Preventive effect of liraglutide on postoperative delirium in elderly patients undergoing cardiac surgery: protocol for a single-centre, randomised, double-blind, placebo-controlled trial

Abstract

Introduction

Postoperative delirium (POD) is a common and serious complication after cardiac surgery, particularly in elderly patients, and is associated with adverse short- and long-term outcomes. Effective preventive strategies remain limited. Liraglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated potential neuroprotective, anti-inflammatory and metabolic benefits, which may reduce the incidence of POD.

Methods and analysis

This is a single-centre, randomised, double-blind, placebo-controlled trial in elderly patients undergoing elective cardiac surgery. Participants will be randomised in a 1:1 ratio to receive liraglutide or placebo from the day before surgery until postoperative day 3. A total of 260 patients are planned to be enrolled in this study. The primary endpoint is the incidence of POD within 7 days, assessed using the Confusion Assessment Method (CAM) or CAM-intensive care unit. Secondary outcomes include delirium severity, neurocognitive and psychological function, cardiac function, clinical outcomes, major adverse cardiovascular events within 1 year and perioperative biomarker changes. Exploratory outcomes include functional MRI in selected subgroups and additional biomarker analyses.

Ethics and dissemination

The protocol has been approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital. Written informed consent will be obtained from all participants. Findings will be disseminated in peer-reviewed journals and academic conferences.

Trial registration number

ChiCTR2500106943.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This trial uses a randomised, double-blind, placebo-controlled design to minimise selection and performance bias.

• Postoperative delirium is assessed using validated and standardised tools (Confusion Assessment Method (CAM)/CAM-intensive care unit and CAM-Severity) with daily structured evaluations.

• The study protocol includes comprehensive perioperative data collection, including anaesthetic exposure, sedation practices and cardiopulmonary variables.

• The single-centre setting and relatively strict exclusion criteria may limit the generalisability of the study population.

• Short-term perioperative administration of liraglutide restricts the ability to assess longer-term recovery trajectories.

Background

Postoperative delirium (POD) is one of the most common neurological complications after cardiac surgery, with occurrence rates varying from 11.3% to 51.6%.¹ It is characterised by acute and fluctuating disturbances in consciousness, attention and cognition. Accumulating evidence indicates that POD is strongly associated with increased perioperative mortality, prolonged intensive care unit (ICU) and hospital stay, higher healthcare costs and long-term cognitive impairment.²,⁵ Advanced age is a well-recognised independent risk factor for POD, with patients over 65 years showing a fourfold to sevenfold higher incidence compared with younger patients.^{6 7} Despite its clinical significance, there are currently no effective pharmacological interventions established for the prevention of POD.⁸

Neuroinflammation is increasingly recognised as a key mechanism underlying POD.^{9 10} During cardiac surgery, perioperative factors such as anaesthesia, cardiopulmonary bypass, surgical stress and ischaemia–reperfusion injury lead to a transient surge in systemic proinflammatory cytokines.^{11 12} This surge disrupts the blood–brain barrier, triggers microglial and astrocytic activation and subsequently amplifies central neuroinflammatory cascades, resulting in neuronal injury and cognitive dysfunction.^{12 13} Previous studies have demonstrated that postoperative cytokine levels peak within 6–24 hours and return to baseline within 2–4 days, a temporal pattern that parallels the incidence of POD, which most frequently occurs during the first three postoperative days.¹⁴,¹⁶

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is widely used in the management of type 2 diabetes mellitus. Accumulating clinical and experimental evidence suggests that liraglutide exerts neuroprotective effects by attenuating neuroinflammation, improving synaptic integrity and reducing cognitive impairment related to type 2 diabetes and Alzheimer’s disease.^{17 18} Furthermore, liraglutide has been shown to provide cardioprotective benefits^{19 20} and to improve perioperative glycaemic control, which is of particular relevance given that more than 90% of patients undergoing cardiac surgery experience perioperative hyperglycaemia—a recognised risk factor for POD.^{21 22}

