Clinical trial NCT03743025
Conditions: Stress Hyperglycemia
Keywords: Coronary Artery Bypass Surgery (CABG) Post Operative Obesity
Sponsor: Emory University
Start date: 2019-03-08; Completion date: 2023-05-02
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a prospective randomized study to examine the effects of exposure to dulaglutide on the prevention of stress-hyperglycemia and the metabolic inflammatory response in the perioperative period.

Detailed description:
Stress hyperglycemia is common in the perioperative period and is associated with increased risk of death postoperatively. Counterregulatory hormones and inflammatory mediators appear to modulate the acute biological response to stress, however, the pathophysiological pathways that result in stress hyperglycemia and its link to poor clinical outcomes are not well understood. At least half of non-diabetes mellitus (DM) patients undergoing cardiac surgery develop stress hyperglycemia shown to be an independent risk factor of morbidity and mortality. The current approach to treat hyperglycemia with insulin has major limitations including high resource utilization and high risk of hypoglycemia. The main goals of this study are to examine baseline and postoperative metabolic profiles of non-diabetic, coronary artery bypass grafting (CABG) patients with stress hyperglycemia and to study the effect of a long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the prevention of stress-hyperglycemia and modulation of metabolic stress during cardiac surgery.

To examine whether exposure to dulaglutide, a GLP-1 RA, can improve glycemic control and ameliorate the inflammatory response to acute surgical stress, obese patients without diabetes mellitus undergoing CABG surgery will be randomized to receive either dulaglutide or placebo two to three days prior to surgery. The researchers of this study ultimately want to provide evidence to support the use of novel therapies to prevent and manage stress hyperglycemia in the inpatient setting.

Arms: arm 1: Participants without a history of DM who are randomized to receive a single injection of dulaglutide (0.75 mg/0.5 mL solution in a single-dose pen) one to three days prior to surgery. arm 2: Participants without a history of DM who are randomized to receive a single injection of a placebo (saline injection of 0.5 mL pre-drawn solution) one to three days prior to surgery.
Interventions: intervention 1: Dulaglutide Injection intervention 2: Saline Injection
Intervention descriptions: intervention 1: Participants randomized at pre-surgery/anesthesia visit and without a history of DM will receive a single injection of Dulaglutide injection: 0.75 mg/0.5 mL solution in a single-dose pen 1 to 3 days prior to surgery intervention 2: Participants randomized at pre-surgery/anesthesia visit and without a history of DM will receive a single injection of Saline injection/0.5 mL pre-drawn solution 1 to 3 days prior to surgery

Protocol documents:
Prot_SAP_001.pdf: 
Study Protocol 
 
Title: Metabolic Phenotyping During Stress Hyperglycemia in Cardiac 
Surgery Patients 
 
NCT Number: NCT03743025 
 
Protocol date: July 30, 2020 


Title:
Metabolic Phenotyping During Stress Hyperglycemia in Cardiac Surgery 
Patients
 
Principal Investigator:        
1Francisco J. Pasquel, MD, MPH*
                                           
Assistant Professor of Medicine
                                           
Department of Medicine/Endocrinology
                                           
Emory University 
Co-Investigators: 
1Guillermo Umpierrez, MD,* 2Michael Halkos, MD*, 3Elizabeth Duggan, MD
Collaborators/Advisors:    1Dean Jones, PhD; 1Jessica Alvarez, PhD; 1Thomas Ziegler MD; 1Karan Uppal, 
4Richard Kibbey, MD, PhD; 4Silvio Inzucchi, MD
 
Statistician: 
5Liming Peng, PhD   
1 Department of Medicine, Emory University
2 Department of Surgery, Emory University 
3 Department of Anesthesiology 
4Yale School of Medicine  
5Rollins School of Public Health 
*Investigators who will have access to identifiers and conduct research under this protocol (consenting, etc.)
Correspondence:
       
Francisco J. Pasquel, M.D., M.P.H.
                                         
Assistant Professor of Medicine
       
Emory University School of Medicine
       
       
       
       
       


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ABSTRACT: 
Research: Stress hyperglycemia is common in the perioperative period and is associated with 
increased risk of postoperative mortality. Counterregulatory hormones and inflammatory mediators 
appear to modulate the acute biological response to stress; however, the pathophysiological 
pathways that result in stress hyperglycemia and its link to poor clinical outcomes are not well 
understood. Comprehensive metabolic profiling (metabolomics) represents a novel tool to examine 
metabolic changes during stress conditions. The current approach to treat hyperglycemia with insulin 
has major limitations including high resource utilization and high risk of hypoglycemia. The 
overarching hypotheses of this research proposal are that: 1) Stress-hyperglycemia is associated with 
changes in unknown and known metabolites (i.e. branched-chain amino acids, acylcarnitines, 
ceramides) and path-specific biomarkers (representing inflammation, coagulation, cell stress, and 
immune modulation) in the perioperative period in cardiac surgery patients, and 2) with a low risk of 
iatrogenic hypoglycemia, exposure to a long acting glucagon like peptide-1 receptor agonist (GLP-1 
RA) will ameliorate the hyperglycemic and inflammatory response to surgical stress. Using 
comprehensive metabolic profiling methods, this study will provide new insights into the mechanisms 
underlying the metabolic and inflammatory responses to surgical stress (Aim 1). This study will also 
examine whether exposure to a long acting GLP-1 RA can improve glycemic control and ameliorate 
the inflammatory response to acute surgical stress (Aim 2). These findings will provide proof-of 
principle to support the use of novel therapies to prevent and manage stress hyperglycemia in the 
inpatient setting.


