Tirzepatide and Obstructive Sleep Apnea: Cardiometabolic Benefits
study design, procedures and participants
Table of Contents
The SURMOUNT-OSA program included two 52-week, randomized, placebo-controlled phase 3 studies. Study 1 included participants who were unwilling or unable to use PAP therapy,and study 2 included participants who had been using PAP therapy for at least 3 months at screening,and who planned to continue PAP for the duration of the trial. Participants were randomly assigned in a 1:1 ratio to receive either tirzepatide at the maximum tolerated dose (10 or 15 mg) or placebo once weekly. The SURMOUNT-OSA program was registered at ClinicalTrials.gov (NCT05412004), and the two studies’ full design, key eligibility criteria, procedures and primary efficacy and safety results have been published previously13,14. Participants were screened and enrolled irrespective of their sex. Sex was self-reported by participants.
Objectives
First, this analysis investigated the association of tirzepatide with changes in cardiometabolic risk markers in participants with moderate-to-severe OSA and obesity. Second, the analysis estimated the relative contribution of weight loss, AHI and SASHB reduction to the improvement in cardiometabolic characteristics of subjects treated with tirzepatide.
parameters measured included change from baseline in SBP,DBP and levels of hsCRP,HDL-C,non-HDL-C,triglycerides,LDL-C,VLDL-C,fasting insulin and HOMA-IR,in tirzepatide versus placebo.
Mediation analysis was performed to estimate the proportion of tirzepatide treatment-associated changes in cardiometabolic risk measures due to either an effect of weight reduction or an effect of changes in sleep-disordered breathing measured by AHI and SASHB. SASHB is a cumulative measure of oxygen desaturation associated with apneas and hypopneas which, in observational studies, predicted OSA-related cardiovascular mortality and morbidity better than AHI all tests of treatment effects were conducted at a two-sided alpha level of 0.05, with 95% confidence intervals calculated. Participants were analyzed as randomized in statistical summaries and analyses. A mixed model repeated measures analysis,based on a restricted-maximum-likelihood model,analyzed continuous longitudinal variables. This analysis included all scheduled post-baseline observations. The model incorporated fixed effects for treatment, strata (pooled country/geographic region, baseline OSA severity, and gender), visit, and the interaction between treatment and visit. A continuous covariate of baseline value was also included. Significance tests utilized least-squares means and Type III tests. Because these endpoints were exploratory, P values were not adjusted for multiplicity. Statistical analyses were performed using SAS version 9.3. mediation analyses decomposed the total effect of tirzepatide on cardiometabolic risk markers into direct and indirect effects. The direct effect represents the impact of tirzepatide versus placebo on changes in cardiometabolic outcomes, independent of changes in mediators. The indirect effect captures the impact of tirzepatide versus placebo on changes in cardiometabolic outcomes through changes in mediators. Natural effect models were employed to estimate these direct and indirect effects, as these comparisons involve non-observable counterfactual scenarios42. The total effect was calculated as the sum of the direct and indirect effects. The proportion mediated was calculated as (indirect effect / total effect) * 100%, with standard errors derived using the bootstrap method.Longitudinal Data Analysis
Mediation Analyses