Our preclinical studies demonstrated that aged mice were more susceptible to delirium-like behaviour after cardiac surgery, and that liraglutide reduced the incidence of such behaviour by suppressing microglial and astrocytic activation.^{23 24} In addition, a recent multicentre randomised controlled trial in cardiac surgery patients reported that perioperative liraglutide administration improved glycaemic control and showed a trend towards reduced POD incidence, although statistical significance was not achieved, possibly due to younger patient age, lower baseline surgical risk and a lower than expected delirium incidence in the control group.²⁵ Importantly, liraglutide was well tolerated, with no significant increase in gastrointestinal adverse events (AEs) compared with placebo.

Taken together, these findings suggest that liraglutide may represent a promising preventive strategy against POD in elderly patients undergoing cardiac surgery. This trial is therefore designed to evaluate the efficacy and safety of perioperative liraglutide in reducing the incidence of POD in this high-risk population.

Methods and analysis

Trial design

This is a prospective, single-centre, randomised, double-blind, placebo-controlled superiority trial designed to evaluate the preventive effect of liraglutide on POD in elderly patients undergoing elective cardiac surgery. The trial will be conducted at the Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, affiliated with Nanjing University Medical School. A total of 260 patients will be enrolled and randomised in a 1:1 ratio to receive either liraglutide or placebo during the perioperative period.

Study population and eligibility criteria

Eligible participants will be screened among patients admitted for elective cardiac surgery. After a full explanation of the trial procedures, written informed consent will be obtained from patients or their legal representatives prior to enrolment.

Inclusion criteria

The inclusion criteria are as follows: (1) Age ≥60 years; (2) Scheduled for elective cardiac surgery.

Exclusion criteria

The exclusion criteria are the following: (1) History of neurological and psychiatric disorders, such as schizophrenia, epilepsy, Parkinson’s disease and severe dementia; (2) Patients with communication difficulties, such as severe visual, auditory or speech impairments; (3) History of central nervous system injury or surgery; (4) Heart failure New York Heart Association class IV; (5) Severe liver dysfunction (Child-Pugh Class C); (6) Patients with severe renal insufficiency reuiring continuous renal replacement therapy (CRRT); (7) History of pancreatitis; (8) Type 1 diabetes mellitus; (9) Patients who have difficulty controlling their blood glucose at 4–10 mmol/L during the screening period; (10) Medullary thyroid carcinoma or relevant family history; (11) Pregnant and lactating women; (12) Intolerance or allergy to liraglutide; (13) History of using GLP-1A inhibitors; (14) Refusal to sign informed consent.

Study outline

After admission, eligible patients will be screened based on their medical records and clinical status. Written information and verbal explanations about the trial will be provided, and informed consent will be obtained prior to enrolment. Baseline characteristics will then be collected, including preoperative delirium occurrence and severity, cognitive function, depression and cardiac function. In addition to baseline psychological and cardiac assessments, demographic and clinical data, including age, sex, body mass index, medical history and current medication use, etc, will also be collected for all participants to characterise the study population and to serve as covariates in subsequent analyses. Plasma samples will be obtained for the measurement of neuronal injury, inflammation, myocardial injury and cardiac function biomarkers. All details of anaesthetic management will be systematically recorded, including the type and dosage of anaesthetic agents, duration of anaesthesia, intraoperative opioid and sedative use, and depth of anaesthesia parameters (eg, Bispectral Index (BIS) values). These data will be collected from anaesthesia records and cross-checked with the electronic medical system. Differences between groups will be assessed to ensure homogeneity, and variables showing significant imbalance will be adjusted for in subsequent statistical analyses.

The study intervention will consist of five doses of liraglutide or placebo: the first administered on the day before surgery, the second after induction of anaesthesia and the third to fifth on postoperative days 1–3. In the event of a rescheduled surgery, dosing will be restarted on the day before the new surgery. The exact date and time of each administration will be documented.

