Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients

Hyperglycemia is seen in approximately 30% of patients who do not have a history of diabetes and undergo general surgery. Hyperglycemia in this setting is associated with increased risk of postoperative complications. The purpose of this study is to investigate risk factors for developing high sugars during the time of surgery, and if these high sugars can be prevented by the use of an injectable diabetes medication (dulaglutide) prior to surgery.

Study Overview

• Status: Terminated
• Conditions: Hyperglycemia Stress
• Intervention / Treatment: Device: Continuous glucose monitor (CGM), blinded; Drug: Dulaglutide; Drug: Placebo

Detailed Description

Stress hyperglycemia (SH), defined as a blood glucose >140 mg/dl in hospitalized patients without a prior history of diabetes mellitus (DM) is associated with increased risk of complications and mortality compared to patients with normoglycemia and with known history of DM. Increased counterregulatory hormones (cortisol, glucagon, epinephrine, growth hormone), free fatty acids, inflammation and oxidative stress are likely involved in the pathogenesis of impaired insulin secretion and action leading to stress hyperglycemia. However, no prospective studies have comprehensively examined preoperative glycemic control profiles and their association with the incidence, clinical predictors and underlying mechanisms of SH in general surgical patients. Accordingly, the researchers propose a prospective study investigating clinical, metabolic and inflammatory/oxidative stress biomarker profiles leading to SH. This study will use continuous glucose monitoring (CGM) technology to fully characterize the onset, duration and severity of SH during the perioperative period.

Given the association between stress hyperglycemia and poor hospital outcomes, this study aims to determine if the prevention of stress hyperglycemia is feasible with the single administration of a weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), a common medication used to treat patients with established diabetes. In addition, the researchers will explore the role of beta-cell function, insulin resistance, and inflammation on the pathogenesis of stress hyperglycemia.

The goals of this study are to: 1) conduct an extensive analysis of preoperative glycemic control and its relationship to clinical, metabolic and biomarker profiles of SH in a high-risk population, and 2) conduct a pilot randomized controlled trial to prospectively determine if single dose use of dulaglutide can improve perioperative glycemic control compared to insulin administration (standard-of-care). Patients qualifying for the study will be approached at their preoperative clinic visit and invited to participate in the prospective observational study arm (Aim 1), and in the interventional trial for prevention of SH with dulaglutide (Aim 2) if they meet inclusion criteria based on oral glucose tolerance testing (OGTT) or lab testing performed for Aim 1. Within 72 hours prior to planned surgery, consented patients will present to the clinical research center (CRC) to undergo evaluation with OGTT and lab testing with CGM placement. Those patients with OGTT or lab results consistent with a diagnosis of prediabetes or newly diagnosed diabetes will be asked if they would like to participate in Aim 2. Patients consenting to participate in Aim 2 will be randomized to receive a subcutaneous injection of dulaglutide 0.75 mg or placebo during the CRC visit, and glycemic control parameters will be followed postoperatively during surgical admission (up to 14 days). In addition to the above, baseline and postoperative levels of serum inflammatory and oxidative stress markers will be obtained to provide further information regarding beta-cell function and insulin resistance in relation to the development of stress hyperglycemia.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30322
      • Grady Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Men and women without known history of diabetes with ages between 45 and 80 years undergoing non-cardiac general or vascular surgery
• BMI ≥30 kg/m2 and pre-DM or DM by OGTT or HbA1c

Exclusion criteria:

