Conditions: Hyperglycemia Stress
Keywords: Perioperative Surgery Stress Hyperglycemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
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:
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.

Arms:
arm 1: Participants randomized to receive dulaglutide within 72 hours prior to a planned surgery. arm 2: Participants randomized to receive a placebo to match dulaglutide within 72 hours prior to a planned surgery.

Interventions: intervention 1: Dulaglutide intervention 2: Placebo intervention 3: Continuous glucose monitor (CGM), blinded
Intervention descriptions: intervention 1: A subcutaneous injection of dulaglutide 0.75 mg will be administered within 72 hours prior to a planned surgical intervention. intervention 2: A subcutaneous injection of a saline placebo will be administered within 72 hours prior to a planned surgical intervention. intervention 3: 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.

Protocol document:
Prot_SAP_000.pdf: 
Study Protocol 
 
TITLE: Perioperative Stress Hyperglycemia in General and Vascular 
Surgery Patients 
 
NCT NUMBER: NCT04862234 
 
Protocol Date: October 8, 2024 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 1 of 30
Protocol Version: Version 7.0 10/08/2024
PROTOCOL TITLE:  Perioperative Stress Hyperglycemia in General and Vascular Surgery 
Patients: An Observational and Randomized Controlled Pilot Trial.
Protocol Number: IRB00097659
National Clinical Trial (NCT) Identified Number: 04862234 
Principal Investigator: Georgia M. Davis, MD
Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Version Number:  v.6.0
08.06.2024
Summary of Changes from Previous Version:
Revision #
Version date
Summary of changes
7/27/2017
Initial Protocol
1
12/10/20
Update PI, add observational study arm
2
1/20/21
Biomedical protocol format change
3
6/15/21
Updated phlebotomy collection procedure and 
participant payment schedule
4
12/20/21
Updated the recruitment methods to include 
Telehealth patients.
5
3/17/2023
i. Changed inclusion criteria for study participants 
from BMI ≥30 kg/m2 to 28 kg/m2
ii. Add Hemoglobin <10 gm/dL to exclusion criteria 
for Aim1.
6
8/6/24
Removal of Clinical Trial procedures (Aim 2) and 
replacement with Updated Aim 2.
Includes updated DSMB meeting schedule changed 
to every 6 months.


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 2 of 30
Protocol Version: Version 7.0 10/08/2024
7
10/08/24
Accommodate surgical procedure rescheduling 
timeline
Table of Contents
1.
Study Summary .......................................................................................................................3
2.
Objectives................................................................................................................................4
3.
Background/Significance.........................................................................................................5
4.
Study Endpoints ......................................................................................................................8
5.
Study Intervention/Investigational Agent...............................................................................9
6.
Study Design............................................................................................................................9
7.
Research Procedures.............................................................................................................10
8.
Data Collection and Data Entry .............................................................................................12
9.
Statistical Analysis .................................................................................................................12
10.
Sample Size Calculation and Power Analysis.....................................................................13
11.
Data Safety and Monitoring Plan (DSMP)..........................................................................14
12.
Human Subject Involvement .............................................................................................15
13.
Characteristics of the Study Population ............................................................................15
14.
Study Sites .........................................................................................................................15
15.
Sources of Materials..........................................................................................................15
16.
Data Collection, Management and Protection ..................................................................16
17.
Informed Consent and Randomization..............................................................................16
18.
Risk Associated with Participation.....................................................................................17
19.
Protection Against Risk......................................................................................................18
20.
Potential Benefits to the Subject.......................................................................................18
21.
Confidentiality ...................................................................................................................19
22.
Payment for Participation..................................................................................................19
23.
Financial Conflict of Interests ............................................................................................19
24.
Study Timelines..................................................................................................................20
25.
References.........................................................................................................................20


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 3 of 30
Protocol Version: Version 7.0 10/08/2024
1. Study Summary
Study Title
Perioperative Stress Hyperglycemia in General and 
Vascular Surgery Patients: An Observational and 
Randomized Controlled Pilot Trial
Study Design
Observational Cohort (Aim 1, updated Aim 2), RCT 
(Aim 2)
Primary Objective
Aim 1: To fully characterize preoperative glycemic 
control and prospectively determine clinical, 
metabolic, and inflammatory biomarker profiles 
associated with stress hyperglycemia.
Aim 2: To conduct a randomized controlled pilot study 
to determine if single dose administration of 
dulaglutide can improve perioperative glycemic 
control in high-risk subjects.
Updated Aim 2: To determine patterns of 
preoperative glycemic control by CGM that are 
associated with SH.
Secondary Objective(s)
Aim 1a: To examine clinical, metabolic and 
inflammatory biomarker characteristics associated 
with SH in individuals at high risk for dysglycemia 
undergoing general and vascular surgery.
Aim 1b: To determine the timing, duration, and 
severity of SH by CGM and its association with 
alterations in inflammatory/oxidative stress 
biomarkers.
Aim 1c: To explore the relationship of the duration 
and severity of SH with perioperative complications.
Aim 2: To conduct a randomized controlled pilot study 
to determine if single dose administration of 
dulaglutide can improve perioperative glycemic 
control in high-risk subjects.
Updated Aim 2a: To identify preoperative CGM 
profiles associated with postoperative SH
Updated Aim 2b: To compare the predictive value of 
preoperative CGM profiles with traditional metrics of 
underlying dysglycemia.
Research 
Intervention(s)/Interactions
Administration of oral glucose tolerance test (Aim 1)
Administration of dulaglutide vs placebo (Aim 2)
Continuous glucose monitor placement (Aim 1, Aim 2, 
updated Aim 2)


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 4 of 30
Protocol Version: Version 7.0 10/08/2024
Study Population
Patients without a known history of diabetes with 
known risk factors for dysglycemia (age >45 years, 
BMI ≥28 kg/m2) undergoing general or vascular 
surgery.
Sample Size
165
Study Duration for 
individual participants
Up to 14 days (depending on length of hospitalization)
Study Specific 
Abbreviations/ Definitions 
CRC: clinical research center
CGM: continuous glucose monitor
DM: diabetes mellitus
GLP-1 RA: glucagon-like peptide-1 receptor agonist
OGTT: oral glucose tolerance test
SH: stress hyperglycemia
Funding Source (if any)
NIH/NIDDK
2. Objectives
Stress hyperglycemia, 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. The 
underlying pathophysiology remains un-explored. 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, we propose a prospective study 
investigating clinical, metabolic and inflammatory/oxidative stress biomarker profiles leading to 
SH. We 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, our initial 
second aim was 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. We also planned to 
explore the role of beta-cell function, insulin resistance, and inflammation on the pathogenesis 
of stress hyperglycemia. However, given safety concerns regarding administration of GLP-1 RA 
medications in the perioperative period, enrollment for this aim was discontinued prior to 
study completion.
There is increasing data surrounding the utility of CGM in identifying underlying dysglycemia by 
characteristic glucose control patterns and associations with longer term clinical outcomes (e.g. 
development of diabetes, cardiovascular risk). To our knowledge, there is no current data on 
how CGM may be used to determine perioperative dysglycemia risk in patients without 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 5 of 30
Protocol Version: Version 7.0 10/08/2024
diabetes. We will analyze preoperative CGM data to better define pre-existing glycemic control 
patterns (profiles) associated with the development of SH. The predictive capability of CGM 
profiles will be compared to traditional assessments of dysglycemia (e.g. OGTT, HbA1c).
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) [DISCONTINUED], and 3) determine how preoperative CGM data profiles 
may be utilized to identify unique groups at risk for SH [UPDATED AIM 2]. 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 updated Aim 2). Prior to discontinuation, 
patients were invited to participate in the interventional trial for prevention of SH with 
dulaglutide (Aim 2) if they met 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. Previously, those patients with OGTT or lab results consistent 
with a diagnosis of prediabetes or newly diagnosed diabetes were asked if they would like to 
participate in Aim 2. Patients consenting to participate in Aim 2 were randomized to receive a 
subcutaneous injection of dulaglutide 0.75 mg or placebo during the CRC visit. Blinded CGM will 
be used to follow glycemic control parameters postoperatively during surgical admission. 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.
Data from this study will help to understand the underlying mechanisms leading to stress 
hyperglycemia and explore if dulaglutide and other GLP-1 RA may help prevent stress 
hyperglycemia in surgical patients. We will also explore characteristic CGM patterns indicative 
of SH risk in non-diabetic patients undergoing general surgery.
Aim 1: To fully characterize preoperative glycemic control and prospectively determine 
clinical, metabolic, and inflammatory biomarker profiles associated with SH.
1a. To examine clinical, metabolic and inflammatory biomarker characteristics associated 
with SH in individuals at high risk for dysglycemia undergoing general and vascular surgery. 
We will conduct a prospective cohort study in patients without a known history of DM with 
known risk factors for underlying dysglycemia (age >45 years, BMI ≥28 kg/m2)1,2 undergoing 
major general or vascular surgery. We will analyze pre- and postoperative clinical, metabolic 
and inflammatory biomarkers to determine profiles predictive of SH (glucose >140 mg/dL), 
create a risk stratification model, and explore potential mechanisms of SH.
1b. To determine the timing, duration and severity of SH by CGM and its association with 
alterations in inflammatory/oxidative stress biomarkers. Enrolled patients will have a CGM 
sensor placed preoperatively and continued during surgical hospitalization to monitor glucose 
levels. CGM data will be analyzed for the degree of hyperglycemia, time in target glucose range 
(70-140 mg/dL) and time in hyperglycemia (>140 mg/dL).