AEs will be recorded throughout the intervention and follow-up periods. POD will be assessed daily for the first 7 days after surgery, together with other secondary outcomes as outlined in online supplemental table S1. Follow-up assessments will continue up to 1 year postoperatively. A SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) flow diagram of the study is presented in figure 1.

Figure 1. Flow diagram. Note: the diagram illustrates the screening of participants aged over 60 years scheduled for elective cardiac surgery, reasons for exclusion and the number of participants eligible and willing to participate. It further details missed inclusion due to logistical or clinical factors, the process of obtaining informed consent and randomisation into the liraglutide and placebo groups. The figure also presents the number of injections received in each group, preoperative assessments, postoperative follow-up schedule and reasons for dropout, including withdrawal of consent, discontinuation of intervention or loss to follow-up.

Randomisation

Participants will be randomly assigned in a 1:1 ratio to the liraglutide or placebo group. Randomisation sequences will be generated by an independent statistician who is not involved in patient recruitment, treatment or outcome assessment, using a stratified block design. Stratification factors include age (60–75 years vs >75 years) and cardiopulmonary bypass status (yes vs no). Block size is set at six. The randomisation list and corresponding blinding codes will be created and stored within the electronic data capture (EDC) system.

After eligibility confirmation and enrolment, the EDC system will automatically assign each participant a randomisation number and match it with a pregenerated blinding code. This ensures allocation concealment and prevents access to group assignment by investigators, clinical staff or participants.

Allocation concealment

Liraglutide and placebo will be identically prepared, packaged and labelled, with matching vial appearance, liquid characteristics and volume to ensure indistinguishability. The placebo consists of sterile normal saline solution, which has no physiological effect at the administered dose. To ensure full blinding, a dedicated research pharmacist, independent of the research team, will dispense the assigned investigational product strictly according to the blinding code provided by the EDC system. All dispensing events, including time, participant ID and assigned blinding code, will be automatically logged in the EDC system to generate a complete medication accountability record. Administration of the study medication will be performed by clinical bedside nurses not involved in the study, ensuring that participants, investigators and all research personnel remain fully blinded to treatment allocation throughout the trial.

Blinding

This is a double-blind trial. Participants, investigators, treating clinicians and outcome assessors will all remain blinded to treatment allocation throughout the study.

Emergency unblinding

Emergency unblinding will only be permitted when knowledge of the allocated treatment is deemed essential for clinical management of a serious AE (SAE). In such cases, investigators will request unblinding through the EDC system. The reason, time and outcome of the unblinding will be automatically documented and reported to the principal investigator and the ethics committee.

Study procedures and interventions

Participants will be randomly allocated to one of two groups: (1) Liraglutide group (subcutaneous injection, s.c.): Patients will receive liraglutide 0.6 mg on the evening of the day before surgery (approximately 20:00), 1.8 mg immediately after induction of anaesthesia on the day of surgery and 0.6 mg once daily at approximately 20:00 on postoperative days 1–3; (2) Placebo group (s.c.): Patients will receive placebo injections of identical volume and appearance at the corresponding time points.

The patient’s pre-existing antidiabetic regimen will generally remain unchanged, except that oral hypoglycaemic agents will be discontinued on the day of surgery. Insulin therapy will be initiated if necessary, with the target of maintaining perioperative blood glucose levels between 4 and 10 mmol/L.

The most common adverse effects of liraglutide are gastrointestinal, particularly nausea and vomiting. Therefore, patients will be assessed daily for nausea from the first administration until the end of the intervention period using a numeric rating scale (0–10 points). A score of ≤3 will result in close observation and, if needed, symptomatic treatment. A score of ≥4 will prompt immediate pharmacological treatment, and the study intervention will be discontinued.

