Continuous positive airway pressure but not Liraglutide-mediated weight loss improves early cardiovascular disease in obstructive sleep apnea: Data from a randomized proof-of-concept study.

Background: Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular (CV) morbidity and mortality, but the benefit of continuous positive airway pressure (CPAP) therapy is uncertain. However, most randomized-controlled trials have focused on the role of CPAP in secondary prevention although there is growing evidence of a potential benefit on early CV disease. Weight loss in combination with CPAP may be superior but is difficult to achieve and maintain with conventional measures alone. The aim of this study was to gain insights into the effect of CPAP on early atherosclerotic processes and to compare it to a glucagon-like-peptide (GLP)-1-mediated weight loss regimen in OSA. Methods: We performed a randomized proof-of-concept study (clinicaltrials.gov: [NCT04186494][1]) comparing CPAP, a liraglutide-based weight loss regimen (Lir) alone or both in combination for 24 weeks in 30 non-diabetic patients with moderate to severe OSA (50±7 years, 80% males, apnea-hypopnea index [AHI] 50±19/hr, body mass index [BMI] 35.0 ±3 kg/m2). Baseline characteristics were similar between groups. Beside extensive evaluation for CV risk factors and endothelial function at baseline and end of study, subjects underwent 18F-fluorodeoxyglucose (FDG)-PET-CT for measurement of aortic wall inflammation (target-to-background ratio [TBR]) and coronary CT angiography (CCTA) for semi-automated coronary plaque analysis. Results: CPAP alone and combination resulted in greater reduction in AHI than Lir alone at 24 weeks (mean difference -45/hr and -43/hr, respectively, vs -12/hr, p<0.05). Both Lir and combination led to significant weight loss of 6±3% and 4±4%, respectively. Despite CPAP resulting in small weight gain, only the CPAP alone group demonstrated a significant decrease in vascular inflammation (aortic wall TBR from 2.03±0.34 to 1.84±0.43, p 0.010) associated with improvement in endothelial function and decrease in C-reactive protein. Low-attenuation coronary artery plaque volume as marker of unstable plaque also decreased with CPAP (from 571±490 to 334±185mm3) and with combination therapy (from 401±145 to 278±126mm3) but not with Lir. Conclusion: These data suggest that CPAP therapy, but not GLP-1 mediated weight loss, improves vascular inflammation and reduces low-attenuation coronary artery plaque volume in OSA patients. These novel findings support the benefit of CPAP therapy in modifying early CV disease. ### Competing Interest Statement KMcD has received grants from Interreg North West Europe and has acted as speaker and consultant for Boehringer Ingelheim, Astra Zeneca, FIRE -1 and Vifor Pharmaceuticals. ML has board membership and shares in Solvotrin Therapeutics, is a named inventor on several patents relating to anti-inflammatory effects of isosorbide prodrugs and novel formulations of iron and in receipt of grant funding from Novartis, Genuity Science, the Irish Research Council and ESTHER Ireland. JDD has received grant support from the Irish Lung Foundation, the St. Vincent?s Hospital Group Foundation, University College Dublin and the FP7 Program of the European Commission for the randomized multicenter DISCHARGE trial (603266-2, HEALTH-2012.2.4.-2); is an Associate Editor of Radiology and the Quarterly Journal of Medicine; is an Editorial Board member of Radiology Cardiothoracic Imaging; is an author in the Stat-Dx book Series Diagnostic Imaging ? Cardiovascular and the textbook CT and MRI in Cardiology, Elsevier and has received speaker fees from Boehringer Ingelheim. SR received unrestricted grants from Novo Nordisk and Fitbit. ### Clinical Trial clinicaltrials.gov: [NCT04186494][1] ### Funding Statement This study was funded by the Health Research Board of Ireland (SR). Further support was provided by an unrestricted grant from Novo Nordisk, Ireland but the company had no influence in the design, the running, and the analysis of the study. The not-for-profit Heartbeat Trust CLG (www.heartbeattrust.ie) founded by KMcD and ML provided the Circle CVI software. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee St Vincent's University Hospital Dublin/Ireland I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04186494&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F28%2F2023.05.23.23290424.atom