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SPECIFIC AIMS    About 400,000 patients undergo coronary artery bypass graft surgery (CABG) yearly. 
Stress hyperglycemia (blood glucose [BG] >140 mg/dl) occurs in ~60-80% of non-diabetic patients during 
CABG and is associated with increased perioperative complications and mortality. The underlying mechanisms 
that lead to hyperglycemia in response to stress during cardiac surgery are not well understood. 
Even though stress hyperglycemia and diabetes are primarily disorders of glucose metabolism, other 
dimensions including lipids (i.e. acylcarnitines, ceramides) and amino acids [i.e. branched-chain amino-acids 
(BCAA)] have been identified in association with hyperglycemia and diabetes through high-resolution 
metabolomics (HRM) techniques. Furthermore, HRM has identified BCAA, ceramides, and acylcarnitines as 
important markers of cardiovascular disease (CVD) risk.  In acutely ill patients presenting with severe 
hyperglycemia we observed a positive association between BCAA and delayed resolution of hyperglycemia 
during intravenous insulin therapy. These relationships suggest that circulating and increased release of 
amino-acids and acylcarnitines during hormone-mediated catabolism during stress could mediate insulin 
resistance, beta-cell dysfunction, and cardiovascular (CV) risk in patients with CAD undergoing surgery. In 
addition, path-specific biomarkers representing inflammation [C-reactive protein (CRP)], hyper-coagulation 
[fibrin degradation products (FDP)], cell stress [heat shock protein-70 (HSP-70)], and immune modulation 
[soluble urokinase-type plasminogen activator receptor (SuPAR)] have emerged as strong predictors of death 
in patients with CVD. Previous studies suggest hyperglycemia can lead to activation of these pathways. 
Continuous insulin infusion therapy (CII) is the treatment of choice of stress hyperglycemia. Although 
effective in improving BG control, CII is costly and labor intensive requiring hourly measurements of glucose 
levels; and carries a high risk of iatrogenic hypoglycemia (12% to 35%), which is associated with increased risk 
of complications and death. Incretin-based therapies have emerged as an effective alternative to insulin 
therapy in improving glycemic control with minimal risk of hypoglycemia and additional cardiovascular benefits. 
By augmenting glucose-dependent insulin secretion and inhibiting glucagon secretion, glucagon-like peptide-1 
receptor agonists (GLP1-RA) target the underlying pathophysiology of stress-induced hyperglycemia and could 
represent a novel prevention and treatment approach with a very low risk of hypoglycemia. 
This project will fill several knowledge gaps by characterizing the underlying mechanisms and metabolic 
signatures of stress hyperglycemia with the use of comprehensive metabolic profiling methods and provide 
proof-of principle with the use of novel therapies for the prevention and management of stress-hyperglycemia.
Aim 1. To examine baseline and postoperative metabolic profiles of non-diabetic CABG patients with 
stress hyperglycemia. With a case-control design we will conduct the following analyses: 
1.1 Targeted Approach: To determine cross-sectional and longitudinal changes of BCAA, ceramides, 
acylcarnitines, inflammatory markers, and a biomarker panel for CV risk [CRP + FDP + HSP-70, SuPAR] and 
their relationship with stress hyperglycemia (BG >140mg/dl) and insulin resistance estimates. We hypothesize 
that elevated ceramides, acylcarnitines, branched-chain amino acids (BCAAs) are associated with incident 
stress hyperglycemia, and that hyperglycemia leads to changes in path-specific biomarkers related to CV risk.  
1.2 Untargeted Analysis: Utilizing untargeted HRM analyses, we aim to identify additional candidate 
metabolites and metabolic pathways associated with incident stress hyperglycemia during cardiac surgery. We 
hypothesize that known (candidate metabolites) and previously unrecognized metabolites and pathways are 
associated with hyperglycemia during surgical stress. 
1.3 Integrative analysis: Metabolome-wide association studies (xMWAS) and integrative network analyses will 
be conducted to find multilevel associations between metabolites, biomarkers, and stress-hyperglycemia. We 
hypothesize that multiple factors associated with diabetes and cardiovascular disease are interrelated and 
predict hyperglycemia during stress conditions. 
Aim 2. To obtain preliminary estimates of the effect of a long-acting GLP-1 RA on the prevention of 
stress-hyperglycemia and modulation of metabolic stress during cardiac surgery. We propose a 
randomized study with assignment to dulaglutide or placebo three days prior to surgery in non-DM obese 
patients (BG<126 mg/dL, HbA1c <6.5%, BMI ≥25, age≥40 years) undergoing CABG surgery.  
2.1 Primary endpoint: to determine if dulaglutide can prevent stress-hyperglycemia.  
2.2 Secondary endpoints: to determine if dulaglutide can result in a lower mean BG during ICU and hospital 
stay. We will also explore the need of rescue therapy with insulin and differences in clinical outcomes. 
2.3 Comparison of changes in candidate metabolites and path-specific biomarkers, as well as beta-cell 
function and insulin resistance estimates in response to dulaglutide or placebo. 


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We will test the hypothesis that exposure to a single dose of dulaglutide can ameliorate the hyperglycemic 
and inflammatory response to surgical stress with a low risk of iatrogenic hypoglycemia. 
A) SIGNIFICANCE 
Coronary artery 
disease (CAD) remains a predominant 
cause of death globally1,2 About 400,000 
patients undergo coronary artery bypass 
graft surgery (CABG) each year in the 
United States5 and more than 80% of 
patients with a known history of diabetes 
(DM) and ~60% of non-DM patients 
develop stress-hyperglycemia [blood 
glucose (BG) >140 mg/dl] after surgery.6-9 
Perioperative hyperglycemia is associated 
with higher rates of wound infections,10,11 
kidney injury,8 longer hospital stay,12,13 
and mortality.10,12,14-17 In non-DM subjects, 
stress-hyperglycemia is associated with 
up to 4-fold increase in complications and 
a 2-fold increase in death compared to 
patients with normoglycemia and to 
subjects with DM.18-27 
The mechanisms leading to stress-
hyperglycemia and the association with 
poor clinical outcomes are not well 
understood. Acute metabolic and 
hormonal changes associated with the response to injury can result in insulin resistance, increased hepatic 
glucose production, and relative insulin deficiency.28-31 Elevated Inflammatory mediators can also contribute to 
hyperglycemia during injury; conversely, hyperglycemia itself can promote inflammation, oxidative stress, and 
a pro-thrombotic state 32-36 (Fig. 1). Metabolomics analysis of human biosamples has undergone a rapid 
technological evolution in recent years and represents a powerful tool to investigate the complexity of all the 
interactions within a complex individual. Even though hyperglycemia and diabetes are primarily considered 
disorders of glucose metabolism, other dimensions including lipids and amino acids have been consistently 
identified in association with prediabetes and diabetes through high-resolution metabolomics techniques 
(HRM).37,38 Analyses of large cohorts using HRM have reported positive associations of branched-chain amino 
acids (BCAAs) and aromatic amino acids (AAAs) with incident prediabetes or diabetes.37-39 Products of fatty 
acid metabolism (i.e. acylcarnitines) are also associated with insulin resistance, insulin secretion defects, and 
incident diabetes.40-42 These relationships suggest that circulating and increased release of amino acids and 
acylcarnitines during hormone mediated catabolism during stress could mediate insulin resistance and beta-
cell dysfunction in surgical patients, Table 1 and Fig 1. Furthermore, HRM has identified BCAA, ceramides, 
and acylcarnitines as important markers of CVD risk.43-46
Table 1.
Candidate metabolites 
and known biomarkers
Rationale / Clinical relevance
Protein Metabolism 
BCAA (Isoleucine, leucine, 
valine) 
Aromatic Acids (tyrosine, 
phenylalanine) 
Other: glycine, 
glutamine/glutamate ratio 
Meta-analyses of multiple cohorts show that BCAA, AAA increase the risk of chronic 
hyperglycemia. Some AA are protective (glyceine, glutamine/glutamate ratio)37,47. BCAA 
lead to mTOR/S6K1 kinase pathway activation and serine phosphorylation of IRS1 leading 
to insulin resistance. BCAA catabolic flux can lead to glutamate transamination to alanine 
and increased gluconeogenesis, as well as insulin secretion defects.48-50 BCAA are also 
associated with CVD.42 The product of valine catabolism, 3-HIB has emerged as a 
potential mediator linking BCAA to regulation of fatty acid flux and insulin resistance 
(IR).51,52 We observed higher abundance of 3-HIB in subjects with hyperglycemic crises 
and delayed response to insulin suggesting IR.  Recently, 3-HIB was associated with 
incident diabetes.53 
Lipid Metabolism 
Acylcarnitines, ceramides / 
sphingosine, 
triacylglycerols (TAGs), 
Elevated medium chain acylcarnitines lead to pancreatic β-cell dysfunction.40 Ceramides, 
and acylcarnitines are associated with insulin resistance and incident CVD41,44-46,54,55 
Sphingosine, a ceramide derivate is elevated in prolonged ketoacidosis, and is associated 
with insulin resistance.56 
Carbohydrate 
Metabolism 
Glucose, Insulin
Hyperglycemia can lead to inflammation, oxidative stress, and a pro-thrombotic state 32-36
HOMA-IR and HOMA-B are well-described surrogates of insulin resistance and insulin 
secretion derived from insulin and glucose levels. 
Figure 1. Study overview. Aim 1 is focused on understanding the underlying mechanisms that lead 
to stress hyperglycemia and increased cardiovascular risk in cardiac surgery patients (see Table 1). 
Green box: main groups of candidate metabolites to be assessed with metabolomics techniques. 
Red box: inflammatory markers and biomarker risk score components known to predict CV 
outcomes. Blue box: assessments of glycemia, insulin secretion (HOMA-B) and insulin resistance 
(HOMA-IR). Aim 2  is focused on obtaining preliminary estimates on stress hyperglycemia 
prevention and glycemic control (RCT) with a strategy with low risk of iatrogenic hypoglycemia. 