Laboratory measurements

Peripheral venous blood samples (approximately 2 mL each) will be collected at predefined time points: (1) Preoperatively: in the morning before breakfast on the day prior to surgery; (2) Immediately on ICU admission on the day of surgery; (3) Postoperative days 3 and 7: in the morning before breakfast. Samples will be collected into EDTA anticoagulant tubes. After collection, samples will be centrifuged at 3000 rpm for 10 min at 4°C. Plasma will be separated, aliquoted and stored at –80°C in the biobank of the Nanjing University Institute of Cardiothoracic and Vascular Diseases. on completion of sample collection for all participants, plasma levels of the following biomarkers will be determined using commercially available ELISA kits: (1) Neuronal injury markers: Neuron-specific enolase (NSE), S100β; (2) Inflammatory markers: C-reactive protein (CRP), interleukin (IL)-6, IL-1α, IL-1β, tumour necrosis factor-alpha (TNF-α), C1q, C3; (3) Myocardial injury markers: Cardiac troponin T (cTnT), Lactate dehydrogenase (LDH), aspartate aminotransferase (AST), Creatine kinase (CK), CK-MB; (4) Cardiac function biomarker: B-type natriuretic peptide (BNP).

Outcome measures

The primary endpoint is the incidence of POD within 7 days after surgery, assessed using the Confusion Assessment Method (CAM) or CAM-ICU. CAM is applied to patients who are awake, communicative and not mechanically ventilated, whereas CAM-ICU is designed for critically ill or intubated patients who cannot communicate verbally.^{26 27} In our study, CAM-ICU will be used during the ICU stay and CAM will be applied after extubation or in the general ward. This approach ensures accurate assessment across all care settings. CAM evaluates four core features: (1) acute onset and fluctuating course; (2) inattention; (3) disorganised thinking; (4) altered level of consciousness. CAM-ICU assesses the same four diagnostic features but uses non-verbal tasks (eg, visual attention tests, simple yes/no or eye-movement responses) to evaluate cognition. A diagnosis of delirium requires the presence of features (1) and (2) plus either (3) or (4). On the day of surgery, the first assessment will be performed once the Richmond Agitation-Sedation Scale (RASS) score is ≥ −2. The RASS scores range from +4 (combative) to −5 (unarousable), a RASS value > −2 (ie, −1=drowsy or 0=alert/calm) indicates that the patient is sufficiently responsive for an accurate CAM/CAM-ICU assessment.²⁸ From postoperative days 1–3, delirium assessments will be conducted two times per day, at 08:00 and 20:00. From postoperative days 4–7, assessments will be performed once daily at 08:00. For all assessments, the prerequisite is that the patient’s RASS score is ≥ –2.

Secondary outcomes including: (1) Delirium severity: evaluated using the CAM-Severity (CAM-S) score. The CAM-S is a validated tool derived from the CAM framework to quantify the severity of delirium symptoms. It assesses the intensity and number of core features of delirium based on four main domains: acute onset and fluctuating course, inattention, disorganised thinking and altered level of consciousness²⁹; (2) Cognitive function will be assessed using the Mini-Mental State Examination, a 30-point questionnaire evaluating orientation, registration, attention/calculation, recall, language and visuospatial ability. Higher scores indicate better cognitive performance, and scores<24 suggest potential cognitive impairment.³⁰ Anxiety symptoms will be evaluated with the Generalised Anxiety Disorder-7 scale, which consists of seven items scored from 0 (‘not at all’) to 3 (‘nearly every day’), yielding a total score between 0 and 21. Cut-off points of 5, 10 and 15 indicate mild, moderate and severe anxiety, respectively.³¹ Sleep quality will be measured using the Athens Insomnia Scale, an eight-item self-report tool aligned with International Classification of Diseases, 10th Revision criteria. Each item is rated from 0 to 3, with total scores ranging from 0 to 24; a score ≥6 indicates clinically significant insomnia.³² Depressive symptoms will be assessed using the Patient Health Questionnaire-9, which includes nine items scored from 0 to 3. Total scores range from 0 to 27, with cut-offs of 5, 10, 15 and 20 defining mild, moderate, moderately severe and severe depression, respectively³³; (3) Cardiac function: echocardiography and BNP measurement; (4) Clinical outcomes: ICU length of stay, duration of mechanical ventilation, total hospital length of stay and in-hospital mortality; (5) Serious cardiovascular events: incidence of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction and stroke, within 1 year postoperatively; (6) Biomarkers: NSE, S100β, CRP, IL-6, IL-1α, IL-1β, TNF-α, C1q, C3, cTnT, LDH, AST, CK, CK-MB, BNP;. (7) Exploratory neuroimaging: In a subset of patients, such as those with coronary artery disease or valvular heart disease who also present with concomitant sleep disturbances, anxiety or depressive symptoms, resting-state functional MRI may be performed to investigate alterations in intrinsic brain network activity and to explore their potential relationships with cardiac disease, POD, sleep disturbance and postoperative cognitive dysfunction. This exploratory assessment is optional and will require separate informed consent. (8) Exploratory biomarker analyses: In addition to the predefined plasma biomarkers, residual plasma samples stored at –80°C may be used for future exploratory analyses of novel biomarkers related to neuroinflammation, neuronal injury or cardiovascular dysfunction, depending on emerging scientific evidence. These analyses will be reported as exploratory and hypothesis-generating.

