In a randomized trial of 1,389 patients, exenatide infusion during and after cardiopulmonary bypass surgery did not reduce death, stroke, kidney failure, or heart failure over nearly 6 years of follow-up.
24% vs. 24%Identical rates of major adverse events in exenatide and placebo groups over nearly 6 years, definitively showing no perioperative cardioprotection.
What the researchers found
In this randomized, double-blind clinical trial of 1,389 predominantly low-risk patients undergoing elective coronary artery bypass grafting or aortic valve replacement:
- 170 patients (24%) in the exenatide group and 165 patients (24%) in the placebo group experienced the primary composite endpoint (death, stroke, renal failure requiring dialysis, or new/worsening heart failure)
- No significant difference in time to first event between groups
- No significant difference in rates of adverse events
- Median follow-up was 5.9 years (range 2.5–8.3 years)
- The study also tested liberal vs. restrictive oxygenation during bypass in a 2×2 factorial design, finding no difference there either (HR 1.0; 95% CI 0.83–1.3; p = 0.80)
Exenatide was administered as a 17.4 µg infusion during cardiopulmonary bypass and for the first hour after weaning from bypass.
Why it matters
This is an important negative result. While GLP-1 agonists have demonstrated cardiovascular benefits in diabetes and obesity trials, this study shows those benefits don't extend to acute perioperative cardioprotection during bypass surgery. This helps define the boundaries of GLP-1 drugs' cardiovascular effects and prevents unnecessary adoption of an ineffective intervention in cardiac surgery.
How the study worked
This was a randomized, double-blind, single-center clinical trial with a 2×2 factorial design. Adult patients undergoing elective cardiopulmonary bypass-assisted CABG or aortic valve replacement were randomized to receive either exenatide (17.4 µg infusion) or placebo during bypass and the first hour post-bypass, and to either liberal (100% FiO2) or restrictive (50% FiO2) oxygenation. The primary outcome was a composite of death, stroke, renal failure requiring dialysis, or new/worsening heart failure. Follow-up extended to a median of 5.9 years.
What this study cannot tell us
The study enrolled predominantly low-risk elective surgery patients, which may have limited the ability to detect benefit in a population with a low event rate. The exenatide infusion was given only during and briefly after bypass — a short exposure window that may be insufficient. Single-center design may limit generalizability. The 2×2 factorial design adds complexity to interpretation.
How to read the evidence
This is a large, well-designed randomized double-blind clinical trial with 1,389 patients and nearly 6 years of follow-up — high-quality evidence. The negative result is as informative as a positive one, establishing what GLP-1 agonists cannot do.
When this study was published
Published in 2025 with data from a trial registered in 2016 (NCT02673931). The long follow-up period (median 5.9 years) adds substantial value to the findings.
The bigger picture
GLP-1 agonists have shown cardiovascular benefits in the LEADER, SUSTAIN-6, and SELECT trials, raising hopes they could protect the heart in other settings. This trial tests the hypothesis in cardiac surgery and finds no benefit, suggesting that GLP-1's cardiovascular protection works through long-term metabolic and vascular mechanisms rather than acute cardioprotection during surgical ischemia-reperfusion injury.
Questions still open
- Would longer perioperative GLP-1 agonist exposure (days rather than hours) provide cardioprotection in cardiac surgery?
- Might GLP-1 agonists show benefit in higher-risk cardiac surgery patients with more room for improvement?
- Does the lack of acute cardioprotection suggest GLP-1's cardiovascular benefits operate through chronic rather than acute mechanisms?
Common questions
If GLP-1 drugs protect the heart in other studies, why didn't exenatide work here?
Does this mean GLP-1 drugs aren't good for the heart?
Read the original research
Efficacy of the Glucagon-Like Peptide-1 Agonist Exenatide in Patients Undergoing CABG or Aortic Valve Replacement: A Randomized Double-Blind Clinical Trial.
Circulation. Cardiovascular interventions, 18(5), e014961
Citation
Kjaergaard, Jesper; Møller, Christian Holdflod; Wiberg, Sebastian; Mikkelsen, Astrid Duus; Møller-Sørensen, Hasse; Ravn, Hanne Berg; Ravn, Jesper; Olsen, Peter Skov; Høfsten, Dan E; Boesgaard, Søren; Køber, Lars; Nilsson, Jens Christian; Hassager, Christian. (2025). Efficacy of the Glucagon-Like Peptide-1 Agonist Exenatide in Patients Undergoing CABG or Aortic Valve Replacement: A Randomized Double-Blind Clinical Trial.. Circulation. Cardiovascular interventions, 18(5), e014961. https://doi.org/10.1161/CIRCINTERVENTIONS.124.014961