• Patients prescribed or taking antihyperglycemic medications
• Patients undergoing cardiac surgery or patients anticipated to require ICU care
• Patients expected to be admitted less than 48-72 hours after surgery
• Severely impaired renal function (eGFR < 30 mL/min) or clinically significant hepatic failure
• Treatment with oral (equivalent to prednisone > 5 mg/day) or injectable corticosteroids
• Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study; unable to consent
• Pregnant or breast feeding at time of enrollment
• Prisoners
• Patients undergoing gastrointestinal surgery or at high risk for gastrointestinal obstruction/ileus or expected to require gastrointestinal suction
• Patients with delayed gastric emptying, pancreatic or gallbladder disease
• Patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dulaglutide; Participants randomized to receive dulaglutide within 72 hours prior to a planned surgery.	Device: Continuous glucose monitor (CGM), blinded; Continuous glucose monitor (CGM) sensor will be placed preoperatively and continued during surgical hospitalization to monitor glucose levels. CGM provides an estimated capillary blood glucose (BG) level through direct measurement of interstitial glucose levels every 5-15 minutes.; Other Names: FreeStyle Libre Pro; Drug: Dulaglutide; A subcutaneous injection of dulaglutide 0.75 mg will be administered within 72 hours prior to a planned surgical intervention.; Other Names: Trulicity
Placebo Comparator: Placebo; Participants randomized to receive a placebo to match dulaglutide within 72 hours prior to a planned surgery.	Device: Continuous glucose monitor (CGM), blinded; Continuous glucose monitor (CGM) sensor will be placed preoperatively and continued during surgical hospitalization to monitor glucose levels. CGM provides an estimated capillary blood glucose (BG) level through direct measurement of interstitial glucose levels every 5-15 minutes.; Other Names: FreeStyle Libre Pro; Drug: Placebo; A subcutaneous injection of a saline placebo will be administered within 72 hours prior to a planned surgical intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Time in Target Glucose Range (70-140 mg/dL) by CGM	The percentage of time in the target glucose range of 70-140 mg/dL, as measured by a continuous glucose monitor (CGM) data was determined.	During hospitalization (up to 5 days postoperatively)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Cortisol Level	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Change in Level of Free Fatty Acids (FFA)	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Change in High Sensitivity C-reactive Protein (hsCRP) Level	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Change in Tumor Necrosis Factor-alpha (TNF-α) Level	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Change in Adiponectin Level	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Change in Level of Thiobarbituric Acid Reactive Substances (TBARS)	Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.	Baseline, 48 to 72 hours postoperatively
Percentage of Time in Hyperglycemia (Glucose>140 mg/dL)	The percentage of time in hyperglycemia with glucose>140 mg/dL will be examined.	During hospitalization (up to 5 days postoperatively)
Percentage of Time in Hyperglycemia (Glucose>180 mg/dL)	The percentage of time in hyperglycemia with glucose>180 mg/dL will be examined.	During hospitalization (up to 5 days postoperatively)
Percentage of Time in Hypoglycemia (Glucose <70 mg/dL)	The percentage of time in hypoglycemia with glucose <70 mg/dL will be examined.	During hospitalization (up to 5 days postoperatively)
Percentage of Time in Hypoglycemia (Glucose <54 mg/dL)	The percentage of time in hypoglycemia with glucose <54 mg/dL will be examined.	During hospitalization (up to 5 days postoperatively)
Percentage of Time in Hypoglycemia (Glucose <40 mg/dL)	The percentage of time in hypoglycemia with glucose <40 mg/dL will be examined.	During hospitalization (up to 5 days postoperatively)
Mean Onset of Stress Hyperglycemia During the Postoperative Period	The mean onset time of stress hyperglycemia during the postoperative period by CGM data will be examined.	During hospitalization (up to 5 days postoperatively)
Mean Duration of Stress Hyperglycemia During the Postoperative Period	The mean duration of stress hyperglycemia during the postoperative period by CGM data will be examined.	During hospitalization (up to 5 days postoperatively)
Mean Daily Glucose Values	The mean daily glucose values, as measured by both point of care (POC) glucose testing and CGM data, will be examined.	During hospitalization (up to 5 days postoperatively)
Maximum Daily Glucose Values	The maximum daily glucose values, as measured by both POC glucose testing and CGM data, will be examined.	During hospitalization (up to 5 days postoperatively)
Perioperative Insulin Requirements	Perioperative insulin requirements will be assessed as the total daily insulin dose.	During hospitalization (up to 5 days postoperatively)

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Georgia Davis, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2021
• Primary Completion (Actual): June 22, 2023
• Study Completion (Actual): June 22, 2023

Study Registration Dates

• First Submitted: April 23, 2021
• First Submitted That Met QC Criteria: April 23, 2021
• First Posted (Actual): April 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Surgery; Perioperative; Stress Hyperglycemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hyperglycemia; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; Dulaglutide
• Other Study ID Numbers: IRB00097659; K23DK122199 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the publication for this study (including text, tables, figures, and appendices) will be available to other researchers, after deidentification.
• IPD Sharing Time Frame: Data will be made available for sharing beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Data will be made available for sharing with researchers who provide a methodologically sound proposal, in order to achieve aims in the approved proposal. Proposals should be directed to gmdavis@emory.edu. To gain access, data requestors will need to sign a data access/use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No