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
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Protocol Version: Version 7.0 10/08/2024
1c. To explore the relationship of the duration and severity of SH with perioperative 
complications. CGM data as above will be analyzed and correlated with data on a composite of 
hospital complications to determine associations between SH and postoperative outcomes. 
Hypothesis: We hypothesize that individuals with preoperative dysglycemia, including reduced 
insulin secretion and sensitivity, and altered inflammatory/oxidative stress markers will be more 
likely to develop SH. Those with high-risk profiles will experience more severe and prolonged SH, 
and a higher risk of complications.   
Aim 2 [DISCONTINUED]: To conduct a randomized controlled pilot study to determine if single 
dose administration of dulaglutide can improve perioperative glycemic control in high-risk 
subjects. We propose a pilot, randomized, placebo-controlled trial to include 80 high-risk 
subjects identified in Aim 1 with OGTT and/or HbA1c results indicative of pre-DM or DM.
Hypothesis: We hypothesize that treatment with dulaglutide will improve the time within the 
optimal glucose range during the perioperative period in high-risk individuals with prediabetes 
and newly diagnosed diabetes.
Aim 2 [UPDATED]: To determine patterns of preoperative glycemic control by CGM that are 
associated with SH. 
a) To identify preoperative CGM profiles associated with postoperative SH. Short-term (<2 
weeks) preoperative CGM data will be used to define and classify CGM profiles indicative 
of different levels of SH risk. Preoperative CGM data will be analyzed using CGM metrics 
(e.g. time-in-range [TIR, 70-140 mg/dL], GV) and machine learning methods to identify 
characteristic glycemic control patterns.
b) To compare the predictive value of preoperative CGM profiles with traditional metrics 
of underlying dysglycemia. Performance of CGM profiles in estimating postoperative SH 
risk will be compared to the performance of OGTT and HbA1c results obtained in Aim 1.
Characterization of preoperative CGM profiles predictive of SH will provide a novel and practical 
method for identification of high-risk patients and guidance for glucose monitoring in the 
perioperative period.
3. Background/Significance
Inpatient and perioperative stress hyperglycemia: Approximately 30% of non-diabetic 
patients undergoing surgery will develop stress hyperglycemia (BG >140 mg/dl) with 
most of them requiring insulin therapy during the perioperative period.3-7 Previous 
studies indicate that the development of stress hyperglycemia in non-diabetic patients 
is associated with worse clinical outcomes when compared to patients with a known 
history of DM.8-14 In patients undergoing general surgery, stress hyperglycemia is 
associated with up to a 4-fold increase in complications and a 2-fold increase in death 
compared to patients with normoglycemia.1,15,16
Our preliminary data through a retrospective database analysis of glycemic control and hospital 
outcomes in 1,971 consecutive patients with preoperative normoglycemia (preoperative 
BG<140 mg/dl) at 4 university-affiliated hospitals showed an increase in hospital complications 
(Figure 1) and mortality (Figure 2) in patients developing stress hyperglycemia.  Of them, 415 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 7 of 30
Protocol Version: Version 7.0 10/08/2024
patients (21%) developed ≥ 1 episode of BG 140-180 mg/dl and 206 patients (10.5%) had a BG > 
180 mg/dl within 48 hours after surgery. Compared to patients with normoglycemia, patients 
with stress hyperglycemia had a longer length of hospital stay (LOS) and significantly higher 
rates of complications and mortality (all, p<0.001). After adjusting for age, gender, BMI, race 
and Charlson comorbidity score, compared to patients with normoglycemia, those with 
postoperative BG 140-180 mg/dl had higher odds ratios (OR) for both complications [1.68 (1.15 
– 2.44)] and mortality [1.72 (0.42-7.1)]. The OR for complications and mortality in patients with 
postoperative BG >180 mg/dl were 3.46 (2.24-5.36) and 6.56 (2.12-20.27), respectively. These 
data emphasize the importance of gaining further understanding into the pathophysiology of 
stress hyperglycemia, as well as how its prevention may lead to improvement in hospital 
outcomes. 
Mechanisms of Stress Hyperglycemia: Several contributing factors are known to favor the 
development of hyperglycemia in the hospital; however, its underlying pathophysiology 
remains un-explored. Acute illness raises levels of counterregulatory hormones (cortisol, 
glucagon, epinephrine, growth hormone), which increases hepatic glucose production, 17,18 
diminishes insulin action in peripheral tissues and results in relative insulin deficiency17-19 
leading to hyperglycemia.  Counterregulatory hormones in the setting of stress leads to 
enhanced lipolysis and increasing fatty acid (FFAs) concentrations 20,21 that leads to a dose-
dependent insulin resistance in peripheral tissues 22 and  increase hepatic glucose output. 23,24  
Furthermore, hyperglycemia leads to generation of reaction oxygen species (ROS), lipid 
peroxidation, elevated cardiovascular inflammatory markers, such as tumor necrosis factor-
alpha (TNF-α), interleukin (IL)-6, and IL-1, which increases insulin resistance and alters the 
system. 25-28
Hospital use of continuous glucose monitors (CGM). CGMs are currently FDA-approved in the 
outpatient setting to complement information obtained from standard self-monitored blood 
glucose (SMBG) testing and to aid in detecting hyper- and hypoglycemic episodes in patients 
with known DM.29,30 CGMs provide an estimated capillary BG level through direct measurement 
Figure 1. Unadjusted and adjusted composite of 
complications in stress hyperglycemia.
Figure 2. Unadjusted and adjusted mortality rates in 
stress hyperglycemia.


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 8 of 30
Protocol Version: Version 7.0 10/08/2024
of interstitial glucose levels every 5-15 minutes. Several available CGM systems have achieved 
accuracy levels determined by mean absolute relative difference (MARD) values of <10% and no 
longer require confirmation testing or calibration with fingerstick glucose testing prior to 
making DM treatment decisions.31-33 Few randomized controlled trials have been published on 
the safety and efficacy of CGM technology in the hospital.34-37 In a recent study of hospitalized 
patients with DM, Gomez and Umpierrez reported increased detection of both hypo- and 
hyperglycemic events with the use of CGM compared to the standard of care POC BG testing in 
insulin treated patients with DM.38 A recent panel of experts in inpatient diabetes care reported 
that CGMs are more effectively identifying trends toward hypoglycemia and hyperglycemia that 
may allow for better and safer management of patients with hyperglycemia, including those 
with SH.37 More recently, several studies have reported on the meaningful use of CGM 
technology in the inpatient setting, assessing glycemic control outcomes using time within 
target glucose range in patients with DM.39,40 
Our previous data indicates that SH is most likely to develop within the first 24-48 hours 
postoperatively (Figure 4); however, the precise onset and duration of SH remains unknown 
given the intermittent nature of POC BG testing. The use of CGMs to study SH will address this 
important gap in knowledge and determine the actual onset, duration, and severity of SH while 
providing information on glycemic control patterns in the perioperative period.
Effects of GLP-1 RA and pharmacokinetics of dulaglutide. GLP-1 is an incretin hormone 
secreted in the gut in response to meal ingestion, targeting multiple tissues throughout the 
body. One of its main targets is the pancreatic β-
cell, resulting in increased insulin secretion and 
inhibition of glucagon production.41 Additionally, 
GLP-1 has been shown to delay gastric emptying 
and promote satiety and weight loss through its 
direct effect on the autonomic nervous system, 
as well as through a centrally-mediated decrease 
in appetite via the hypothalamus.42-44 Previous 
studies have shown cardiovascular (CV) 
benefits45,46 mediated through both effects on 
CV risk factors (weight loss, reduction in blood 
pressure, improved lipid metabolism), as well as 
direct effects on the vascular endothelium  
(vasodilation, decreased inflammation).46,47 
Dulaglutide is a fusion protein of a GLP-1 
analogue and a modified IgG Fc fragment, 
leading to a longer acting, relatively flat 
insulinotropic profile with increased plasma 
half-life suitable for once-weekly administration.48 Previous trials have demonstrated improved 
glycemic control with both available doses of dulaglutide (0.75 mg and 1.5 mg administered 
once-weekly) when compared to other antihyperglycemic agents.49-51 Phase 1 
pharmacodynamic analysis in non-diabetic participants demonstrated median maximum 
plasma concentrations of dulaglutide between 24-48 hours after single-dose administration.52 
Figure 1. From: Barrington et al. Diabetes Obes Metab. 2011
May;13(5):434-8. “Figure 2. Insulin levels (A) and the ratio of insulin
to glucose (B) were plotted vs. time following stepped glucose 
infusion in healthy subjects.”


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 9 of 30
Protocol Version: Version 7.0 10/08/2024
Further evaluation with stepped glucose infusion 3 days after dulaglutide administration 
revealed a dose-dependent rise in insulin secretion (Figure 3) and associated decline in serum 
glucose concentration.52 Similar to other GLP1-RA, the most frequent adverse effects with 
dulaglutide were gastrointestinal and dose-dependent, with lower rates compared to short-
acting GLP-1 RA.52,53 The above data suggest that a single subcutaneous dose of 0.75 mg of 
dulaglutide will increase glucose-dependent insulin secretion and decrease glycemic excursions 
which may prove effective in preventing the development of stress hyperglycemia.
Glycemic control profiles and underlying dysglycemia risk. Over the past several years, there 
has been a growing interest in understanding CGM data in populations without diagnosed 
diabetes. With the amount of glucose data obtained by CGM, there is an opportunity to detect 
early patterns of dysglycemia that may not be captured by more traditional methods (e.g., 
OGTT, HbA1c).54-57 Recent studies have demonstrated the potential predictive value of CGM to 
detect patterns of glucose dysregulation associated with pre-diabetes, diabetes and 
cardiovascular risk.58-60 Similarly, emerging data from studies in pregnant women has suggested 
that early CGM patterns are useful in predicting the development of gestational diabetes and 
neonatal outcomes.61,62
In the perioperative period, interest in CGM has mainly surrounded use of real-time glucose 
monitoring for people with diabetes. To our knowledge, there is no current data on how CGM 
may be used to determine perioperative dysglycemia risk in patients without diabetes. 
Furthermore, there is no data on the duration of preoperative CGM wear needed to detect 
meaningful patterns of glucose dysregulation associated with SH. Preoperative assessments of 
dysglycemia have historically relied heavily on HbA1c testing, though there is concern that this 
metric may fall short in detecting dysglycemia particularly among some racial ethnic minority 
populations.63,64 However, performing more comprehensive preoperative analyses, including 
OGTT, raises questions of feasibility and practicality for patients and providers within the 
current preoperative care model. Understanding the predictive value of shorter duration 
preoperative CGM wear for anticipating development of SH presents an opportunity to change 
the paradigm of preoperative screening practices. 
4. Study Endpoints 
Primary outcome (Aim 1): 

Incidence of SH in a population at high-risk for perioperative dysglycemia
Secondary outcomes (Aim 1):

Differences in baseline insulin secretion and sensitivity between patients with and without 
SH.

Differences in pre- and postoperative inflammatory and oxidative biomarker levels between 
patients with and without SH.

Average onset and duration of SH by CGM (glucose >140 mg/dL) during the postoperative 
period.

Mean and maximum daily glucose values (as measured by both POC glucose testing and 
CGM data).

Identification of phenotypes and demographics associated with the development of SH.


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 10 of 30
Protocol Version: Version 7.0 10/08/2024

Differences in clinical endpoints between patients with and without SH, including: total daily 
insulin dose, length of hospital stay, ICU transfer, hospital readmission and emergency room 
visit after discharge 

Individual and 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).
Primary outcome (Aim 2): 

Time in target glucose range (70-140 mg/dL) as determined by CGM during the 
postoperative period in high-risk patients undergoing major general and vascular surgery. 
Secondary outcomes (Aim 2): 

Time-in-hyperglycemia (>140 mg/dL and >180 mg/dL).

Percentage of time in hypoglycemia (glucose <70 mg/dL, <54 mg/dL, and <40 mg/dL) by 
CGM.

Glycemic variability (as determined by coefficient of variation and standard deviation).  

Average onset and duration of SH during the postoperative period by CGM data.

Mean and maximum daily glucose values (as measured by both POC glucose testing and 
CGM).

Perioperative insulin requirements (total daily insulin dose).