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Hormonal response 
 
Cortisol, glucagon
Counterregulatory hormones are expected to increase during cardiovascular surgery 
(GLUCO CABG).3,4
Inflammatory pathways 
TNF-a, IL-6, CRP 
TNF-a, IL-6 are Inflammatory markers known to cause insulin resistance (TNF-a, IL-6) and 
insulin secretion defects57-62 and associated with cardiovascular risk. Inflammatory cytokine 
concentrations are acutely increased by hyperglycemia in humans.36 Levels of 
inflammatory markers are increased for days after CABG surgery.3 CRP is an established 
CVD risk factor.63 
Cell stress 
Heat shock protein (HSP) 
Hyperglycaemia upregulates HSP60 & HSP70.64 HSP70 is associated with incident 
CVD.2,65,66 (Quyyumi) 
Immune pathways
suPAR 
SuPAR is a marker of immune activation associated with all-cause death and myocardial 
infarction in patients with CVD. 
Pro-thrombosis 
Fibrin degradation products 
(FDP) 
Hyperglycemia and diabetes are associated with a prothrombotic state.  FDP associated 
with incident cardiovascular disease in patients with and without diabetes.2,65,66
BCAA: branched-chain amino acids, AAA aromatic amino acids, 3-HIB 3-Hydroxyisobutyric acid
Recently, four biomarkers identified susceptible individuals and predicted meaningful clinical endpoints.65-
68 A simultaneous evaluation of biomarkers representing inflammation (C-reactive protein), coagulation (fibrin 
degradation products), cell stress (HSP-70), and immune pathways (suPAR) significantly predicts risk of death 
in patients with coronary artery disease (CAD).65,66 Previous research suggests that hyperglycemia can lead to 
activation of these pathways36,64,69,70, however; no longitudinal assessment of the relationship between 
biomarkers and stress-hyperglycemia has been conducted. It is important to characterize the molecular 
changes that occur during stress hyperglycemia to identify preventive strategies and maximize the potential to 
find cost-effective interventions. To fill this knowledge gaps, we will conduct targeted and untargeted analyses 
to further understand the underlying biology of metabolic changes during surgical stress. 
Large number of observational and randomized control studies have shown that improvement of 
glycemic control reduces perioperative complications in critically and non-critical ill patients but is 
also associated with high risk of hypoglycemia. Glycemic control with continuous insulin infusion therapy 
(CII) can reduce complications and mortality,11,71-76 particularly among non-DM subjects.77 In the GLUCO-
CABG trial4, we reported a significant reduction in a composite of perioperative complications in non-DM 
patients with stress-hyperglycemia treated with intensive vs conservative glycemic control. Although 
effective,71,72,76 the use of CII is costly and labor intensive, and carries a 12-35% risk of hypoglycemia.78-82 
Hypoglycemia after cardiac surgery has been associated with increased risk of complications and mortality.83-85
Hospital use of incretin-based therapies is a safe alternative to complex insulin regimens. To 
simplify the management of hyperglycemia and avoid the risk of hypoglycemia we have examined the role of 
DPP-4 inhibitors86  and GLP-1 receptor analogs (RA) in the hospital setting (see preliminary results). GLP-1 is 
an incretin hormone secreted in the gut in response to meal ingestion, targeting multiple tissues. One of its 
main targets is the pancreatic β-cell, resulting in increased insulin secretion and inhibition of glucagon 
production.87 In patients with and without diabetes,88-90 native GLP-1 and GLP1-RA treatments have shown to 
improve glycemic control similar to insulin administration during corticosteroid-induced hyperglycemia,91 acute 
cardiovascular (CV) events,91 in the perioperative period of patients undergoing CABG surgery,92 and mixed 
ICU populations.93 In patients with CV disease, compared to insulin therapy native GLP-1 resulted in better 
glycemic control, fewer arrhythmias,94 and improved cardiac function,95,96  CV events.97,98 
Dulaglutide, a long-acting GLP-1RA suitable for once-weekly administration,99 have demonstrated 
improved glycemic control compared to other antidiabetic agents.100-102 Phase 1 pharmacodynamics analysis in 
non-DM subjects showed median maximum plasma concentrations of dulaglutide between 24-48 hours after a 
single dose.103 Evaluation with stepped glucose infusion 3 days after dulaglutide administration revealed a 
dose-dependent rise in insulin secretion and associated decline in serum glucose concentration.103 Compared 
to short-acting GLP-1 RA, dulaglutide results in fewer and dose-dependent gastrointestinal side effects.103,104 
Dulaglutide has also been shown to be better tolerated compared to other long-acting GLP-1RA.105 GLP-1 RA 
can be used before surgery in patients with diabetes.106,107 The above data suggest that a single subcutaneous 
administration of dulaglutide can improve glucose-dependent insulin secretion and decrease glycemic 
excursions that may result in stress-hyperglycemia prevention with low risk of hypoglycemia.
B) INNOVATION  
1) The underlying mechanisms leading to stress hyperglycemia and poor hospital outcome are not well 
understood. It is unknown if hyperglycemia is a mediator in the development of hospital complications, or a 
bystander marker only representing severity of disease. Serial assessments of relevant candidate metabolites 
and biomarkers before and after the acute stress episode will facilitate our understanding of potential 
mediators of stress hyperglycemia and the metabolic response to stress. CABG surgery represents a unique 
human model to study in depth these relationships. 


