Effect of tirzepatide on OSA-related cardiometabolic risk measures in SURMOUNT-OSA

Background: Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. Results from the SURMOUNT-OSA studies demonstrated significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Objectives: Systematically analyze all tirzepatide treatment related changes of cardiometabolic risk measures in SURMOUNT-OSA studies and investigate to what extent these changes were mediated by reductions in weight and/or OSA-related measures. Methods: The SURMOUNT-OSA master protocol comprised two 52-week, randomized, double-blind, placebo-controlled Phase 3 studies. Study 1 (N=234) and 2 (N=235) included participants with moderate-to-severe OSA and obesity, who at screening reported not using, or using positive airway pressure (PAP) therapy, respectively. The design and rationale of the studies have been published previously (1). The current analysis investigated the association of treatment with tirzepatide or placebo with SURMOUNT-OSA pre-specified cardiometabolic risk measures including blood pressure, and levels of high-sensitivity C-reactive protein (hsCRP), HDL-C, non-HDL-C, triglycerides, fasting insulin. Further analyses included change in HOMA-IR with tirzepatide compared to placebo, and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea-hypopnea index (AHI) and sleep apnea-specific hypoxic burden (SASHB). Results: In Study 1, participants experienced greater difference in change from baseline with tirzepatide compared to placebo in SBP (-7.9 mmHg; 95% CI -11.0 to -4.9; p<0.001), and DBP (-3.2 mmHg; 95% CI -5.4 to -1.0; p=0.005) at 48 weeks, and hsCRP (-28.9±8.2%; p=0.003), HDL-C (7.2±2.1%; p<0.001), non-HDL-C (-13.0±3.1%; p<0.001), triglycerides (-32.2±3.7%; p<0.001), fasting insulin (-41.4±5.0%; p<0.001), and HOMA-IR (-48.0±4.9%; p<0.001) at 52 weeks. In Study 2, participants experienced greater differences in change from baseline following tirzepatide compared to placebo in SBP (-4.3 mmHg; 95% CI -7.3 to -1.2; p=0.007) at 48 weeks, and hsCRP (-45.1±8.0%; p<0.001), HDL-C (10.0±2.8%; p<0.001), non-HDL-C (-14.3±2.5%; p<0.001), triglycerides (-31.5±3.7%; p<0.001), fasting insulin (-45.4±5.4%; p<0.001), and HOMA-IR (-54.8±5.0%; p<0.001) at 52 weeks. Statistically significant independent mediation effect of changes in OSA metrics was observed on hsCRP, HOMA-IR and triglycerides. In addition, the combination of changes in weight and OSA metrics, but not weight or OSA improvements alone, had a significant mediation effect on non-HDL-C. There was no significant mediation effect of weight or OSA metrics observed on DBP. Conclusions: In the SURMOUNT-OSA program trials, tirzepatide appeared to have significant cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize cardiometabolic benefits for patients with OSA and obesity.