Differences in postoperative inflammatory and oxidative stress biomarker levels.
Primary outcome (Updated Aim 2): 

Characterization of glycemic control profiles (groups) indicative of SH risk.
Secondary outcomes (Updated Aim 2):

Preoperative CGM metrics (time in ranges [TIR, TAR, TBR], %CV, MAGE) associated with SH.

Minimum preoperative CGM data necessary for determination of pattern association with 
SH.

Concordance of high-risk CGM profiles with established measures of dysglycemia (OGTT, 
HbA1c).
5. Study Intervention/Investigational Agent
Both aims of this study will employ the use of a blinded CGM (Abbott FreeStyle Libre 
Pro, FDA-approved) that will capture continuous glucose data. This data will not be 
visible to providers or used for clinical care. The device will be handled and managed by 
the study team only. The CGM sensor will be placed at the preoperative study visit in 
the CRC by an approved study team member. 
The interventional aim [Aim 2, DISCONTINUED] of this study involved the administration 
of dulaglutide, a once weekly injectable GLP-1 RA approved for the treatment of type 2 
diabetes, within 72 hours prior to surgery to determine if single dose administration of 
this agent can prevent the development of stress hyperglycemia. There is an IND 
exemption for dulaglutide for this study. The dulaglutide was handled by the Emory and 
Grady research pharmacies. Administration of dulaglutide occurred preoperatively at 
the CRC and was administered by a CRC nurse (study team blinded).


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
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Protocol Version: Version 7.0 10/08/2024
The standard of care for management of hyperglycemia in the hospital is insulin 
therapy. During hospital admission, should any participant develop elevated blood 
glucose values, they will receive standard-of-care insulin therapy as per hospital 
protocol (outlined below in Research Procedures section). 
6. Procedures Involved
A total of 245 patients were planned for enrollment in order to have 80 patients from this 
group randomized to participate in Aim 2 (Figure 4). This number has been updated to a 
planned enrollment of 165 patients (Aim 1 and Updated Aim 2) since the discontinuation of the 
clinical trial aim (Aim 2). 
Patients will be consented and randomized at their CRC visit for OGTT and CGM placement. 
Participants will undergo a 2-hour 75g OGTT with blood samples measured at 6 timepoints 
during the 2 hour timeframe (at 0, 15, 30, 60, 90, 120 minutes). 
Those with OGTT or HbA1c results revealing presence of pre-DM or newly diagnosed DM were 
previously asked to participate in Aim 2. Patients consenting to participation received a single 
subcutaneous injection of dulaglutide or saline placebo (within 72 hours prior to planned 
surgical intervention). Both study team and patient were blinded to randomization with the 
assistance of the Research Pharmacist and CRC nurse.
Preoperative glycemic control and inflammatory/oxidative stress biomarkers will be collected 
as described in Aim 1. Inpatient glycemic control parameters will be followed with POC glucose 
testing (standard-of-care) and blinded CGM.
Prior to admission:

Patients will be invited to participate prior to or at their preoperative clinic visit. Informed 
consent will be obtained by designated study personnel.

Within 72 hours preoperatively: 
Aim 1, Aim 2, Updated Aim 2
- Oral glucose tolerance testing (OGTT) to assess insulin secretion and action, and for the 
presence of dysglycemia or diabetes.
- Placement of blinded CGM sensor (Abbot FreeStyle Libre Pro).
- Collection of blood samples for inflammatory/oxidative stress biomarkers and hemoglobin 
A1c.
Aim 2 only [DISCONTINUED]
- Subcutaneous injection of dulaglutide or saline placebo.

Patients are liable to have surgery dates rescheduled for varying reasons after the study 
preoperative clinic visit. In the event that patients have their surgery dates changed after 
the preoperative clinic visit to a later date that falls out of the window period of 72 hours 
before surgery, the patient will only be retained to complete the study if the new date is 
within 3 months from the day of the study preoperative clinic visit. This category of patients 
will have their blinded CGM sensor retarted within 72hours of the new surgery date but the 
OGTT procedure will not be repeated. However,if the new surgery date falls outside a 
duration of 3 months from the study preoperative clinic visit, the patient will be excluded 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
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from the study as a screen failure. They may choose to participate in the study, but will be 
consented again and undergo full study procedures. 
During hospital admission:

Standard-of-care POC capillary BG will be measured prior to surgery, hourly during surgery 
and in the recovery room. After the patient is transferred to regular floor, POC BG testing 
will be performed as per hospital protocol. 

Patients who develop SH postoperatively will be treated with insulin as per institution 
protocol (standard of care, outlined below). 

The CGM sensor placed before surgery will be continued during the hospital stay (up to 14 
days in total, life of sensor). 
Inflammatory and oxidative stress biomarkers will be measured at 48-72 hours postoperatively. 
Initiation of “rescue therapy” with subcutaneous insulin. Patients with fasting and/or premeal 
BG >180 mg/dl will receive coverage with sliding scale insulin (supplements).  Those with 2 
consecutive fasting and/or premeal BG >180 mg/dl or with average daily BG >180 mg/dl, will be 
started on basal (detemir or glargine) insulin once daily as per Emory protocols (see below). 
Supplemental (correction) insulin. Supplemental (lispro or aspart) insulin will be administered 
following standard “sliding scale” protocol outlined below.
Supplemental Sliding Scale Insulin (number of units) - administer dose before meals.  
Blood Glucose
 
(mg/dl)
                  Sensitive
           Usual
     Resistant            
181-220
2
   3
4
221-260
3
   4
5
261-300
4
   5
6
301-350
5
   6
7
351-400
6
   7
8
> 400
7
   8
9
______________________________________________________________
** Check appropriate column below and cross out other columns
At bedtime, give according to Bedtime Supplemental Sliding Scale Insulin starting at BG >220 
mg/dl:
Blood Glucose
 
(mg/dl)
                  Sensitive
           Usual
     Resistant            
221-260
1
   2
3
261-300
2
   3
4
301-350
3
   4
5
351-400
4
   5
6
> 400
5
   6
7
______________________________________________________________


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** Check appropriate column below and cross out other columns
The numbers in each column indicate the number of units of aspart or lispro insulin per dose. If 
a patient is able and expected to eat all or most of his/her meals, supplemental insulin will be 
administered before each meal following the “usual” column dose.  Supplemental insulin at 
bedtime = half of premeal insulin dose at BG > 220 mg/dl.  If a patient is not able to eat (NPO), 
supplemental insulin will be administered every 6 hours (6-12-6-12) following the “sensitive” 
column dose. 
Basal insulin therapy with Detemir or Glargine:

Patients with average BG between >180 mg/dl= start detemir or glargine at 0.2 units per 
kg weight per day.

Patients with GFR <50 or over the age of 70= start detemir or glargine at 0.1 units per kg 
weight per day.

Basal insulin will be given once daily, at the same time of day.  
Insulin adjustment.  The total detemir or glargine daily insulin dose will be adjusted as follows: 

Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous 
day: no change 

Fasting and pre-meal BG between >180-240 mg/dl: increase detemir or glargine dose by 
10% every day

Fasting and pre-meal BG >241 mg/dl: increase detemir or glargine dose by 20% every 
day 

Fasting and pre-meal BG <100 mg/dl: reduce detemir or glargine by 20% or stop if 
patient is already on less than 0.1 units/kg of body weight
7. Data and Specimen Banking
The study coordinator and/or investigator will enter baseline and daily data into data collection 
paper forms and an electronic database provided by the Emory Research Information 
Technology Department (REDCap). Baseline data will include demographics/history form 
(subject gender, date of birth, ethnicity, dates of hospitalization and operation, comorbid 
conditions, body weight, BMI, and type of surgery). Daily information will be collected on 
treatment (insulin dosage, antibiotics), nutrition support, BG and laboratory values, hospital 
complications and adverse events, and length of ICU and hospital stay.
Participants in both aims of the study will have their blood samples and data stored for future 
research and use by Dr. Davis and designated study team for further investigation into the 
mechanisms of stress hyperglycemia and other aspects of glycemic control. Samples will be 
stored in a secured freezer in the study team’s designated lab with restricted access 
indefinitely.
8. Sharing of Results with Participants


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This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
-
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals.  Data from this study may 
be requested from other researchers up to 12 months after the completion of the primary 
endpoint by contacting the Principal Investigator.  
-
Dr. Davis will ensure proper registration of the clinical trial and that results are submitted to 
“Clinicaltrials.gov”, per Emory internal policy and as stated in the program. Data obtained 
from the observational study (Aim 1, Updated Aim 2) and clinical trial (Aim 2) will be 
presented at national and local meetings, in a de-identified format. All final peer-reviewed 
publications will be placed in the digital archive in PubMed Central.  
9. Study Timelines
The duration of active study participation for each individual participant will be up to a 
maximum of 14 days, depending on their length of surgical hospitalization. We 
anticipate completion of enrollment for all Aims (Aim 1, Aim 2, Updated Aim 2) over a 
total of 5 years.
10. Inclusion and Exclusion Criteria
Inclusion criteria (Aim 1, Updated Aim 2):

Men and women between the ages of 45 and 80 years undergoing non-cardiac general or 
vascular surgery 

BMI ≥28 kg/m2 without a previously known history of DM 
Exclusion criteria (Aim 1, Updated Aim 2):

Patients prescribed or taking antihyperglycemic medications

Patients undergoing cardiac surgery or patients anticipated to require ICU care

Patients with Hemoglobin <10 gm/dL

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
Inclusion criteria (Aim 2) [DISCONTINUED]:
   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. 