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2) Metabolomics (HRM) is an emerging scientific field that enables profiling of thousands of metabolites to 
provide a functional readout of cellular metabolism in plasma and other bio samples. The use of metabolomics 
can identify metabolites and metabolic pathways implicated in the development of stress hyperglycemia. We 
expect to find an association of metabolites derived from protein and fatty acid catabolism (such as BCAA, and 
specifically 3-HIB) with stress hyperglycemia. In addition, serial assessments of glucose levels, candidate 
metabolites and biomarkers as well as an integrative network analysis to find multilevel associations between 
them will facilitate for the first time an approximation to causality interpretations. No previous studies have 
applied metabolomics analysis to understand stress-hyperglycemia. Novel bioinformatics tools such as 
metabolome-wide association studies (xMWAS) have the capability to facilitate an integrative network analysis 
to find multilevel associations and identify metabolic pathways and network structures in association with 
stress-hyperglycemia. 
3) We will examine biomarkers associated with meaningful cardiovascular disease outcomes that represent 
inflammation (C-reactive protein), coagulation (fibrin degradation products), cell stress (heat shock protein-70), 
and immune activation (suPAR). Hyperglycemia can lead to activation of these pathways. This study will for 
the first time examine longitudinally the relationship between clinically relevant biomarkers and stress-
hyperglycemia in patients with established cardiovascular disease. 
4) Current approach to manage hyperglycemia is a reactive care model. In a setting associated with high 
incidence of stress-hyperglycemia, we will test for the first time (Aim 2) if the use of a GLP-1 RA can prevent 
the onset of stress-hyperglycemia (proactive care) during the perioperative period of cardiac surgery. The use 
of novel agents with prolonged action is ideal for this purpose. 
5) The proposed study will provide critical first steps aiming at understanding and preventing stress-
hyperglycemia and will lay the groundwork to study the links between stress-hyperglycemia and hospital 
complications (career goal). This strategy has the potential to impact millions of patients undergoing cardiac 
surgery and to other scenarios associated with high risk of stress hyperglycemia and related complications. 
6) Next steps (R03/R01 applications): Results from Aim 1: once the most relevant metabolites are identified I 
plan to conduct primed continued tracer infusions to better understand if concentration changes are related to 
faster, slower production or both. I will conduct metabolic flux analysis in vivo to further examine the dynamic 
flow of specific metabolites through metabolic pathways during stress conditions. To understand what tissues 
are responsible for these changes, I will collaborate with scientists such as Dr. Kibbey to design additional 
studies. I also plan to integrate multi-omics approaches (metabolomics along with genomics/epigenomics) and 
reproduce findings in independent cohorts. Results from Aim 2 will provide preliminary estimates on 
hyperglycemia prevention, insights into risk stratification, and characterization of subjects most likely to 
respond to GLP-1RA to design additional RCTs.  
7) In summary: this project will under the guidance of a mentoring/advisory team: a) leverage the state-of-the-
art innovative technology available at Emory by applying new high-resolution metabolic profiling capabilities 
developed by co-mentor Dr. Jones and collaborators Dr. Yu, Dr. Uppal and Dr. Ziegler; b) integrate data with 
clinically meaningful biomarkers; c) help understand the underlying biology of stress hyperglycemia (under the 
guidance of Dr. Kibbey and Dr. Alvarez); and e) test potential solutions along with experts in inpatient diabetes 
(Dr. Umpierrez and Dr. Inzucchi).
C) PRELIMINARY DATA     Our research team has extensive research experience in inpatient management of 
hyperglycemia and has published several randomized controlled trials in ICU and non-ICU settings.24,27,86,108-114 
C.1. Impact of perioperative stress-hyperglycemia: In a retrospective analysis of glycemic control and hospital 
outcomes in 1971 patients with confirmed preoperative 
normoglycemia, we observed an increase in complications 
and mortality in patients developing stress-hyperglycemia.115 
Compared to patients with normoglycemia (<140 mg/dl), 
patients with stress-hyperglycemia had a longer length of 
hospital stay (LOS) and 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 for both complications [odds ratio 
(OR) 1.7 (1.2 – 2.4)] and mortality [OR 1.7 (0.4-7.1)]. The OR 
Figure 2. Non-DM patients randomized to the intensive group had 
a lower composite of complications compared to subjects in the 
conservative target.4
!!
Intensive (BG 100-140 mg/dl) 
Conservative (BG 100-140 mg/dl) 
P=0.008!


