Tirzepatide and Obstructive Sleep Apnea: Cardiometabolic Benefits

study design, procedures and participants

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 previously^13,14. 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^{Statistical Analysis of Tirzepatide Treatment Effects}

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.

Longitudinal Data Analysis

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

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.