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   BMI ≥28 kg/m2 and pre-DM or DM by OGTT or HbA1c. 
Exclusion criteria (Aim 2) [DISCONTINUED]:

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)
11. Local Number of Participants
We plan to recruit a total of 165 patients for this prospective study, enrolling at least 100 
patients with adequate CGM data for analysis in Updated Aim 2. No further enrollment will 
occur for the clinical trial (Aim 2).
12. Recruitment Methods
All proposed aims will take place at Grady Memorial Hospital and Emory University Hospital. 
There will be no other collaborating sites.  All patients scheduled to undergo general or vascular 
surgery will be considered potential candidates in this study. We will also recruit study 
participants scheduled for perioperative appointments via the Emory Telehealth services. 
A partial HIPAA waiver will be obtained to review electronic health records, scheduling logs and 
inpatient admission rosters to identify potential study participants undergoing perioperative 
evaluation. Patients will be approached and informed of this study by a member of the study 
team or their treating surgical team prior to (by telephone) or during their preoperative clinic 
evaluation prior to scheduled surgery. Potential participants interested in study participation 
will be invited over and consented at an in-person visit (CRC) before administering study 
procedures.  
13. Withdrawal of Participants

If a subject becomes incarcerated during the study, develops a serious medical or 
psychiatric illness during the study, they will be disqualified from participating further in the 
study. If a participant wishes to discontinue participating in the study, they will be able to 
withdraw at any time by informing the study team. Study data collected up until participant 
withdrawal will remain part of the data for this study. This information continues under the 
Certificate of Confidentiality. Patients who have their surgery rescheduled to a later date 
that falls outside a duration of 3 months from the study preoperative clinic visit will be 
excluded from the study as a screen failure. 
14. Risks to Participants


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Risks associated with use of dulaglutide: Dulaglutide is a widely used antidiabetic agent with a 
proven safety profile.  The major adverse events most frequently reported with dulaglutide 
0.75 mg weekly dosing are mainly gastrointestinal; nausea (12.4%), vomiting (6%), and diarrhea 
(8.9%), abdominal pain (6.5%), decreased appetite (4.9%), dyspepsia (4.1%), and fatigue (4.2%). 
In most cases nausea is mild and transient with less than 5-10% discontinuation of the drug due 
to side effects. In our preliminary studies with daily administration of the short-acting 
exenatide, less than 10% of patients developed nausea and none out of over 100 patients in our 
pilot study discontinued the drug due to GI side effects. Dulaglutide, like other GLP-1 RA, is a 
rare cause of pancreatitis.
New information regarding the risk of GLP-1 RA use in the perioperative period includes 
concern for an increased risk of gastric aspiration during anesthesia procedures. For this reason, 
Aim 2 has been discontinued.
Risk of hyperglycemia and hypoglycemia:  Patients with perioperative hyperglycemia remain at 
risk for increased rates of complications, and those developing blood glucose levels >180 mg/dl 
will receive insulin therapy. The risk of hypoglycemia with the use of dulaglutide is low, nearly 
comparable to placebo. There is an increase in hypoglycemia risk with the use of insulin. The 
number of mild and severe hypoglycemic episodes and clinical consequences (neurological and 
cardiovascular) will be analyzed. 
Risk of oral glucose tolerance testing (OGTT):  The oral glucose solution used for the 75g OGTT 
carries minimal risk and is used commonly to diagnose diabetes. Potential rare adverse 
reactions: nausea, vomiting, abdominal bloating, and headache. In addition, there is a rare 
incidence of hypoglycemia.
Risk of continuous glucose monitor (CGM) use: No major risks are anticipated with the use of 
the CGM device. Pain and bleeding with insertion is minimal. Skin irritation may occur in 
relation to the adhesives. Other potential risks of using CGM described in the literature include 
unrealistic glycemic control expectations, and effects of continued alerts and alarms; these 
potential drawbacks will not be associated with the use of the FreeStyle Libre Pro CGM given 
results will be blinded to patients and nursing staff.
Treatment of hypoglycemia: Hypoglycemia, defined as a BG <70 mg/dl will be treated by a 
standard hypoglycemia protocol available at the institution.
Phlebotomy: Risks associated with phlebotomy and IV insertion are low and include small 
amounts of pain, possible bruising, swelling, redness, and rarely an infection at the site or 
fainting.  A total of ~60 ml of blood will be obtained during the pre- and postoperative lab 
collections. 
15. Potential Benefits to Participants
Potential Benefit: Patients with stress hyperglycemia experience more complications and higher 
rates of mortality. For Aim 1 and Updated Aim 2, There is no direct benefit to the study subject 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
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Protocol Version: Version 7.0 10/08/2024
for participation in this prospective observational trial. However, the study may increase the 
subjects’ awareness and identify early abnormalities in glucose metabolism. 
For Aim 2 [DISCONTINUED], there is a potential for direct benefit to the study subject for 
participating in the study should dulaglutide be effective in the prevention of stress 
hyperglycemia.
Risk of anticipated benefit: The overall risk associated with the observational aims (Aim 1 and 
Updated Aim 2) of this study is low. 
We have discontinued Aim 2 that involves the administration of dulaglutide due to the 
potential risk of gastric aspiration during anesthesia. We will take extensive precautions to 
reduce risks associated with CGM use and phlebotomy and ensure that subjects’ data remains 
confidential.  Although the subject may or may not benefit directly from this study, this study 
can yield important information regarding patients who may be at risk of developing 
perioperative hyperglycemia, leading to poor clinical outcomes. Therefore, the risk to benefit 
ratio favors conducting Aim1 and Updated Aim 2 of this study.
16. Compensation to Participants
Study participants will be given an incentive for the time and effort required to be a part of this 
study.  For study Aims 1 and Updated Aim 2, 165 participants will undergo oral glucose 
tolerance testing (OGTT) at the Clinical Research Center and will wear a CGM during surgical 
admission. They will receive compensation of ($50) at completion of their CRC study visit and 
an additional $25 at hospital discharge. 
Those participants enrolled previously in Aim 2 [DISCONTINUED] and completing a preoperative 
OGTT, CGM sensor wear and dulaglutide or placebo injection received ($50) at completion of 
their CRC study visit and were compensated an additional $50 at the time of hospital discharge.
17. Data Management and Confidentiality 
Statistical Analysis Plan: 
Assessment of baseline clinical characteristics. Preoperative information regarding 
demographics, anthropometrics, medical, family and social histories will be obtained through 
direct patient interview and review of the electronic medical records.
Assessment of insulin secretion and action during OGTT. Plasma glucose and insulin response 
during a 75g OGTT reflect the ability of pancreatic β-cells to secrete insulin, as well as the 
sensitivity of tissues to insulin action.65-71 We propose using a battery of indices calculated from 
the OGTT to assess insulin dynamics including: a)  insulin secretion capacity from pancreatic β-
cell by measurement of fasting insulin (FI), calculation of the Insulinogenic Index72 and the 
Corrected Insulin Response at 30 minutes (CIR30)73  b) whole body insulin sensitivity through 
use of the reciprocal of the Homeostasis Model Assessment of insulin resistance (1/HOMA),70 
Quantitative Insulin Sensitivity Check Index (QUICKI)65,70,71 and the Composite Insulin Sensitivity 
Index (CISI).74  During the OGTT, blood samples will be obtained at six timepoints: 0, 15, 30, 60, 


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90, and 120 minutes. OGTT will be performed at Emory University and Grady Hospital Clinical 
Research Centers.
Formulas of Insulin Secretion:
CIR30 = I30 x 100 / [G30 x (G30 - 70)]
               (I30 = Insulin at 30 minutes, G30 = glucose at 30 minutes)
Insulinogenic Index =  __I30 – FI μU/mL___
                                          G30 – FBG mg/dL
Formulas for Whole Body Insulin Sensitivity:
CISI =    
________________________________10000______________________________
      Square Root [(FI x FBG) x (mean insulin (0-120 min) x mean glucose (0-120 min)
QUICKI = (I/log FI μU/mL) + log FBG
Assessment of inflammatory and oxidative stress markers. Serum inflammatory and oxidative 
stress markers measured preoperatively and 48-72 hours postoperatively will include: plasma 
cortisol, free fatty acids (FFA), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-
alpha (TNF-α), adiponectin, and thiobarbituric acid reactive substances (TBARS).
Assessment of perioperative glycemic control by CGM. Glycemic control will be 
assessed by POC testing (standard-of-care) and blinded CGM. Placing the Abbott 
FreeStyle Libre Pro CGM sensor preoperatively will allow for stabilization and calibration 
of estimated glucose levels prior to surgical intervention. Patients will wear the CGM 
sensor during surgical hospitalization, up to 14 days in total (lifetime of CGM sensor). 
The study team, patients and nursing staff will remain blinded to CGM values, 
continuing to provide standard-of-care blood glucose monitoring through POC testing.  
Aim 1a: We will obtain information on patient demographics, as well as glucose and insulin 
levels during OGTT to estimate insulin sensitivity and β-cell function. The primary outcome for 
Aim 1a is the binary outcome indicating whether or not SH has occurred. 
We will first summarize collected clinical characteristics and metabolic and inflammatory 
biomarkers over all subjects and by the status of SH occurrence, using standard summary 
statistics, such as mean+/- standard deviation (SD), median and (interquartile) range, count and 
relative frequency. Next, we will assess the marginal association of each of the potential SH 
predictors with the occurrence of SH. To this end, we will apply t-tests or nonparametric 
Wilcoxon tests when the potential predictor is continuous and apply Chi-square or Fisher’s 
exact tests when the potential predictor is discrete. Following the marginal association 
analyses, we will build multivariate models for the occurrence of SH based on logistic regression 
models to develop a risk prediction tool. To select variables included in the final predictive 
model, we will consider three strategies: (i) using classic forward or backward model selection 
procedures based on criterion such as Akaike information criterion (AIC) or Bayesian 
information criterion (BIC); (ii) employing regularized logistic regression based on Lasso, 


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                                     An Observational and Randomized Controlled Pilot Trial
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adaptive Lasso, or elastic-net penalty to simultaneously achieve variable selection and 
shrinkage estimation; iii) utilizing the random forest technique to provide intuitive illustrations 
of the importance of each potential predictor and obtain simple decision rules for predicting 
the occurrence of SH. We will evaluate and compare the SH prediction rules derived from the 
approaches described above using accuracy measures, such as Yoden’s index for receiver 
operating characteristic (ROC) and different types of C-statistics. The assessment of these 
accuracy measures may be conducted via K-fold cross validations.
Aim 1b: We will summarize various temporal features of glucose patterns during the hospital 
stay (e.g. duration of SH, glycemic variability) using CGM data. The primary outcome for Aim 1b 
is the percentage of time with glucose >140 mg/dL, as determined by CGM data. 
Similar to the analysis plan for Aim 1a, we will first calculate summary statistics, followed by 
marginal association analysis between the percentage of time with glucose >140 mg/dL and 
each potential risk factor. Then we will conduct multivariate analyses based on linear 
regression. We will perform variable selection following the first two strategies outlined for Aim 
1a. We will assess the multivariate models based on predictive measures such as apparent error 
or absolute prediction error, possibly obtained from cross-validation. For the secondary 
outcome regarding the timing of SH, we will consider formal survival analysis to summarize its 
distribution by Kaplan-Meier curves and perform univariate and multivariate analyses based on 
Cox regression models or censored quantile regression models. 
Aim 1c: The primary outcome for Aim 1c is the binary outcome indicating the occurrence of any 
perioperative complications. We will compare the duration and severity of SH between the 
patient groups with and without any perioperative complications based on t-tests or Wilcoxon-
tests. Further multivariate analyses will be conducted similarly to those described for Aim 1a.
Aim 2 [DISCONTINUED]: The primary outcome of Aim 2 is the proportion of time in target 
glucose range (70-140 mg/dL) by CGM. We will use nonparametric Wilcoxon tests for 
comparisons between the two treatment groups, followed by multivariate linear regressions 
that adjust for potential confounders, such as age and gender. For discrete secondary 
outcomes, we will use two-sided Chi-square tests or Fisher’s exact test to compare the primary 
outcome between the dulaglutide treatment group and the placebo group. We will also 
perform multivariate logistic or Poisson regression to estimate the difference between the two 
treatment groups while adjusting for other relevant covariates. To build an adequate 
multivariate linear or logistic regression model, we will adopt standard stepwise, backward, or 
forward model selection strategies. Standard diagnostic and model checking procedures, such 
as residual/leverage plots, deviance residual plot and Hosmer-Lemeshow test, will be applied to 
examine the fit of the final linear or logistic regression models.
The planned statistical analysis for this discontinued Aim 2 will be exploratory and include all 
patients enrolled prior to discontinuation.
Updated Aim 2: 
Assessment of CGM data adequacy. Based on preliminary estimates, adequate CGM data for 
analysis will be defined by more than12 hours of preoperative and over 24 hours of 
postoperative sensor wear with at least 70% sensor glucose data acquisition. The first 6 hours 