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for complications and mortality in patients with BG >180 mg/dl were 3.5 (2.2-5.4) and 6.6 (2.1-20.3), 
respectively. 
C.2. GLUCO-CABG Trial:24 in this RCT we aimed to determine whether intensive BG control (target: 100-140 
mg/dl) could reduce perioperative complications compared to conservative BG control (141-180 mg/dl) in 
hyperglycemic patients undergoing CABG. A total of 302 patients were randomized to intensive (n=151) or 
conservative (n=151) glucose control. The mean ICU daily BG was 132±14 mg/dl (IQR 124-139) in the 
intensive and 154±20 mg/dl (IQR 142-164) in the conservative group (p<0.001). Overall, we observed a similar 
number of patients in the intensive and conservative groups experiencing ≥ 1 complications (42% vs. 52%, 
p=0.08). We observed no differences in the composite or individual complications in patients with DM; 
however, the composite of complications was lower in non-DM patients with stress-hyperglycemia assigned to 
the intensive group, p=0.008, (Fig.2). Since all patients enrolled GLUCO-CABG patients had stress-
hyperglycemia, we recently analyzed phenotypic and biological characteristics of non-diabetic individuals at 
risk for perioperative stress hyperglycemia during CABG. The two most important features in patients who 
developed >2 episodes of BG >140 mg/dL were older age (67.0 ± 9.2 vs 59.1± 9.4, p=0.004) and higher BMI 
(28.9 ± 5.8 vs 26.1 ± 4.3, p=0.06). All six patients older than 50 years and BMI>30kg/m2 developed 
hyperglycemia. These characteristics were confirmed in an additional cohort (i.e. age >45 years). Older age 
and obesity are well-established risk factors for insulin resistance and DM. 
C.3. Inflammatory markers during CABG: Circulating 
levels of cortisol, inflammatory and oxidative stress 
markers increase for several days in the perioperative 
period (Fig. 3).  No difference was observed between 
conservative and intensive insulin therapy groups in the 
perioperative period of patients undergoing CABG 
surgery. Changes in these markers did not explain the 
benefits associated with tighter glycemic control with 
insulin therapy.3 
C.4. GLP-1 RA safety and non-inferiority to insulin 
therapy. In a recent RCT, we observed that a similar proportion of subjects reached goal (70-180mg/dL) with 
exenatide alone (61%) compared to basal bolus (63%) in the hospital. Exenatide (twice a day) was well 
tolerated, with higher, but not significant incidence of gastrointestinal side effects. Longer acting (once a week) 
GLP-1 RAs have been shown to be non-inferior or superior to insulin therapy and have a lower incidence of  
gastrointestinal side effects compared to exenatide or other short acting GLP-1 RAs.116-119 Recently dulaglutide 
was shown to have lower incidence of side effects compared to another long acting GLP-1 RA, semaglutide. 
Native GLP-1 continuous infusion (very short half-life) was well tolerated in patients undergoing CABG.120 GLP-
1 RA may be used before surgery in patients with DM.106,107 
C.5. Biomarkers and CV Death: Dr. Quyyumi et al. have demonstrated that a biomarker risk score (BRS) 
comprising suPAR (a biomarker of immune system activation and of inflammation) in addition to CRP 
(inflammation), FDP (coagulation), and HSP-70 (cell stress) significantly predicts 
all major outcomes in patients with coronary disease independently of traditional 
risk factors (Fig. 4). Correlations between biomarkers are modest suggesting 
that they act independently involving separate biological pathways.30 This 
findings have been recently reproduced in CABG patients (BARI-2 trial).2 
 C.6. Metabolomics in patients with hyperglycemic crisis: Following a 
metabolomics analysis flow developed in the lab of Dr. Jones (Fig. 7) we 
examined plasma samples from 29 adults with diabetic ketoacidosis (DKA). Out 
of 4,144 metabolites, we found 
216 significant baseline 
features that differed between 
patients with severe and non-
severe DKA; 87 features were 
down-regulated and 129 were 
up-regulated in severe 
DKA. A total of 373 
metabolites differed 
according to duration of 
continuous insulin 
infusion therapy. 
C.7. Protein and lipid 
catabolism: We observed that 
Figure 3. Cortisol and inflammatory markers during CABG surgery (Source:  
GLUCO-CABG trial)3,4
Figure 4. Path-specific biomarkers predict 
Mortality in patients with CAD. 30 
Figure 5. 3-Hydroxyisobutyrate (Panel A) a product of BCAA and 
sphingosine (Panel B), a product of lipid metabolism was associated with 
prolonged resolution of hyperglycemic crises in patients with diabetes, 
suggesting prolonged resistance to insulin (Pasquel et al. preliminary data)


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3-Hydroxyisobutyrate (3-HIB), and sphingosine were associated with prolonged resolution of ketoacidosis 
suggesting resistance to insulin therapy (Fig. 5) BCAA are implicated in the development of insulin resistance 
based on epidemiological and experimental data.49 3-HIB a catabolic intermediate of the BCAA valine is 
secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in 
vivo and promotes lipid accumulation in muscle, leading to insulin resistance.52 Recently, 3-Hydroxyisobutyrate 
has been associated with insulin resistance in humans and has also been identified as a predictor of incident 
type 2 diabetes.52,53,121  In addition, sphingosine, a sphingolipid derived from ceramide was also associated 
with prolonged resolution of ketoacidosis. Ceramides and acylcarnitines are associated with insulin resistance 
and incident CVD. 41,44-46,54,55  These initial metabolomics analyses represent an innovative approach in 
diabetes related research. To better understand mechanisms leading to stress-hyperglycemia in hospitalized 
patients (career goal) we will apply these technologies in a setting were a baseline and longitudinal 
assessment is more feasible (elective CABG surgery) and very clinically relevant.  
 
In summary, our preliminary studies indicate that stress-hyperglycemia is common and associated with 
increased rate of complications. Plasma BCAA, ceramides and acylcarnitines provide an intermediate link 
between metabolic stress, overnutrition, and mechanisms underlying insulin resistance and cardiovascular 
disease (CVD). Metabolic changes during hyperglycemia are complex and further explorations before and after 
stress in patients with and without perioperative stress-hyperglycemia are needed. Previous studies suggest 
that protein catabolism related products are associated with increased risk of pre-diabetes and diabetes. Our 
results suggest that 3-Hydroxyisobutyrate (3-HIB) a product of valine catabolism, and sphingosine are 
associated with prolonged response to insulin in acutely ill patients. A simultaneous and longitudinal 
assessment of biomarkers and relevant metabolites before and after surgery is essential to understand these 
complex relationships.  
D) APPROACH
 General overview: The proposed research will 
test in a nested case- control study 
associations of individual metabolites and 
broader metabolomics profiles as well as 
counter-regulatory hormones and biomarkers 
with stress-hyperglycemia (Aim 1). For this 
analysis patients will be stratified according to 
the outcome of stress-hyperglycemia (cases) 
and compared to controls (no hyperglycemia). 
For Aim 2 a randomized clinical trial will be 
conducted to examine the effects of exposure 
to dulaglutide on the prevention of stress-
hyperglycemia and the metabolic inflammatory 
response in the perioperative period, (Fig. 6).
Specific Aims
D1. Case – control study
Aim 1. To examine baseline and postoperative metabolic profiles of non-diabetic CABG patients with 
stress hyperglycemia.
Rationale: the underlying mechanisms leading to stress-hyperglycemia and its association with poor outcomes 
in cardiac surgery patients are not well understood. We aim to study metabolic signatures associated with 
hyperglycemia and path-specific biomarkers. We will test the temporal relationships between candidate 
metabolites/pathways (Table 1) and specific biomarkers with stress-hyperglycemia. 
Study design: In a nested case-control study (N=50) we will compare the characteristics of patients developing 
postoperative stress-hyperglycemia (cases) compared to patients that do not develop stress-hyperglycemia 
(age-matched controls). A proportion of patients will be derived from the placebo arm of the randomized trial. 
This design will allow efficient recruitment from our cohort of CABG patients to allow substantial savings in cost 
Figure 6. General overview. Aim 1 will be tested with a case-control study design. In Aim 2 we 
will conduct a clinical trial.  


