GLORIOUS: Exenatide Lacks Preventive Effect on Organ Injury in Cardiac Surgery

Intravenous exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, did not notably lower the likelihood of death, stroke, or organ failure during cardiopulmonary bypass-assisted cardiac surgery, according to late-breaking science at the American Heart Association (AHA) Scientific Sessions 2024.¹

The GLORIOUS trial evaluated whether a 17.4μg intravenous infusion of exenatide could reduce complications during and after cardiac surgery, which included the assistance of cardiopulmonary bypass, compared with a placebo infusion initiated at the time of anesthesia before surgery.

“The evidence for perioperative treatment of patients undergoing cardiac surgery is limited,” Sebastian Wiberg, MD, PhD, an anesthesiologist at The Heart Centre, Copenhagen University Hospital Rigshospitalet, said in a statement.² “As such, there is a large unmet need for clinical trials investigating strategies to optimize treatment and reduce the risk of complications, such as organ injury, inflammation, and the formation of blood clots.”

Exenatide was first approved in April 2005 by the US Food and Drug Administration (FDA) as an adjunctive therapy to improve blood sugar control in patients with type 2 diabetes (T2D).³ The GLORIOUS trial was a randomized, double-blind, placebo-controlled clinical trial, in which patients were randomized to receive either a 6-hour and 15-minute infusion of exenatide or a placebo before surgery.¹

Approximately 1400 adults scheduled for elective or subacute cardiopulmonary bypass-assisted coronary bypass grafting or surgical aortic valve replacement in Denmark were enrolled between February 2016 and December 2021. According to the population data, patients were an average age of 68, 17% were female, and 98% self-identified as White.

This population was monitored during surgery—investigators collected nearly 6 years of follow-up data for post-surgical outcomes, including death, kidney failure requiring renal replacement therapy, stroke, new-onset heart failure, and hospital readmission for heart failure or other cardiovascular causes.

Overall, upon analysis, the study identified no significant differences between intravenous infusion of exenatide and placebo, during an average follow-up time of 5.9 years.² Approximately 14% of patients receiving exenatide died during the follow-up period, compared with 13% of the placebo cohort.

Further data showed that 5.8% of patients in the exanatide cohort experienced a stroke, compared with 4.8% in the placebo cohort. Approximately 9.8% of the exenatide cohort experienced new or worsening heart failure post-surgery versus 10% of the placebo cohort—4.8% of the exenatide cohort displayed acute kidney injury during initial hospital admission for surgery, compared with 5.3% in the placebo cohort.

As the trial evaluated the effect of exenatide over a brief period at a single heart center, Wiberg indicated these results may not be generalizable to other medications in other patient populations. He noted that different GLP-1s, a longer period of administration, or a larger dose could benefit patients undergoing cardiopulmonary bypass-assisted cardiac surgery.

In addition, Wiberg pointed to a large knowledge gap in supporting patients on bypass during surgery, citing an “urgent need” for further clinical trials to identify methods to optimize patient outcomes during and after surgery.

“We had hoped exenatide might protect patients from developing heart failure or other common complications after heart bypass surgery, however, the results suggest that this GLP-1 analog does not offer significant benefits,” Wiberg added.² “Of note, these findings provide important insights into what does and doesn’t work in the complex setting of cardiac surgery.”

References

1. _{Wiberg S, Moeller CH, Kjaergaard, Duus A, et al. Efficacy of Restrictive versus Liberal Oxygenation in Patients undergoing Coronary Artery Bypass Grafting or Aortic Valve Replacement – a randomized clinical trial. Presented at the American Heart Association (AHA) Scientific Sessions 2024. Chicago, Illinois. November 16-18, 2024.}
2. _{Exenatide, a GLP-1 analog, by IV during cardiac surgery did not reduce organ injury or death. American Heart Association. November 17, 2024. Accessed November 17, 2024. https://newsroom.heart.org/news/exenatide-a-glp-1-analog-by-iv-during-cardiac-surgery-did-not-reduce-organ-injury-or-death?preview=9757&preview_mode=True.}
3. _{Amylin and Lilly announce FDA approval of Byetta(TM) (exenatide) injection. Eli Lilly and Company. April 29, 2005. Accessed November 17, 2024. https://investor.lilly.com/news-releases/news-release-details/amylin-and-lilly-announce-fda-approval-byettatm-exenatide.}