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of wear will be excluded to ensure sensor reading stability and to exclude glucose changes 
related to OGTT testing. 
Assessment of preoperative glycemic control by CGM. Preoperative CGM data will be assessed 
using established glycemic control metrics including: time in range (TIR, 70-140 mg/dL), time 
above range (TAR, >140 mg/dL, >180 mg/dL), time below range (TBR, <70 mg/dL, <54 mg/dL), 
percent coefficient of variation (%CV), mean amplitude of glycemic excursions (MAGE) to 
determine the association of these indices with the development of SH postoperatively.
Identification of high-risk preoperative glycemic control profiles by CGM. Clustering analysis 
techniques will be used to identify unique patterns of glycemic control associated with 
postoperative SH and define groups or participants at high risk for SH based independently on 
preoperative CGM data. 
Comparison of CGM profiles with established metrics of dysglycemia. CGM profiles associated 
with varying SH risk will be compared to metrics of dysglycemia obtained in Aim 1 (OGTT, 
HbA1c) to assess for concordance.
Sample Size and Power Calculation: 
We plan to recruit 165 patients for Aim 1, obtaining 100 patients with adequate CGM data for 
Updated Aim 2. Based on preliminary data in over 7,000 high-risk surgical patients (age >45 
years and/or BMI >25 kg/m2) at our institution without a known history of DM, preoperative 
HbA1c testing revealed normoglycemia (<5.7%) in 69%, pre-DM (5.7-6.4%) in 27.2% and newly-
diagnosed DM (≥6.5%) in 3.9% of patients.75 We anticipate higher rates of pre-DM and DM in 
our population with higher BMI (≥28 kg/m2) and the use of IFG and IGT criteria in addition to 
HbA1c for improved detection of underlying dysglycemia. 
Our preliminary data from retrospective chart review showed that 38% of non-DM patients 
with age >45 years and BMI ≥28 kg/m2 developed SH following general surgery by POC testing. 
With CGM, we anticipate a higher rate of SH detection, and assume 50% of high-risk subjects 
with underlying dysglycemia will develop SH. Our power calculations are performed 
conservatively based on multiple univariate comparisons of potential predictors, such as β-cell 
function, insulin sensitivity and inflammatory/oxidative biomarkers between patients with SH 
and without SH. A final sample size of 205 will provide 80% power to detect a mean difference 
in potential predictor equal to 0.66 times the corresponding SD, based on two-sample, two-
sided t-tests with FDR controlled under 20%. 
For Updated Aim 2, we anticipate sufficient pre-op and post-op CGM data from 100 patients. 
Considering 10 CGM features and assuming 50% rate of SH, with the sample size of 100, we 
would have 80% power to detect the effect of a CGM feature with the effect size (i.e. mean 
difference) equal to 0.75 times the corresponding SD, based on two-sample, two-sided t-tests 
and Bonferroni correction. Regarding the clustering analyses, aiming for at least 20-30 patients 
per subgroup (or cluster), the sample size of 100 would be reasonable to identify three well-
separated clusters.64


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We will compare our research endpoints between male and female subjects and will include 
sex as a covariate when building our predictive models.
Data Management and Confidentiality:
Data to be collected: Demographic information, physical exam findings during hospitalization 
such as blood pressure, weight etc.., checklist of inclusion/exclusion criteria, lab and glycemic 
control data will be collected. 
Access to identifiable private information: Only study investigators and staff will have access to 
individually identifiable private information of the study subjects. The unique study subject 
charts will be kept in a locked cabinet in the study team’s research office. An access card and 
badge are needed to enter the research office.
All subjects will be assigned a unique study identification number.  The study ID numbers linking 
to the identifiable information will be kept in a locked cabinet. All samples collected from this 
study will be stored using the unique study ID number.  Information needed for this study will 
be collected by the PI and the study coordinator. All the study team members will have 
completed and documented the appropriate human subjects training.  The nursing staff will 
perform the phlebotomy. Only approved study team members and CRC staff will have access to 
the specimens. Data and specimens will be stored indefinitely using study ID numbers in a 
secured freezer within the CRC or designated research team lab with restricted access to 
approved personnel. If specimen transport is required for certain testing, all shipment 
procedures will be handled in concordance with institution and lab safety and processing 
requirements by a member of the study team.
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health.
18. Provisions to Monitor the Data to Ensure the Safety of Participants
The Data and Safety Monitoring Plan (DSMP) will include 4 independent reviewers [Data Safety 
Monitoring Board (DSMB)] to monitor safety, treatment compliance, and clinical procedures in 
this observational study (Aim 1 and Updated Aim 2). The DSMB will meet at 6-month intervals 
and report on study progress to the IRB. 
Interim Analysis and Stopping Rules: Safety monitoring analysis will be performed every 3 
months or when half of the subjects are randomized. The trial will be stopped at the discretion 
of the DSMB if there is concerning evidence of a difference in the rate of death and/or hospital 
complications (two-sided alpha level, <0.01) between the treatment groups. 
Should the rate of mild hypoglycemia (BG <70 mg/dL) exceed 40%, or the rate of severe 
hypoglycemia (BG <40 mg/dL) exceed 20% in the treatment group, the trial will be stopped.
The DSMP outlined below will adhere to the protocol approved by the CRN Scientific Advisory 
Committee and the Emory University IRB.  An IRB-approved written informed consent will be 
obtained from each subject at entry into the study; elements of informed consent will include:  
(a) having the subject and/or guardian/proxy review the study consent form; (b) having the 
investigator(s) or study staff meet with the subject and/or guardian/proxy to review the 


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consent, confirm understanding, and answer any questions; and (c) once the investigator(s) or 
study staff are convinced that the protocol is understood and that there is agreement to 
participate, having the consent signed.   
Research meetings will be held regularly (at least monthly during the first three months of 
study initiation and bimonthly from then on) where study progress will be discussed to include 
enrollment numbers, any unanticipated issues with protocol logistics or adherence, adverse 
events, potential risks, need for protocol modifications, compliance with Clinical Trial Protocol 
requirements and any emergent problems. Those not attending the meeting will be updated via 
email regarding the matters discussed during the meeting. 
The PI and other study team members will review all data collection forms for completeness 
and accuracy of the data as well as protocol compliance.  The PI will review this protocol on a 
continuing basis for subject safety and include the results of the review in annual progress 
reports submitted to the DSMB.  The results of the review will also be included in annual 
progress reports submitted to the local institutional IRB, as required.
Patient Monitoring: will be performed by the PI, Co-Investigators, and Research Coordinator(s).
Patient safety data examination, monitoring procedures/oversight:  

All adverse events (AEs) will be graded as to their attribution (unrelated to protocol, or 
possibly, probably, or definitely related to protocol).  

Any AE that is reported to either the site investigator or designated research associates 
by a study subject or medical staff will be documented as per IRB protocol.  

This study will be entered into the Emory REDCap computerized database system to 
permit tracking of adverse events. 
o
This system will then be used by all investigators to report “expected” AEs 
(predefined AEs which will be monitored over the course of the trial – see 
below), “observed” AEs (AEs which occur but which may or may not have been 
anticipated), and all serious adverse events (SAEs).  
o
Serious adverse events are predefined as:  any experience that suggests a 
significant hazard, such as events which: a) are fatal, b) are life threatening, c) 
result in permanent disability, d) require inpatient hospitalization, or e) involve 
cancer, a congenital anomaly, or drug overdose.  
The standard Emory IRB reporting guidelines for AE and SAE reporting will be followed.  The site 
investigators and staff will enter all AEs into the Emory REDCap database, and evaluate the 
SAEs.  The investigators and staff will track and summarize AE frequency, severity, and 
relatedness at a frequency appropriate to ensure subject safety. 
A periodic (annual unless otherwise specified) report of AEs with a frequency > 5% will be 
provided to the DSMB for this clinical trial 1-2 months prior to IRB annual review. The Emory 
IRB reporting guidelines for UP, AE and SAE reporting will be followed. 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 23 of 30
Protocol Version: Version 7.0 10/08/2024
19. Provisions to Protect the Privacy Interests of Participants
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health, which limits identifiable information from being shared with other parties.
Participants will be informed of all planned procedures during the informed consent process 
and will have the opportunity to ask questions at any time to members of the study team 
during their participation. Should they not wish to continue with study procedures, they may 
withdraw from participation at any time. 
Patients enrolled in the study will receive standard of care treatment for any hyperglycemia 
that develops postoperatively. Insulin treatment for stress hyperglycemia is standard of care 
and all subjects in this study will receive this if needed. This will be made clear before any 
subject signs the informed consent. If subjects do not want to participate in the study, they will 
be assured that they will receive care that they are otherwise entitled to without bias.
20. Economic Burden to Participants
Patients will be responsible for costs associated with attending the preoperative study visit at 
the CRC. They will be compensated for their time and participation as previously described. 
Patients will be responsible for the costs of their planned surgical hospitalization but will not be 
charged for study-related labs.
21. Informed consent and randomization 
All patients scheduled to undergo surgery will be considered potential candidates in this study. 
Patients will be invited to participate during or prior to their preoperative clinic evaluation at 
least 72 hours prior to scheduled surgery. The investigators or study coordinators will review 
and explain the contents of the informed consent document to the eligible patient.  The 
potential subject will be informed of the purpose of the study, the randomization procedure, 
and the risks and benefits of participation.  The potential subject will also be informed that 
he/she may refuse to participate, and that even if he/she consents to participate he/she may 
withdraw from the study at any time. 
Prior to inclusion, individuals meeting inclusion/exclusion criteria will be provided basic 
information regarding the study. If interested, the consent form, potential risks and benefits, 
and the rights of research participants will be explained. Patients will be given ample time to 
review the consent form and ask questions about participation in the study. The consent form 
will be in accordance with the IRB and HIPAA guidelines of Emory University. Eligible and 
interested individuals will then begin the study after signing informed consent. The person 
obtaining consent will ensure participant understanding by assessing participant knowledge of 
the study procedures and potential risks. Participants will be assured that if they do not want to 
participate in the study, they will receive care that they are otherwise entitled to without bias. 
A signed copy of the consent form will be provided to the participant and a copy will be placed 
in a file that will be maintained for each participant in a locked cabinet in the study office.
Circumstances under which consent will be obtained:  There will be no waiver of informed 
consent. If a potential subject has any psychiatric illness or a serious medical illness, he/she will 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 24 of 30
Protocol Version: Version 7.0 10/08/2024
not be included in the study. All individuals that will be obtaining informed consent will have 
the appropriate training and certifications to perform human subjects’ research.  They will also 
be informed that this study will be for research purposes only and if they do not wish to 
participate, it does not preclude them from receiving usual medical care. They will also be 
informed of the right to withdraw from the study at any time and that their study information 
will be anonymous. Copies of the written consent will be given to all participants. 
Non-English-Speaking Participants  
The consent form for this study will be translated into Spanish. Spanish-speaking 
participants will go through the same consent process outlined above in the presence of 
an interpreter/interpretation service approved by the institution. Consent will be 
obtained by the same approved study personnel via interpretation services.
22. Setting
Participants who are scheduled for perioperative clinic evaluation will be recruited from the 
Grady Health System and Emory University Hospital. We will also recruit participants scheduled 
for perioperative evaluation via the Emory Telehealth services. Potential participants will be 
recruited prior to or during preoperative clinic visits within each hospital system. Research 
procedures preoperatively will take place at the Grady or Emory Clinical Research Centers, part 
of the Georgia CTSA. 
23. Resources Available
Grady Memorial Hospital/Grady Health System: The Grady Health System is a large urban 
health care network located in Atlanta, Georgia. Grady operates under the Fulton-Dekalb 
Hospital Authority, helping to deliver care to their uninsured and underserved populations. The 
Grady Heath System includes separate adult and children’s hospitals, as well as multiple 
hospital-based clinics throughout the Atlanta Metro area. The outpatient clinics provide care 
for more than 800,000 annual patient visits. Grady Memorial Hospital is a ~900-bed acute care 
facility located in downtown Atlanta, sustaining more than 45,000 admissions and performing 
~7,000 inpatient and 3,000 outpatient surgeries annually. This will provide ample potential for 
recruitment of surgical patients to participate in this study. 
Emory University Hospital: Emory University Hospital is a 587-bed tertiary care medical and 
surgical facility with over 24,000 admissions annually and performing ~10,000 inpatient and 
3,000 outpatient surgeries in the most recent year reported. Emory University Hospital system 
is staffed by over 2100 faculty who are members of the Emory University School of Medicine, 
providing opportunities for interdisciplinary research endeavors. This environment will promote 
continued collaboration with surgical subspecialties and successful recruitment of surgical 
patients for this study. 
Georgia Clinical &Translational Science Alliance and Clinical Research Network sites: Georgia 
Clinical and Translational Science Alliance (Georgia CTSA): The Georgia CTSA (georgiactsa.org), 
created in 2017 through a multi-institutional partnership between Emory University, 
Morehouse School of Medicine, University of Georgia and Georgia Institute of Technology, is 
one of 60 medical research institutions working as a national consortium funded by NIH/NCATS 
through the Clinical and Translational Science Awards (CTSA) program to improve clinical and 