Version 6 July 30, 2020
9
and time. Case definition: stress-hyperglycemia is defined as a BG >140mg/dl on arrival to the ICU. Please 
see additional details in Human Subjects section.  
Study Population: we will include patients with ages between 18-80 years without a history of diabetes [BG 
≤125 mg/dl and HbA1c <6.5%] undergoing CABG surgery. Patients will be recruited from three academic 
hospitals, including Emory University Hospital, Emory Hospital Midtown (EUHM), and Grady M Hospital in 
Atlanta, GA. Dr. Halkos (Chief of Division and Director of the CTS Center for Clinical Research) is a key 
collaborator and will facilitate recruitment and perform CABG surgeries. 
Aim 1.1 Targeted Approach: We will determine cross-sectional and longitudinal changes of ceramides, 
acylcarnitines, BCAA, and a biomarker panel for CVD outcomes and their relationship with stress 
hyperglycemia (BG >140mg/dl on ICU arrival). Path-specific biomarkers include: TNF-α and C-reactive protein 
(inflammation), fibrin degradation products (pro-thrombosis), heat shock protein-70 (cell stress), and suPAR 
(immune modulation and inflammation). Counterregulatory hormones include: cortisol, glucagon. Glucose, 
insulin and indexes of insulin sensitivity/insulin resistance: will be derived from glucose, insulin and c-peptide 
values. Methods: Plasma samples will be stored at − 80 °C until analysis. Serum CRP and FDP including 
fragments D and E, D -dimer, and additional intermediate cleavage products will be determined (FirstMark, 
San Diego, CA). Serum HSP-70 will be measured with a sandwich enzyme-linked immunosorbent assay (R&D 
Systems, Minneapolis, MN). Plasma suPAR levels will be measured using commercially available kits 
(suPARnostic kit; Virogates, Copenhagen, Denmark). Minimum detectable CRP, FDP, HSP-70, and suPAR 
have been reported at 0.1 mg/L, 0.06 μg/mL, 0.313 ng/ml, and 0.1 ng/ml, as described previously.65-68 Liquid 
chromatography tandem mass spectrometry techniques will be used to quantitatively profile ceramides, 
acylcarnitines, branched chain amino acids (leucine, isoleucine, valine), and aromatic amino acids (tyrosine 
and phenylalanine) in plasma samples along with standard reference samples. Glucose levels will be analyzed 
by the hexokinase method (Beckman-Coulter, Los Angeles, CA). Counterregulatory hormones, insulin, C-
peptide levels by two-site sequential chemiluminescent immunometric assays. Surrogates of beta cell function 
(HOMA-B) and insulin resistance (HOMA-IR) will be derived from fasting glucose, c-peptide and insulin. 
Analysis: Student’s t test and χ2 tests will be used when appropriate. Mann–Whitney U or Kruskal–Wallis 
nonparametric tests will be used for non-normally distributed variables. Analysis will account for age-matching. 
The relationship between biomarkers and stress-hyperglycemia and surrogates of insulin sensitivity and beta 
cell function will be determined using the Cox proportional hazards regression in unadjusted models and in 
models adjusted by gender, and smoking status to evaluate the impact of each 1 U increase in a biomarker 
risk score based on previously defined cut points for CRP, FDP, HSP-70, and suPAR (3 mg/L, 1.0 
μg/mL,0.313 ng/ml, and 3.5 ng/ml, respectively) as previously described.65,66,68


