Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients

Conditions
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Hyperglycemia Stress

Intervention / Treatment
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* Drug: Dulaglutide
* Drug: Placebo
* Device: Continuous glucose monitor (CGM), blinded


Participation Criteria
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Eligibility Criteria
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Inclusion criteria (Aim 1): Men and women between the ages of 45 and 80 years undergoing non-cardiac general or vascular surgery BMI ≥30 kg/m^2 without a previously known history of DM Inclusion criteria (Aim 2): Men and women without known history of diabetes with ages between 45 and 80 years undergoing non-cardiac general or vascular surgery participating in Aim 1. BMI ≥30 kg/m2 and pre-DM or DM by OGTT or HbA1c. Exclusion criteria (Aim 1): 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 Exclusion criteria (Aim 2): Same as in Aim 1, with the following additional exclusion criteria: 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)

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants with normoglycemia will be in Aim 1. Participants with lab results indicative of pre-DM or DM will be randomized to Aim 1 or Aim 2, and those in Aim 2 will be further randomized to receive dulaglutide or placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continuous Glucose Monitoring<br>Aim 1 participants will have a continuous glucose monitor (CGM) placed preoperatively and will wear the CGM throughout hospitalization. | Device: Continuous glucose monitor (CGM), blinded<br>* 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.<br>* Other names: FreeStyle Libre Pro;|
| Experimental: Dulaglutide<br>Aim 2 participants randomized to receive dulaglutide within 72 hours prior to a planned surgery. | Drug: Dulaglutide<br>* A subcutaneous injection of dulaglutide 0.75 mg will be administered within 72 hours prior to a planned surgical intervention.<br>* Other names: Trulicity;Device: Continuous glucose monitor (CGM), blinded<br>* 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.<br>* Other names: FreeStyle Libre Pro;|
| Placebo Comparator: Placebo<br>Aim 2 participants randomized to receive a placebo to match dulaglutide within 72 hours prior to a planned surgery. | Drug: Placebo<br>* A subcutaneous injection of a saline placebo will be administered within 72 hours prior to a planned surgical intervention.<br>Device: Continuous glucose monitor (CGM), blinded<br>* 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.<br>* Other names: FreeStyle Libre Pro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of stress hyperglycemia (SH) | Incidence of stress hyperglycemia will be determine in a population at high-risk for perioperative dysglycemia among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of time in target glucose range (70-140 mg/dL) by CGM | Proportion of time in target glucose range (70-140 mg/dL) by CGM data will be calculated for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Insulin Secretion | Baseline insulin secretion between patients with and without stress hyperglycemia will be examined among participants in Aim 1. | Baseline | 
| Baseline Insulin Sensitivity | Baseline insulin sensitivity between patients with and without stress hyperglycemia will be examined among participants in Aim 1. | Baseline | 
| Mean Onset of Stress Hyperglycemia (Glucose >140 mg/dL) | Mean onset time of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Mean Duration of Stress Hyperglycemia (Glucose >140 mg/dL) | The mean duration of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Mean Daily Glucose Values | The mean daily glucose values values, as measured by both point-of-care (POC) glucose testing and CGM data, will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Maximum Daily Glucose Values | The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Total Daily Insulin Dose | The total daily insulin dose in patients with and without stress hyperglycemia will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Length of Hospital Stay | The length of hospital stay (in days) in patients with and without stress hyperglycemia will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Number of ICU Transfers | The number of ICU transfers in patients with and without stress hyperglycemia will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Number of Hospital Readmissions After Discharge | Number of hospital readmissions after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1. | Up to 3 months after discharge | 
| Number of Emergency Room Visits After Discharge | The number of emergency room visits after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1. | Up to 3 months after discharge | 
| Number of Participants Experiencing Complications | A composite of complications including wound infection, respiratory failure, pneumonia, acute kidney injury (increase in creatinine by 0.5 mg/dL), and major adverse cardiac events (MACE) will be examined among participants in Aim 1. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of Time in Hyperglycemia (Glucose>140 mg/dL) | The percentage of time in hyperglycemia with glucose>140 mg/dL will be examined for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of Time in Hyperglycemia (Glucose>180 mg/dL) | The percentage of time in hyperglycemia with glucose>180 mg/dL will be examined for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of Time in Hypoglycemia (Glucose <70 mg/dL) | The percentage of time in hypoglycemia with glucose <70 mg/dL will be examined for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of Time in Hypoglycemia (Glucose <54 mg/dL) | The percentage of time in hypoglycemia with glucose <54 mg/dL will be examined for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Percentage of Time in Hypoglycemia (Glucose <40 mg/dL) | The percentage of time in hypoglycemia with glucose <40 mg/dL will be examined for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| 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 for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| 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 for participants of Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Mean Daily Glucose Values (Aim 2) | The mean daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Maximum Daily Glucose Values (Aim 2) | The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| Perioperative Insulin Requirements | Perioperative insulin requirements will be assessed as the total daily insulin dose, among participants from Aim 2. | Up to 14 days (depending on length of hospitalization) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perioperative, Surgery, Stress Hyperglycemia