Protocol Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: 
                                     An Observational and Randomized Controlled Pilot Trial
Page 25 of 30
Protocol Version: Version 7.0 10/08/2024
translational research nationally. A major goal of this program is to bring together basic, 
translational and clinical investigators, community clinicians, professional societies and industry 
collaborators in dynamic clinical and translational research projects. Included among priorities 
of the Georgia CTSA are to 1) create an Atlanta-wide translational science workforce to advance 
discoveries impacting human health, 2) encourage collaboration and community involvement 
to advance translational research, 3) create and provide new informatics solutions promoting 
best clinical practices and integrating clinical and basic data for translation to complex 
populations, and 4) integrate, improve and innovate the quality of education and training 
programs for the next generation of clinical and translational researchers. The Georgia CTSA 
includes units at Emory University Hospital, Children’s Hospital of Atlanta at Egleston Hospital, 
Grady Memorial Hospital, and the Ponce HIV Center. Georgia CTSA resources include inpatient 
and outpatient units, research nurse support, Core Laboratory support and support from the 
Bionutrition Unit and Biostatistics and Informatics Unit. 
The Grady CRC is located within Grady Memorial Hospital, 5C (5th floor) area and is part of the 
NIH-funded Georgia CTSA Clinical Research Network. The CRC area includes four outpatient 
care rooms, a nursing station, and a private room used for patient interviews. The inpatient 
portion has functional capacity for two research overnight beds, which will not be required for 
this proposal. The outpatient area consists of two beds and three infusion recliners, an 
outpatient nursing station and a rest room, which will be used for completion of the 
preoperative oral glucose tolerance tests and all phlebotomy procedures. There are 
administrative offices (medical director, nursing director, and a generic office for patient 
interviews shared by participating research staff). CRC nursing staff has extensive experience in 
conducting inpatient and outpatient clinical and metabolic studies, including performance of 
oral glucose tolerance testing required for this proposal. The Grady research laboratory 
occupies 1,824 square feet and is equipped with a specimen processing and aliquotting 
laboratory, -20°C and -80°C freezers, 4°C refrigerator, centrifuges, and molecular cell biology 
laboratory. As with the CRC at Emory University Hospital, all freezers/refrigerators are equipped 
with CO2 back-up system and web-based temperature monitoring system. The laboratory can 
collect, process and store blood assays generated by this research project. The Grady CRC is 
fully equipped, and the staff is well-trained to handle the procedures required by this research 
project.
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Regimen. J Diabetes Sci Technol. 2015;10(2):325-329.
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ICF_001.pdf: 
Informed Consent Form 
 
 
TITLE: Perioperative Stress Hyperglycemia in General and Vascular 
Surgery Patients 
 
 
NCT NUMBER: NCT04862234 
 
 
IRB APPROVAL DATE: April 17, 2024 
 


Page 1 of 17
Version Date: 10/01/2021
IRB Form 06162020
You Are Being Asked to Be in a Research Study
You are being asked to be in a research study. A research study is designed to answer a 
scientific question. If you agree to be in the study, you will be one of 245 people who are being 
studied at Emory and Grady Health System. 
Why is this study being done? 
This study is being done to understand the blood sugar control of individuals before surgery 
and to learn about factors that may cause poor blood sugar control in individuals who do not 
have known diabetes. We also want to compare dulaglutide (diabetes injection medication) 
and placebo (saline injection) for the prevention of high blood sugar during surgery. You are 
being asked to be in this research study because the knowledge gained from this study may be 
used to help others. Research studies are not intended to benefit you directly, though some 
might.
Do you have to be in the study? 
It is your decision to be part of this research study. You do not have to be in it. Your choice will 
not affect your access to medical care for your condition. Before you make your decision, you 
should take time to learn about the study.
What do I have to do if I choose to participate in this study?
If you are eligible and want to be part of the study, you may be in only in the observational 
part of the study (study visit before surgery and blood tests/glucose monitoring during 
hospital stay) or also in the medication part of the study if you qualify and consent to it (study 
visit before surgery, administration of study medication and blood tests/glucose monitoring 
during hospital stay).  The researchers will ask you to do blood tests and a glucose tolerance 
test at the study visit before surgery.  If you join in the study and you qualify for the 
medication part of the study, you will receive an injection of study medication (dulaglutide) or 
placebo within 3 days before surgery at your study visit. ALL of these procedures will be paid 
for by the study.   
How is this study going to help you? 
If you are in the study, you will be helping the researchers to understand more about the high 
blood sugars that can happen around the time of surgery. You will also help the researchers to 
determine if dulaglutide can prevent the development of high blood sugars after surgery.
 
