in the SBP (MD −4.93 mmHg,95% CI [−7.67, −2.19], p = 0.0004, 3 RCTs, 826 patients, with moderate Certainty evidence (Figure 4). The pooled studies in SBP change were significantly heterogeneous (I2 = 64%). By excluding Malhorta et al. trial 1 [7] in a sensitivity analysis, heterogeneity was significantly reduced (I2 = 0%), and the benefit of reduction in SBP remained significantly favoring the GLP-1/tirzepatide group over the placebo group (MD −3.53 mmHg,95% CI [−5.54, −1.51], p = 0.0006) (Figure S9).
Figure 4.
Forest plot of the efficacy outcomes (change in SBP and DBP), RR: Risk ratio, CI: Confidence interval.
Change in DBP at 48 weak
The included studies in the pooled analysis of DBP change were homogenous (I2 = 38%). In the meta-analysis, the reduction in DBP compared did not favor either GLP-1/tirzepatide or the placebo group (MD −1.34 mmHg, 95% CI [−2.80, 0.12], p = 0.07, 3RCTs, 826 patients, with moderate certainty evidence] (Figure 4).
Change in the level of hsCRP (mg/dl) at 52 weeks
The pooled analysis for the change in hsCRP enrolling homogenous studies (I2 = 17%) showed a significant reduction in the level of hsCRP at 52 weeks for the tirzepatide group compared to the placebo group (MD −0.89 mg/dl, 95% CI [−1.25, −0.54], p < 0.00001, 2RCTs, 469 patients, with moderate certainty evidence (Figure S10).
Adverse effects
GLP-1 use compared to placebo did not increase the risk of developing severe adverse effects, nasopharyngitis, upper respiratory tract infections, and injection-site reactions. However, compared to the placebo, the GLP-1/tirzepatide group experienced a significantly greater risk of developing adverse effects, nausea, vomiting, diarrhea, constipation, dyspepsia, and gastroesophageal reflux. All studies enrolled in the pooled analysis for each secondary outcome were homogenous (I2 = 0% to 8%) except for adverse effects and injection-site reaction I2 = 71% and 77%, respectively. Forest plots for secondary outcomes are shown in (Figure 5).
Figure 5.
Forest plot of the safety outcomes, RR: Risk ratio, CI: Confidence interval.
Discussion
We investigated the efficacy and safety of GLP-1 agonists and tirzepatide in patients with OSA. Our systematic review and meta-analysis included three RCTs with 828 patients. Our analysis revealed that GLP-1 agonists/tirzepatide improved the AHI, weight reduction, and SBP. On the other hand, no significant difference was found in DBP or the incidence of serious adverse events.
In adults with moderate to severe OSA, our study demonstrated that GLP-1 agonists/tirzepatide significantly improved AHI compared to placebo, with a mean difference of −16.57 events per hour, meeting the clinical significance threshold set by the American Academy of Sleep Medicine [25]. In patients not receiving CPAP, GLP-1/tirzepatide showed a significant reduction of 20 events per hour, while those receiving CPAP showed a clinically, but not statistically, significant reduction of 14.9 events per hour. Javaheri et al. [26] suggest that low adherence to CPAP could explain this null outcome. Thus, GLP-1 agonists may be an alternative for patients unwilling or unable to use CPAP.
Subgroup analysis revealed that tirzepatide led to a significant reduction of 21.89 AHI events per hour, while liraglutide showed a smaller reduction of 6.1 events, suggesting tirzepatide’s superior efficacy, likely due to its dual GLP-1 and GIP agonist action [27]. Tirzepatide’s greater impact on weight loss [28] may explain the higher rate of patients achieving ≥ 50% AHI reduction, which is clinically significant [24,29] and reaching lower OSA severity levels, potentially avoiding CPAP therapy [30,31].
Obesity, a bidirectional risk factor for OSA [32], worsens AHI, while weight loss improves it [33]. Moreover, a recent meta-analysis showed that a weight loss of 20% resulted in a 57% improvement in AHI [34]. GLP-1 agonist and tirzepatide in our study led to a mean weight reduction of 12.71%, consistent with prior research [35]. These effects on OSA may be due to both weight loss [11] and decreased systemic inflammation [8], as seen in our study with a significant reduction in CRP levels (−0.89) at 52 weeks. Other studies confirm these findings at 8 and 14 weeks of follow-up [36,37], with meta-analyses showing GLP-1 agonists may reduce OSA incidence in patients with obesity or type 2 diabetes [38]. Notably, While our findings may indicate an association between weight loss and AHI reduction, original RCTs, did not distinguish whether the improvement was more pronounced in hypopnea or apnea. Since AHI encompasses both events, further research is needed to clarify whether the observed effect is greater for hypopnea than apnea in this group of patients.