Version 6 July 30, 2020
10
1.2 Untargeted Analysis: Utilizing untargeted 
LCMS-derived high-resolution metabolomics (HRM) 
analysis we aim to identify additional candidate 
metabolites and new metabolic pathways associated 
with incident stress hyperglycemia during cardiac 
surgery. Methods: HRM analysis is a major 
component of my career development plan. Data 
analysis will be conducted under the supervision of 
Dr. Jones. Data Interpretation will be conducted 
under the guidance of Dr. Richard Kibbey (expert in 
metabolism). I will also have local support from Dr. 
Alvarez for interpretation of metabolomics results, as 
well as statistical support from Dr. Tianwei Yu. Dr. 
Uppal will provide guidance for hands-on use of 
metabolomics tools. Co-mentors and collaborators are 
experts in the data management requirements of the 
LCMS-derived high-resolution metabolomics (HRM) 
analysis proposed in this project. Serial samples will be 
collected: at baseline (up to seven days before surgery), and intra-op at 15 minutes (after cardiac bypass has 
started for on pump surgeries) or 2hrs after sternum incision (for off pump surgeries), 24hrs, 72-96hrs and 30 
days after surgery. Plasma samples will be stored at −80°C until analysis. The methods use UPLC with ultra-
high resolution mass spectrometry with a dual chromatography, dual ionization approach with each sample 
being analyzed with three technical replicates.122-124 With advanced data extraction provided by xMSanalyzer 
and apLCMS, I will be able to also measure a spectrum of high and low abundance metabolites. We will utilize 
a well-established computational metabolomics workflow with rigorous standard operating procedures outlined 
in Fig. 7.124 Data Selection and Annotation (Biostatistics and Bioinformatics Tools): HRM data will be 
processed using apLCMS with xMSanalyzer 125,126. Feature annotation will be performed using 
xMSannotator.127 xMSannotator provides confidence scores for more than 2,000 metabolites, with more than 
300 metabolites having confirmed identities and including most major pathways. The quality of data will be 
judged based on established rigorous criteria (e.g. coefficient of variation within replicatesand QC samples, the 
percentage of missing values, the percentage of data exceeding detection limits of the machinery, batch-
effects, and the percentage of outliers, etc.). Principal Component Analysis (PCA) will be used for batch-effect 
evaluation and ComBat122 will be used for batch- effect correction if necessary. Identifying expressed 
metabolites across different time points: we will use univariate and multivariate statistical methods, such as 
linear mixed effects models with post-hoc Tukey tests, LIMMA, and multilevel sparse Partial Least Squares 
Discriminant Analysis (msPLSDA).128,129 Multiple hypotheses testing correction will be performed using the 
Benjamini-Hochberg method.130 Identifying putative biomarkers: we will use a consensus feature selection 
approach such that metabolic signatures identified by both univariate and multivariate approaches will be used 
for downstream analyses. K-fold and leave-one-out cross-validation using Support Vector Machine (SVM) will 
be performed to evaluate predictive accuracy of putative biomarkers. Two-way hierarchical clustering analysis 
will be performed to identify clusters of correlated metabolic features and to evaluate the ability of the 
discriminatory features to separate samples based on stress-hyperglycemia. Pathway enrichment analysis: 
Pathway analysis will be performed with pathway enrichment software for untargeted metabolomics data 
(Mummichog and MetabNet)131,132 Where appropriate, additional chemical verification will be performed for 
significant metabolites of interest according to retention time and characteristic ion dissociation (MS/MS) 
patterns relative to authentic standards. Metabolome-wide association study (MWAS) of specific metabolites 
will be conducted (MetabNet) to facilitate detection of their related metabolic pathways and network structures 
in association with glucose levels (continuous) and stress-hyperglycemia as a discrete dichotomous variable. 
1.3 Integrative Analysis: A metabolome-wide association study (MWAS) of specific metabolites will be 
conducted (using MetabNet) to facilitate detection of their related metabolic pathways and network structures 
in association with stress-hyperglycemia. In addition, we will use xMWAS133 for integrative network analysis to 
find multilevel associations between glucose levels, metabolites and biomarkers.
Expected outcomes of Aim 1: During our analysis of candidate metabolites and discovery phase in Aim 1 we 
expect to find an association between candidate metabolites (i.e. BCAA, ceramides, acylcarnitines) and 
pathways associated with stress-hyperglycemia. We also expect to find an association between pathway-
xMSanalyzer
Data Table
m/z, RT, Intensity
Quality metrics
apLCMS, XCMS,
MZmine options
Biostatistics
Bioinformatics
Annotation, pathway
and network analysis: 
Mummichog, MetabNet, 
xMSannotator, others
Metabolite
forensics
Unequivocal 
Identification
MSn; UHRAM MS; 
1-D, 2-D NMR; ion
Mobility; Chemical
Reactivity, etc
MWAS 
PLS-DA
Data
extraction
ESI LC-MS 
Ultra-high resolution MS 
LTQ-FT
LTQ-Velos Orbitrap
Q-Exactive HF
Thermo Fusion 
GC-Orbitrap
Metabolites of 
interest 
Figure 7. Workflow for high-resolution metabolomics.  Samples are processed 
and analyzed in triplicate using liquid chromatography coupled to ultra-high 
resolution mass spectrometry.  Data extraction and quality assessment is 
automated with stringent quality control requirements.  Data are analyzed with 
well-established univariate and multivariate methods, with false discovery rate 
adjustment as appropriate.  Selected features are tested for pathway 
enrichment, and suspect metabolites are confirmed by coelution and MS/MS 
with authentic standards.  Reference standardization is used for quantification 
of metabolites of interest. (Uppal, Jones et al)


Version 6 July 30, 2020
11
specific biomarkers and stress-hyperglycemia with a higher degree of association according to the number of 
biomarkers based on pre-specified cut points (biomarker risk score).66 We expect to find multilevel associations 
between glucose, biomarkers and candidate metabolites. Serial measurements including measurements 
before the acute stress episode will facilitate causal interpretations. 
Potential Pitfalls, and Alternative Considerations: It is possible that some comparisons do not yield false 
discovery rate (FDR)-significant metabolites. In this scenario, and to provide a balance between type I and type 
II statistical error, metabolites with raw p<0.05 will be used for subsequent analyses, with statistical tests for 
pathway enrichment. Pathway enrichment analysis is less susceptible to type II error.134 We hypothesize that 
stress-hyperglycemia leads to elevation of path-specific biomarkers, however it is possible that pre-surgical 
elevation of biomarkers predicts the development of stress-hyperglycemia. Elucidating this scenario is 
important as identifying susceptible subjects before surgery (baseline elevation of biomarkers) will facilitate the 
design of cohort studies as well as recruitment of at-risk patients in future trials. 
D2. Randomized Clinical Trial 
Aim 2. To obtain preliminary estimates of the effect of a long-acting GLP-1 RA on the prevention of 
stress-hyperglycemia and modulation of metabolic stress during cardiac surgery.
Rationale: At least half of non-DM patients undergoing cardiac surgery develop stress hyperglycemia,8,9,72,135 
shown to be an independent risk factor of morbidity and mortality.10,12,14-16 To maximize exposure to subjects at 
high risk of stress hyperglycemia, we will enroll obese individuals older than 50 years of age. Most patients 
with stress-hyperglycemia require insulin infusion in the ICU and about half continue to receive subcutaneous 
insulin after transition to regular wards.24,136 GLP1 treatment has been shown to improve glycemic control 
similar to insulin administration in critically ill patients,88-90 CABG surgery,92 and in mixed ICU populations.93 
Dulaglutide is effective in improving glycemic control in patients with DM,100-102 with lower rate of side effects 
compared to other long acting GLP-1-RA.105 Phase 1 pharmacodynamics analysis in non-DM participants 
demonstrated median maximum plasma concentrations of dulaglutide between 24-48 hours after single-dose 
administration103 with a dose-dependent rise in insulin secretion and progressive reduction in glucose 
concentration.103 The rapid onset and sustained action, safety and efficacy with low-rate of hypoglycemia,102,137 
indicate that dulaglutide is an ideal agent for the prevention of stress-hyperglycemia.
Study Design: This randomized, placebo controlled study will include 60 obese subjects with ages between 40-
80 years of age without a history of diabetes [BG ≤125 mg/dl and HbA1c <6.5%] undergoing CABG surgery. 
Due to the study design (i.e. need of surgical care), there will be no run-in period.  Women in childbearing 
potential will have urine β-HCG measured before participating in the study.   
Study population: 
Inclusion criteria:  Males or females between the ages of 40 and 80 years and BMI ≥25kg/m2 undergoing 
elective CABG surgery. No previous history of diabetes or hyperglycemia. 
Exclusion criteria: a) Hyperglycemia (BG>125 mg/dl or HbA1c > 6.5%) or previous treatment with antidiabetic 
agents; b) impaired renal function (GFR < 30 ml/min) or clinically significant hepatic failure; c) subjects with 
gastrointestinal obstruction expected to require gastrointestinal suction; d) patients with clinically relevant 
pancreatic or gallbladder disease; e) treatment with oral or injectable corticosteroid; f) mental condition 
rendering the subject unable to understand the possible consequences of the study; g) pregnancy or 
breast-feeding at time of enrollment. Additional considerations are outlined in the Human Subjects section. 
Aim 2.1 Prevention of hyperglycemia (primary endpoint): 
The primary endpoint of this exploratory study is to compare the frequency of stress-hyperglycemia defined as 
any post-CABG hospital-obtained BG > 140 mg/dl between patients randomized to dulaglutide or placebo. 
Aim 2.2 Secondary Endpoints: To determine the difference between groups in mean BG level in the ICU.  
Additional endpoints include differences between treatment groups on: 1) the number of patients with stress-
hyperglycemia requiring rescue therapy with SC insulin after discontinuation of CII; 2) need for CII treatment of 
hyperglycemia in the ICU; 3) mean ICU and floor BG concentration; 4) mean insulin dose during ICU (insulin 
infusion per hour (unit/hour) and per day); 5) duration of CII (hours); 6) days of SC insulin after discontinuation 
of CII; 7) amount of SC insulin in ICU and non-ICU stay; 8) hyperglycemic events (BG > 200 mg/dl) in ICU and 
non-ICU; 9) hypoglycemic events in ICU and non-ICU (<70, < 54, and <40 mg/dl); 10) composite of mortality 
and complications including sternal wound infection, bacteremia, pneumonia], acute kidney injury, and acute 
myocardial infarction; 11) gastrointestinal adverse events (nausea, vomiting, ileus, pancreatitis); 12) ICU and 
hospital LOS, and ICU readmissions; 13) cerebrovascular events; 14) ICU and hospital mortality. 