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What are the risks or discomforts I should know about before making a decision?  
The study will take time. The drug/procedure that is being tested may not work any better 
than regular care, and may even cause harm. All studies have some risks.  Some risks are 
relatively small, like being bored or losing time.  Some are more serious – for this study, these 
include loss of privacy and breach of confidentiality.  A full list of expected risks, their 
frequency and severity are in the “What are the possible risks and discomforts?” section of 
this document.
Alternatives to Joining This Study
If you decide to not enter this study, there is care available to you outside of this research 
study.  You should know that there are other types of diabetes drugs and insulins available to 
treat elevated blood sugar in the hospital. The study doctor will discuss these options with 
you. You do not have to be in this study to be treated for high blood sugars after surgery.
Costs
There are no research costs to you for participating in the study. However, you will still be 
responsible for your usual ongoing care, including any procedures and/or medications that 
your regular doctor requires as part of your usual medical care.  You will not be charged for 
any of the research activities. You will be billed for the standard care you receive for the 
treatment of your condition. You may also have to pay for basic transportation costs. There is 
more information in the cost section below.
What Should I Do Next?
1. Read this form, or have it read to you.  
2. Make sure the study doctor or study staff explains the study to you. 
3. Ask questions (e.g., about exact time commitment, about unfamiliar words, more details 
on specific procedures, etc.) 
4. Make sure you understand which parts of these are research and which are standard 
care that you would have even if you did not join the study.  
5. Take time to consider this, and talk about it with your family and friends.
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Emory University and Grady Health System 
Consent to be a Research Subject / HIPAA Authorization 
Title: Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients: An 
Observational and Randomized Controlled Pilot Trial.
IRB #:  STUDY00097659
Principal Investigator: Georgia M. Davis, M.D.
Study Supporter: National Institutes of Health/National Institute of Diabetes and Digestive and 
Kidney Diseases
Introduction
You are being asked to be in a medical research study. This form is designed to tell you 
everything you need to think about before you decide if you want to be a part of the study.  It 
is entirely your choice.  If you decide to take part, you can change your mind later on and 
withdraw from the research study. The decision to join or not join the research study will not 
cause you to lose any medical benefits.  If you decide not to take part in this study, your doctor 
will continue to treat you.
Before making your decision:
•
Please carefully read this form or have it read to you
•
Please listen to the study doctor or study staff explain the study to you 
•
Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about 
whether you would like to participate. You may wish to discuss your decision with family or 
friends. Do not sign this consent form unless you have had a chance to ask questions and get 
answers that make sense to you.  By signing this form, you will not give up any legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law. This Web site will not include information that can identify you. At most the Web 
site will include a summary of the results. You can search this Web site at any time.
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What is the purpose of this study?
The purpose of this study is to characterize the blood sugar control of individuals before 
surgery and learn about factors that may lead to poor blood sugar control in individuals who 
do not have known diabetes. We also want to compare dulaglutide (diabetes injection 
medication) and placebo (saline injection) for the prevention of high blood glucose (sugar) 
during surgery. About 30% of patients (3 out of 10) develop high glucose after general surgery. 
High glucose is linked to a higher risk of hospital complications. High glucose increases the risk 
of wound infection, kidney failure and death. Patients with high glucose are treated with 
insulin given through an arm vein or by frequent injections. This study will help us to 
understand more about high blood sugars that happen around the time of surgery. The study 
will also determine if dulaglutide can prevent the development of high sugars after surgery. 
Dulaglutide is a diabetes medication approved by the Food and Drug Administration (FDA) to 
treat clinic patients with diabetes. Dulaglutide has been shown to improve blood sugar control 
in patients with diabetes. It is not known if dulaglutide can prevent the development of high 
blood sugars in the hospital.
We will also measure levels of certain blood tests related to blood sugar metabolism before 
and after surgery. We will use a Continuous Glucose Monitoring (CGM) medical device that 
provides constant readings of blood sugars to determine when high blood sugars may happen 
after surgery. This medical device is approved by the Food and Drug Administration (FDA). You 
will have the option of authorizing these blood samples to be stored for use in future research 
that may help understand more about blood sugar control in the hospital.
A total of 245 patients from Grady Memorial Hospital and Emory University Hospitals will 
participate in this study. A total of 80 of these patients who qualify will be invited to be in the 
medication part of the study. You will have the option of authorizing your participation in each 
part of this study.
What will I be asked to do?
Patients with no history of diabetes and with normal blood glucose who are undergoing 
surgery will be considered for this study. If you are a woman of child bearing age, you will take 
a pregnancy test one time prior to enrollment in the trial. If you join in the study and you 
qualify for the medication part of the study, the medication you receive will be decided 
randomly (by chance or like flipping a coin). You will either be given 1) dulaglutide injection, or 
2) placebo (saline) injection within three days before your surgery at your study visit. 
Study:
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The study will be carried out in two parts as follows:
A. Prior to hospital admission (Within 72 hours before surgery) at the clinical research center:
•
You will have the Oral glucose tolerance testing (OGTT) blood test to assess how your 
body controls blood sugar. For this test, we will ask you to fast the night before your 
visit. You will have your blood drawn in the morning at your study visit in the clinical 
research center. You will then drink a small amount of high sugar solution and blood 
samples will be taken several times over a 2-hour period to check how your body 
handles the high sugar solution. 
•
You will have the Continuous Glucose Monitoring (CGM) medical device placed on your 
body to monitor blood sugar values for up to 14 days, even when you are in the hospital 
for surgery. These glucose values will not be seen or used for clinical care.
•
We will collect blood samples to test for certain blood markers. A total of about 60 mL 
(or 4 tablespoons) of blood will be drawn.
•
If the results from your OGTT show your body has difficulty processing the high sugar 
solution, or if your blood sugar goes high enough to diagnose diabetes, you will be asked 
if you want to participate in the medication part of this study. 
•
In the medication part of this study, you will be given an injection of a diabetes medicine 
called dulaglutide, or placebo saline. The injection you receive is decided randomly. If 
you agree to be in the medication part of the study, you will be given either dulaglutide 
or placebo at your study visit in the clinical research center.
B. During hospital stay:
•
During and following surgery, blood sugars will be checked by fingerstick testing by the 
usual hospital protocol. Blood glucose levels will be used to see if insulin is needed to 
control your blood sugar.
•
You will continue to wear your CGM during your surgery and hospital stay, up to a total 
of 14 days or until you go home. The study team will remove the sensor before you 
leave the hospital. 
•
If your fingerstick blood sugar is greater than 180 mg/dl, you will be treated with 
subcutaneous insulin (under the skin) shots. This is the standard or usual care for 
patients with diabetes and high blood sugars in the hospital.
•
A blood draw will also be done once after surgery to test certain blood markers. You 
may have additional blood draws if requested by your primary hospital team.
How the CGM (Abbott Freestyle Libre) System Works:
The Abbott Freestyle Libre Pro CGM System includes a sensor and receiver. The sensor is 
circular and about 1.5 inches in diameter. The sensor probe is a little thicker than a strand of a 
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human hair and is about a ½ inch long. The needle is slightly thicker and the same length as 
most insulin syringe needles. The sensor probe is inside the needle. Once the sensor is 
inserted, the needle is pulled out and the sensor probe stays under your skin for up to 14 days. 
The sensor continuously measures your blood sugar levels. The sensor collects and stores 
blood sugar information.
If your sensor is displaced or removed before a medical procedure or at any point in time 
before the end of 14 days, please ask the research staff or nurse to remove and replace the 
sensor if you have:
•
Discomfort or
•
Are going for magnetic resonance imaging (MRI), computed tomography (CT) scan, or 
high-frequency electrical heat (diathermy) treatment. The FreeStyle Libre sensor hasn’t 
been tested in those situations. The magnetic fields and heat could damage the 
components of the sensor, which may cause it to not function properly. 
How will my medicine be provided? 
The medicine that you will take will be dispensed by the pharmacy and delivered to the 
principal investigator or study team member. The principal investigator or health care 
providers on his/her research team will provide the medicine to you. If you have questions 
about the medicine, you should ask the principal investigator or study nurse. You may also call 
the pharmacy if you have questions about the medicine. The number for the pharmacy is 
included on your medicine package.
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information. You will not be 
given any compensation if your samples or information are used to make a new product. If you 
withdraw from the study, data and samples that were already collected may be still be used 
for this study.
What are the possible risks and discomforts?
There may be side effects from the study drug or procedures that are not known at this time.
The most common risks and discomforts expected in this study are:
Oral Glucose Tolerance Test: The risks for this test are similar to that of drawing blood. This 
includes pain and discomfort from placing the tubes in your arm. You may experience bruising, 
lightheadedness, fainting and on rare occasions, an infection. Occasionally, after drinking the 
Glucola (the high sugar solution), some people may experience nausea or stomach discomfort. 
This usually lasts for a short time and goes away.
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Hypoglycemia (low blood sugar): Low blood sugar (less than 70 mg/dl) can occur in about 20% 
(20 patients out of one hundred) of insulin treated patients in the hospital. Dulaglutide and 
placebo are unlikely to cause low blood sugars. However, the combination of dulaglutide and 
insulin may cause more low blood sugars than insulin alone. Symptoms of low blood glucose 
include sweating, nervousness, confusion, agitation, sleepiness and even coma (loss of 
awareness). If it occurs, low sugar will be managed by a standard protocol, including 
decreasing the amount of insulin and by the use of dextrose (sugar) solution.
Hyperglycemia (high blood sugar): High blood glucose levels (greater than 300 mg/dl) can 
occur in 10-20% of patients (10 to 20 patients out of one hundred) in the hospital. It is possible 
that the combination of dulaglutide may cause more high blood sugars than insulin. Symptoms 
of high blood sugar include increased thirst, dry mouth, urinating more, blurred vision, dry 
skin, weakness, sleepiness and confusion. If not treated, high blood sugars can even lead to 
serious illness, blacking out or death. During the study, if your blood sugar becomes too high, 
you will receive extra doses of insulin.
Dulaglutide side effects: Dulaglutide may cause certain side effects in some people. These 
possible side effects include: diarrhea or loose stools (8.9%), nausea (12.4%), vomiting (6%), 
abdominal pain (6.5%), decreased appetite (4.9%), indigestion (4.1%), and fatigue (4.2%). In 
people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids 
(dehydration) which may cause kidney problems to get worse.
Risks of Wearing the CGM System
When the sensor is inserted you should expect to feel a feeling like an insulin injection. After 
insertion, you may feel some tenderness, but you should not feel any large amount of pain.
Pain, redness, swelling, minor infection, and minor bleeding at the sensor insertion site are 
possible risks with use of the device. In very rare cases an infection might spread to other parts 
of the body. Significant or serious health risks with the study device are not expected.
Redness may occur where the adhesive pads are placed. This will occur in most research 
participants and will clear up no more than a week after removal. You may develop an allergic 
reaction to one or more parts of the sensor and transmitter. This is like allergies that occur due 
to hospital tape or jewelry. Allergic reactions will usually be mild and require only a skin cream 
to make them better. Major allergic reactions are rare. If you have an allergic reaction you 
should notify the study researcher or study staff.
On rare occasion, the sensor may cause skin to blister or peel. If this happens you should 
notify the study staff as soon as possible.
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There is a chance that the sensor or needle may break. This is not expected to occur; but, if it 
does, you should talk with your Study Clinician about what to do. Usually, if there is no sign of 
infection or irritation and you cannot see the sensor above the skin, it is not recommended to 
remove it.
The radio waves that the study device puts out will not hurt you and you will not be aware of 
them.
Shot (Injection) Site and Allergic Reactions: Shot site reactions with insulin include redness, 
pain, itching, hives and swelling. Regularly changing of the place where insulin is given may 
help to reduce or prevent these reactions. Most minor reactions resolve in a few days to a few 
weeks. Generalized insulin allergy is rare and may cause skin rash, shortness of breath, fast 
heart beat, sweating and a drop in blood pressure. Skin irritation, pain or a small amount of 
bleeding may occur in relation to the CGM device or adhesives.
Blood Draws: Phlebotomy. Risks associated with blood draws are low and include small 
amounts of pain, possible bruising, swelling, redness, and rarely an infection at the site or 
fainting.
The less common risks and discomforts expected in this study are:
Dulaglutide has also been reported to cause allergic reactions (itching, swelling of the skin and 
difficulty breathing).
Pancreatitis or inflammation (irritation) of the pancreas is a possible complication of the study 
drug, dulaglutide. Symptoms of pancreatitis include vomiting and persistent, bad abdominal 
pain.
Rare but possible risks include:
Possible thyroid tumors, including cancer. It is not known if dulaglutide causes thyroid tumors 
or a type of thyroid cancer called medullary thyroid carcinoma in people. Possible symptoms 
of thyroid cancer include a lump or swelling in your neck, hoarseness, trouble swallowing, or 
shortness of breath.
If you are a woman: to protect against possible side effects of the study drug, women who are 
pregnant or nursing a child may not take part in this study. If you become pregnant, there may 
be risks to you, the embryo, or fetus. These risks are not yet known. If you are a woman of 
childbearing ability, you and the study doctor must agree on a method of birth control to use 
throughout the study. Insulin glargine and dulaglutide are not approved for use during 
pregnancy. Their effects on an unborn child are unknown.
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If you think that you have gotten pregnant during the study, you must tell the study doctor 
immediately. Pregnant women will be taken out of the study.
It is possible that the researchers will learn something new during the study about the risks of 
being in it. If this happens, they will tell you about it. Then you can decide if you want to 
continue to be in this study or not. You may be asked to sign a new consent form that includes 
the new information if you decide to stay in the study.
Will I benefit directly from the study? 
This study is not designed to benefit you directly. This study will determine if dulaglutide (a 
diabetes injection) can prevent the development of high blood glucose in the hospital. The 
study results may be used to help other patients having general surgery in the future.
Will I be compensated for my time and effort?
You will get $50.00 for completion of the study visit at the clinical research center. You will 
receive an additional $25.00 when you leave the hospital if you completed the observational 
part of the study only, or an additional $50.00 if you completed the medication part of study. 
What are my other options?
If you decide not to enter this study, there is care available to you outside of this research 
study. You should know that there are other types of diabetes drugs and insulins available at 
Emory and Grady Hospitals to treat elevated blood sugar in the hospital. The study doctor will 
discuss these with you. You do not have to be in this study to be treated for high blood sugars 
after surgery.
Taking part in this study, however, may make you unable to participate in some other research 
studies, if they exclude people who have taken certain treatments. You should discuss this 
with the researchers if you have concerns. You may wish to research other study options at 
websites like clinicaltrials.gov and ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records. 
Your name and other identifying information will not appear when we present or publish the 
study results.
Certificate of Confidentiality
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  
The Certificate of Confidentiality helps us to keep others from learning that you participated in 
this study.  Emory will rely on the Certificate of Confidentiality to refuse to give out study 
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information that identifies you.  For example, if Emory received a subpoena for study records, 
it would not give out information that identifies you.
The Certificate of Confidentiality does not stop you or someone else, like a member of your 
family, from giving out information about your participation in this study.  For example, if you 
let your insurance company know that you are in this study, and you agree to give the 
insurance company research information, then the investigator cannot use the Certificate to 
withhold this information. This means you and your family also need to protect your own 
privacy.
The Certificate does not stop Emory from making the following disclosures about you:
•
Giving state public health officials information about certain infectious diseases,
•
Giving law officials information about abuse of a child, elderly person or disabled 
person.
•
Giving out information to prevent harm to you or others.
Giving the study sponsor or funders information about the study, including information for an 
audit or evaluation.
Storing and Sharing your Information
De-identified data from this study (data that has been stripped of all information that can 
identify you), including your de-identified genetic information, may be placed into public 
databases where, in addition to having no direct identifiers, researchers will need to sign data 
use agreements before accessing the data. We will remove or code any personal information 
that could identify you before your information is shared. This will ensure that, by current 
scientific standards and known methods, it is extremely unlikely that anyone would be able to 
identify you from the information we share. Despite these measures, we cannot guarantee 
anonymity of your personal data.
Your data and specimens from this study may be useful for other research being done by 
investigators at Emory or elsewhere. To help further science, we may provide your de-
identified data and/or specimens to other researchers. If we do, we will not include any 
information that could identify you. If your data or specimens are labeled with your study ID, 
we will not allow the other investigators to link that ID to your identifiable information.
If you join this study, you will be donating your samples and study information.  You will not 
receive any compensation if your samples or information are used to make a new product. If 
you withdraw from the study, data and samples that were already collected may be still be 
used.  These samples may be kept indefinitely and used for future studies involving to test for 
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other abnormalities such as how your body controls glucose.  We may also use the samples 
collected in this study for future studies without another consent.  If you want us to destroy 
your samples, you will need to send this request in a letter to: 
Dr. Georgia Davis 
Address: 
 