Safety

All AEs and SAEs will be recorded from the first study drug administration until hospital discharge. Particular attention will be given to gastrointestinal side effects of liraglutide, including nausea and vomiting, which are the most common treatment-related AEs. Daily assessments of nausea will be performed using a numeric rating scale (0–10 points) during the intervention period. Patients with a score of ≤3 will not receive medication and will instead be closely observed for any symptom progression or side effects. A score of ≥4 will prompt immediate pharmacological intervention, and the study drug will be discontinued.

SAEs will be defined according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP) guidelines and reported to the ethics committee within the required timelines. All SAEs will be reviewed by the principal investigator. After discharge, only predefined MACE (cardiovascular death, myocardial infarction, stroke) will be monitored during the 1-year follow-up period.

Study medication will be discontinued in the event of severe gastrointestinal intolerance, suspected pancreatitis, hypersensitivity reactions or other SAEs judged to be related to the investigational product.

Sample size calculation

Based on previous studies and preliminary data, we assume a POD incidence of approximately 30% in the control group.^{34 35} To detect a 50% relative reduction in the incidence of POD in the liraglutide group with a two-sided significance level of 0.05 and a power of 80%, 236 patients are required. Considering an estimated dropout rate of 10%, the total planned sample size is 260 participants (130 per group).

The assumption of a 50% relative reduction was based on two considerations. First, liraglutide has demonstrated multiple neuroprotective and anti-inflammatory effects including improved metabolic stability, reduced systemic inflammation, attenuation of oxidative stress and potential modulation of neural network connectivity which together suggest the possibility of a moderate-to-large preventive effect.³⁶,³⁸ Second, a 50% reduction represents a clinically meaningful and realistic effect size commonly used in preventive intervention trials to ensure that the study is adequately powered to detect an effect of practical significance.^{34 39} Sample size calculation was performed using PASS 15.0 software.

Statistical analyses

Baseline demographic characteristics and vital signs will be summarised and compared between groups. Descriptive statistics for continuous variables will include the mean, SD, median and IQR, while categorical variables will be presented as counts and percentages.

Between-group comparisons will be performed using appropriate statistical tests according to the type and distribution of variables: (1) Continuous variables: independent-samples t-test (if normally distributed with equal variances) or Wilcoxon rank-sum test (if not normally distributed); (2) Categorical variables: χ² test or Fisher’s exact test (if χ² assumptions are not met); (3) Ordinal variables: Wilcoxon rank-sum test or the Cochran-Mantel-Haenszel (CMH) test.