OSA increases cardiovascular risk [39,40], and its severity correlates with hypertension [41]. Our study found that GLP-1 agonists/tirzepatide significantly reduced SBP by −3.53 mmHg, consistent with previous findings [42]. This reduction is clinically important, as studies have linked SBP reductions to decreased cardiovascular risk and mortality: the Heart Outcomes Prevention Evaluation (HOPE) Trial showed that a 2–3 mmHg reduction in SBP was associated with a 4%–8% reduction in mortality [43]. Similarly, Adler et al. reported that each reduction of 10 mmHg in SBP was associated with an 11% reduced risk of myocardial infarction [44]. No significant effect for GLP-1 agonists/tirzepatide was observed on DBP, which aligns with a recently published meta-analysis [45]. In an experimental study, Flavia et al. demonstrated that long-term blockade of GLP-1 receptor signaling increases SBP but does not affect DBP in both normotensive and hypertensive rats [46]. This finding, along with evidence that SBP is the primary component influenced by GLP-1 receptor signaling in humans and experimental models, suggests that GLP-1 receptor – mediated blood pressure regulation is primarily driven by its effects on extracellular volume homeostasis [46]. Notably, the overall cardiovascular benefits are noteworthy, as GLP-1 agonists have been shown to reduce the risk of major adverse cardiovascular events [47].
Regarding the safety of GLP-1 agonists/tirzepatide, we found no significant difference in the incidence of serious adverse events. However, patients receiving GLP-1 agonists/tirzepatide had a significantly higher risk of developing adverse effects, mainly gastrointestinal, which is consistent with the findings of previous studies [48,49].
Lastly, although this study provides evidence supporting the efficacy and safety of GLP-1 agonists in patients with OSA, further RCTs with extended follow-up periods are needed to confirm these findings. Additional research should investigate the combined use of CPAP and GLP-1 agonists, the comparative efficacy of different GLP-1 agonists, and their effects across various severities of OSA, while considering medication adherence given the potential gastrointestinal side effects. Moreover, further studies should clarify whether the observed reduction in AHI is more pronounced for hypopneas than for apneas in this patient population.
Limitations
There are several limitations that warrant cautious interpretation of these results. First, this meta-analysis includes only two valid studies (one with two trial arms). Although 828 participants were initially enrolled, only 743 completed the tests (354 in the Blackman et al. study and 389 in the Malhotra et al. study). Second, different medications were used in these studies; tirzepatide is generally more effective than liraglutide in reducing body weight and may consequently have a greater impact on OSA treatment. The test durations also differed (32 vs. 52 weeks). In the Malhotra et al. [13] study, an additional CPAP intervention was provided in one trial arm, whereas in the Blackman et al. [11] study, liraglutide was combined with a 500 kcal/day diet and exercise regimen. These differences make it difficult to isolate the specific effects of GLP-1 agonists alone.
In the subgroup of patients receiving CPAP in the Malhotra study, there was no statistically significant difference in AHI reduction between the tirzepatide group (n = 194) and the placebo group. We also limited our search to English-language publications, and high heterogeneity was observed in some outcomes – particularly AHI changes and body weight – initially lowering the certainty of evidence. Nevertheless, sensitivity analyses resolved this heterogeneity without altering the main findings. In addition, the included studies focused on patients with moderate to severe OSA, so our results may not be generalizable to those with mild disease.
Lastly, although we assessed the impact of GLP-1 agonists on hypoxia burden, it was not possible to investigate the incidence of cardiovascular events due to the relatively short follow-up period in the included studies.
Conclusion
Although GLP-1 agonists improved the Apnea/Hypopnea Index, hypoxia burden, weight, and systolic blood pressure in adults with moderate-to-severe obstructive sleep apnea, the evidence remains limited to only two randomized controlled trials using different pharmacological agents. Consequently, further studies are needed before firm conclusions can be drawn.
Supplementary Material
Funding Statement
The author(s) reported there is no funding associated with the work featured in this article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
O.A. conceived the idea. O.A. designed the research workflow. O.A. and M.T. searched the databases. O.A. and M.T. screened the retrieved records, extracted relevant data, assessed the quality of evidence, and M.A. resolved the conflicts. E.B. performed the analysis. O.A., E.B., M.A. and A.G. wrote the final manuscript. O.A. and M.T. supervised the project. All authors have read and agreed to the final version of the manuscript.
Availability of data and materials
The data is available upon reasonable request from the corresponding author.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/20018525.2025.2484048
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Associated Data
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Supplementary Materials
Data Availability Statement
The data is available upon reasonable request from the corresponding author.