 
Medical Record
If you have been an Emory and Grady Health System patient before, then you already have an 
Emory and Grady Health System medical record. If you have never been an Emory and Grady 
Health System patient, you do not have one. An Emory and Grady Health System medical 
record will be made for you if an Emory and Grady Health System provider or facility gives you 
any services or procedures for this study.
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory and 
Grady Health System medical record you have now or any time during the study.
Emory and Grady Health System may create study information about you that can help with 
your care. This may include the results of study tests or procedures. These study results may 
be put in your Emory and Grady Health System medical record. Anyone who has access to your 
medical records will be able to have access to all the study information placed there. The 
confidentiality of the study information in your medical record will be protected by laws like 
the HIPAA privacy rule. State and federal laws may not protect the research information from 
disclosure.
The results of some study tests and procedures will be used only for research purposes and 
will not be placed in your medical record. For this study, those items include:
Tests and procedures done at non-Emory and Grady Health System places may not become 
part of your Emory and Grady Health System medical record. If you decide to be in this study, 
it is up to you to let your other health providers know.
In Case of Injury
If you get ill or injured from being in the study, Emory and Grady Health System will help you 
to get medical treatment. Emory and Grady Health System and Principal Investigator have not, 
however, set aside any money to pay you or to pay for this medical treatment. The only 
exception is if it is proven that your injury or illness is directly caused by the negligence of an 
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Emory and Grady Health System or sponsor employee. “Negligence” is the failure to follow a 
standard duty of care.
If you become ill or injured from being in this study, your insurer will be billed for your 
treatment costs. If you do not have insurance, or if your insurer does not pay, then you will 
have to pay these costs.
If you believe you have become ill or injured from this research, you should contact Dr. 
Georgia Davis at telephone number 
 You should also let any health care 
provider who treats you know that you are in a research study.
Costs
The study sponsor will pay for certain items and services that you may receive if you take part 
in this study.
You will have to pay for the items or services for which the study sponsor does not pay. The 
sponsor will not pay for your regular medical care. If you have insurance, Emory will submit 
claims to your insurance for items and services that the sponsor does not cover. Emory will 
send in only those claims for items and services that it reasonably believes your insurance will 
pay and that the sponsor has not paid.
The actual amount that you have to pay depends on whether or not you have health insurance 
and whether or not that insurance will pay for any research study costs. Generally, insurance 
companies will not pay for items and services that are required just for a research study. Some 
insurance companies will not pay for regular medical treatment or treatment for complications 
if you are in a study. How much you will have to pay for any co-payments, deductibles or co-
insurance depends on your plan. Emory and the sponsor will not pay for these costs.
It is a good idea to contact your insurance provider and tell them you want to be in this 
research study. Ask them what they will pay for and what they will not pay for. You can also 
ask the study team for help in figuring out what you will have to pay.
If you do not have insurance, Emory will review your case as part of its program for low-
income patient care. The standard policies of that program will apply. The program will figure 
out if you have to pay any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.
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The researchers also have the right to stop your participation in this study without your 
consent for any reason, especially if they believe it is in your best interest or if you were to 
object to any future changes that may be made in the study plan.
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us. We call your health information that 
identifies you, your “protected health information” or “PHI.” To protect your PHI, we will 
follow federal and state privacy laws, including the Health Insurance Portability and 
Accountability Act and regulations (HIPAA). We refer to all of these laws as the “Privacy Rules.” 
Here we let you know how we will use and disclose your PHI for the main study.
Main Study
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:
•
Medical information about you including your medical history and present/past 
medications.
•
Results of exams, procedures and tests you have before and during the study.
•
Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study. We 
will use and share your PHI to provide you with study related treatment and for 
payment for such treatment. We will also use and share your PHI to conduct normal 
business operations. We may share your PHI with other people and places that help us 
conduct or carry out the study, such as laboratories, data management centers, data 
monitors, contract research organizations, Institutional Review Boards (IRBs) and other 
study sites. If you leave the study, we may use your PHI to determine your health, vital 
status or contact information.
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes 
laws that require us to report child abuse or abuse of elderly or disabled adults. 
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in 
this document. You do not have to sign this form to authorize the use and disclosure of 
your PHI. If you do not sign this form, then you may not participate in the research study 
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or receive research-related treatment. You may still receive non-research related 
treatment.
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the 
research study:
•
The Principal Investigator and the research staff will use and disclose your PHI to 
conduct the study and give you study related treatment.
•
Emory and Grady Health System may use and disclose your PHI to get payment 
for study related treatment and to run normal business operations. 
•
The Principal Investigator and research staff will share your PHI with other people 
and groups to help conduct the study or to provide oversight for the study.
•
 The National Institutes of Health is the Sponsor of the study.  The Sponsor may 
use and disclose your PHI to make sure the research is done correctly and to 
collect and analyze the results of the research.  The Sponsor may disclose your 
PHI to other people and groups to help conduct the study or to provide oversight 
for the study.  
•
The following people and groups will use your PHI to make sure the research is 
done correctly and safely:
o Emory and Grady Health System offices that are part of the Human 
Research Participant Protection Program and those that are involved in 
study administration and billing.  These include the Emory IRB, the Grady 
Research Oversight Committee, the Emory Research and Healthcare 
Compliance Offices, and the Emory Office for Clinical Research. 
o Government agencies that regulate the research including: Food and Drug 
Administration, Office for Human Research Protections (OHRP). 
o National Institutes of Health (NIH).
o Public health agencies.
o Research monitors and reviewer.
o Accreditation agencies.
•
Sometimes a Principal Investigator or other researcher moves to a different 
institution. If this happens, your PHI may be shared with that new institution and 
their oversight offices. PHI will be shared securely and under a legal agreement to 
ensure it continues to be used under the terms of this consent and HIPAA 
authorization.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
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Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to 
use your information. If you want to do this, you must contact Dr. Georgia Davis at: 
At that point, the researchers would not collect any more of your PHI. But they may use 
specimens or disclose the information you already gave them so they can follow the 
law, protect your safety, or make sure that the study was done properly and the data is 
correct. If you revoke your authorization you will not be able to stay in the main study.
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules. HIPAA only applies to health care 
providers, health care payers, and health care clearinghouses. If we disclose your information 
to people who are not covered by the Privacy Rules, including HIPAA, then your information 
won’t be protected by the Privacy Rules. People who do not have to follow the Privacy rules 
can use or disclose your information with others without your permission if they are allowed 
to do so by the laws that cover them.
To maintain the integrity of this research study, you generally will not have access to your PHI 
related to this research until the study is complete. When the study ends, and at your request, 
you generally will have access to your PHI that we maintain in a designated record set. A 
designated record set is data that includes medical information or billing records that your 
health care providers use to make decisions about you. If it is necessary for your health care, 
your health information will be provided to your doctor.
We may remove identifying information from your PHI. Once we do this, the remaining 
information will not be subject to the Privacy Rules. Information without identifiers may be 
used or disclosed with other people or organizations for purposes besides this study.
Contact Information
Contact Dr. Georgia Davis at 
•
if you have any questions about this study or your part in it,  
•
if you feel you have had a research-related injury or a bad reaction to the study drug, or
•
if you have questions, or concerns about the research
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or 
irb@emory.edu:
•
if you have questions about your rights as a research participant.
IRB00097659
IRB Approved
4/17/2024


Page 16 of 17
Version Date: 10/01/2021
IRB Form 06162020
•
if you have complaints about the research or an issue you rather discuss with someone 
outside the research team.
You may also let the IRB know about your experience as a research participant through our 
Research Participant Survey at https://tinyurl.com/ycewgkke.
If you are a patient receiving care from the Grady Health System and have a question about your 
rights, you may contact the Office of Research Administration at research@gmh.edu.
Consent and Authorization
Consent and HIPAA Authorization for optional medication part of Main Study:
If I qualify, I agree to participate in the medication part of the Main Study: 
Yes
No
(check one box only)
 ____________Initials 
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in this research study, and any 
optional studies you initialed above. By signing this consent and authorization form, you will not 
give up any of your legal rights. We will give you a copy of the signed form to keep.
Name of Subject 
Signature of Subject (18 or older and able to consent)
Date              Time
Signature of Legally Authorized Representative  
Date              Time
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
IRB00097659
IRB Approved
4/17/2024


Page 17 of 17
Version Date: 10/01/2021
IRB Form 06162020
Signature of Person Conducting Informed Consent Discussion
Date              Time
IRB00097659
IRB Approved
4/17/2024