Efficacy analyses will be conducted based on both the full analysis set (FAS) and the per protocol set (PPS). The FAS will include all randomised participants who receive at least one dose of the study medication and have at least one postbaseline delirium assessment. The PPS will include individuals in the FAS who adhere sufficiently to the study protocol without major protocol deviations that may influence efficacy assessments. The primary efficacy endpoint (incidence of POD) will be compared between groups using the χ² test or Fisher’s exact test, as appropriate. The between-group difference in incidence will be reported with a 95% CI. If the lower limit of the 95% CI for the difference in delirium incidence is greater than 0, liraglutide will be considered superior to placebo. In addition to the primary unadjusted comparison, a predefined multivariable logistic regression analysis will be conducted to adjust for potential confounders associated with POD. Covariates will include demographic variables (eg, age), baseline cognitive status, comorbidities, cardiopulmonary bypass duration (if applicable), depth of anaesthesia, sedation practices, intraoperative opioid and sedative exposure, and anaesthetic agents used. These factors were selected based on established POD risk determinants reported in prior studies. The adjusted treatment effect will be presented as an OR with a 95% CI.

For missing data, multiple imputation based on the missing-at-random assumption will be used for the primary analysis in the FAS. Sensitivity analyses, including complete-case analysis and worst-case imputation, will be performed to evaluate the robustness of the results.

For secondary efficacy endpoints, continuous variables will be analysed using independent-samples t-tests or Wilcoxon rank-sum tests, categorical variables using χ² or Fisher’s exact tests and ordinal variables using Wilcoxon rank-sum or CMH tests, as appropriate.

All statistical analyses will be performed using SPSS V.27.0 (IBM, Armonk, New York, USA). A two-sided p value <0.05 will be considered statistically significant.

Monitoring

A data safety monitoring plan will be implemented in accordance with the assessed risk level of the study. All AEs will be comprehensively documented, appropriately managed and followed until resolution or stabilisation. SAEs and unexpected AEs will be reported without delay to the ethics committee, regulatory authorities and relevant drug supervision agencies, in compliance with applicable regulations. The principal investigator will perform regular cumulative reviews of all reported AEs and will convene investigator meetings as necessary to evaluate the overall risk–benefit profile of the trial and to determine whether any protocol modifications or additional safety measures are required.

Patient and public involvement

Patients were not involved in the design of this study.

Limitation

Several methodological limitations should be acknowledged. First, this is a single-centre trial, which may limit the generalisability of the findings to other surgical settings or patient populations. Second, the strict exclusion criteria, particularly those related to psychiatric and neurological disorders, may reduce external validity and restrict applicability to broader clinical populations. Third, although POD is assessed using validated and standardised tools, inter-rater variability cannot be entirely excluded. Fourth, liraglutide is administered only during a short perioperative window, which prevents assessment of potential long-term effects on recovery trajectories. Finally, the absence of a standard-of-care comparison group may limit the ability to distinguish treatment effects from contextual or placebo-related influences.

Ethics and dissemination

The clinical study will adhere to relevant regulations, including the Declaration of Helsinki by the World Medical Association. The study protocol was approved by the Medical Ethics Committee of Nanjing Drum Tower Hospital, Affiliated to Medical School of Nanjing University (Approval No.: 2025-0410-02) prior to the commencement of the trial. Before enrolment in the study, researchers are responsible for providing participants or their representatives with a complete and thorough explanation of the study’s purpose, procedures and potential risks, and obtaining a signed written informed consent form. Participants will be informed of their right to withdraw from the study at any time, and the signed informed consent forms will be retained as part of the clinical research records. An example of the participant consent form is provided in the online supplemental material. During the study, the personal privacy and data confidentiality of participants will be protected.

Planning and dissemination

In this study, we will provide all participants with clear information regarding the purpose of the investigation, methods, potential conflicts of interest, estimated benefits, foreseeable risks and any inconveniences that may arise. This study has been approved by the ethics committee and plans to enrol the first patient in September 2025, with the experimental plan lasting for 2 years. All study results (positive, negative and inconclusive) will be presented at international scientific conferences in the form of oral presentations or posters. Additionally, the findings will be published in an international peer-reviewed scientific journal.