The GLORIOUS trial, presented at the American Heart Association 2024 Scientific Sessions, reveals that neither the use of exenatide, a glucagon-like peptide 1 (GLP-1) receptor agonist, nor restrictive oxygenation strategies during cardiopulmonary bypass (CPB)-assisted coronary artery surgery and/or valve replacement surgery significantly improves clinical outcomes. The study, a 2x2 factorial-designed trial, found no reduction in mortality or morbidity from renal failure, stroke, or heart failure.
Neutral Results Inform Clinical Practice
Despite the neutral findings, the GLORIOUS trial provides valuable insights into clinical practice. According to lead investigator Sebastian Wiberg, MD, PhD (University of Copenhagen, Denmark), there is a significant evidence gap in how to conduct cardiopulmonary bypass and treat patients undergoing these procedures. The trial aimed to address this gap by investigating the potential benefits of exenatide and restrictive oxygenation.
Cardiac surgeon Subodh Verma, MD (St. Michael’s Hospital, Toronto, Canada), who was not involved in the study, commended the researchers for conducting the trial, emphasizing the need for well-conducted clinical trials in cardiac surgery, particularly in the perioperative setting.
Possible Reasons for the Lack of Benefit
Sigrid Sandner, MD (Medical University of Vienna, Austria), suggested that the interventions may have failed because the CABG/AVR procedures were relatively straightforward, with short median durations of CPB and aortic cross-clamp times (87 and 56 minutes, respectively), and performed in low-risk surgical patients. This made it challenging to detect small or moderate differences in clinical outcomes.
Verma echoed this sentiment, noting that the study population consisted of elective patients at low perioperative risk. He suggested that testing these strategies in more vulnerable and high-risk patients might yield different results.
Sandner proposed that focusing on outcome measures more directly affected by myocardial protection, such as those associated with myocardial function, could increase the ability to detect a treatment effect. She also noted that the extended follow-up period may have introduced additional events unrelated to the interventions, diluting any potential treatment effect.
Details of the GLORIOUS Trial
The GLORIOUS trial randomized 695 patients to restrictive oxygenation (administered oxygen fraction of 50%) and 694 to liberal oxygenation (administered oxygen fraction of 100%) during CPB and in the first hour after weaning off bypass. Patients were also randomized to a perioperative 6.25-hour infusion of exenatide 17.4 μg or placebo.
The majority of patients (mean age 68 years; male 83.2%) underwent CABG surgery, with 22% undergoing AVR surgery alone, and approximately 10% undergoing a combined CABG/AVR procedure. After a median follow-up of 5.9 years, neither intervention reduced the primary endpoint of mortality, stroke, renal failure requiring replacement, and new-onset or worsening heart failure.
There was no increased risk of adverse events with exenatide compared to placebo. However, the restrictive-oxygenation arm showed a trend toward more surgical site infections (22 vs 11 with liberal oxygenation; P = 0.05).
Future Directions
Verma suggested that future research should explore the appropriate dosing of GLP-1 receptor agonists in the perioperative period. He also proposed that GLP-1 receptor agonists, such as semaglutide, could be introduced as part of a comprehensive approach to cardiac surgery, with prehabilitation providing patients with cardiometabolic remodeling and weight loss benefits prior to surgery.
The researchers are currently conducting GLORIOUS II, a randomized trial testing four different interventions in patients undergoing CABG and/or AVR surgery, including dexamethasone, olanzapine, blood flow-targeted hemodynamic strategies, and low-tidal ventilation.