Version 6 July 30, 2020
12
Methods for Aims 2.1 and 2.2: 
Treatment Groups: Patients will be randomized at pre-
surgery/anesthesia visit. Patients without a history of DM will 
receive a single injection of dulaglutide/placebo 1-3 days prior 
to surgery (Fig. 8). 
Inform consent and randomization: Patients will be consented 
during the preoperative evaluation on admission at least 24-72 
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. Additional 
details are outlined in the Human Subjects section. 
Study Sites: This pilot study will be conducted at Emory University Hospital, Emory Midtown Hospital, and 
Grady Memorial Hospital, Atlanta.
ICU Stay: Study patients who develop stress-hyperglycemia (BG >140 mg/dl) in the ICU will be started on 
intravenous CII adjusted to maintain a BG target between 100-140 mg/dl following a standard hospital protocol. 
Transition from ICU to Regular Floor: Patients with fasting and/or premeal BG >140 mg/dl will receive 
coverage with sliding scale insulin (supplements), those with 2 consecutive BG >180 mg/dl, or average daily 
BG >180 mg/dl will be started on rescue therapy with SC basal insulin (glargine or levemir) once daily.111 
Rescue Therapy with Basal Insulin in Non-ICU Settings111:
  BG between 140-200 mg/dl= start basal insulin at 0.1 units per kg weight per day. 
  BG between 201-400 mg/dl= start basal insulin at 0.2 units per kg weight per day.
  Basal insulin will be given once daily, at the same time of the day.  
Insulin adjustment and supplemental (correction) insulin: we will use a standard insulin treatment protocol.4,86
Investigational drugs: 

Dulaglutide injection: 0.75 mg/0.5 mL solution in a single-dose pen will be provided to patients 

Saline injection/0.5 mL pre-drawn solution, a tuberculin syringe will be provided to patients

A research pharmacist at the site-specific Clinical Research Network Unit will provide dulaglutide and 
saline. Patients will be instructed on self-injection technique. 
Withdrawal Criteria (please see additional details in Human Subjects and DSMP sections):

The subject may withdraw at any time during the study by primary care provider or research team.

The subject may be withdrawn at the investigator’s discretion due to a safety concern or for contravention 
to the inclusion and/or exclusion criteria.

Subject diagnosed with acute pancreatitis by clinical and/or radiographic criteria.
Analysis: The primary endpoint of Aim 2 is the frequency of stress-hyperglycemia (BG >140 mg/dl) requiring 
insulin therapy during the postoperative period (Aim 2.1). We will use two-sided Chi-square test or Fisher’s 
exact test for the primary outcome. In Aim 2.2 we will compare the difference in mean BG upon ICU arrival and 
the frequency of rescue therapy with SC insulin after transition to regular floor. We will also explore differences 
in complications between groups. Secondary outcomes of interest can be a binary outcome (e.g. whether CII is 
needed in ICU), or a count outcome (e.g. number of perioperative complications), or a continuous outcome 
(e.g. mean ICU BG concentration). We will adopt the same strategy proposed for the primary outcome to 
analyze any binary secondary outcomes. For secondary outcomes measured as counts, we plan to use 
nonparametric tests such as Krustal-Wallis tests. Univariate Poisson regression (or Negative Binomial 
regression) will be performed to estimate the marginal treatment effect. In addition, we will also conduct 
multivariate Poisson regression (or Negative Binomial regression) to assess the outcome differences between 
the two study groups with potential confounders considered. For secondary endpoints that produce continuous 
outcomes, we will use two-sample t-tests or nonparametric Wilcoxon tests to compare study groups. 
Transformations will be applied if normality violation is detected.  
Aim 2.3. To compare changes in metabolites and biomarkers in response to dulaglutide or placebo 
(measured in Aims 1.1 and 1.2), as well as beta-cell function and insulin resistance estimates. 
Methods: Biomarkers and assessment of candidate metabolites will follow the same procedures as specified 
in Aim 1. Surrogates of beta cell function and insulin resistance will be derived from glucose, insulin, and c-
peptide measurements acquired during the perioperative period. 
Pre-
Surgery/
anesthesia
visit
Dulaglutide
Placebo
-3
-2
-1
SURG
1
2
3
4
5
6
7
Day -10 to -3
Randomization
Surgery
Study
Drug
Treatment Period (days)
Figure 8. Treatment groups in Aim 2. Patients will be assigned to 
receive dulaglutide or placebo 1-3 days before surgery. 


Version 6 July 30, 2020
13
Analytic Techniques: Glucose levels will be analyzed by the hexokinase method (Beckman-Coulter, Los 
Angeles, CA). Insulin and C-peptide levels will be measured by two-site sequential chemiluminescent immuno- 
metric assays as previously described. Surrogates of beta cell function (HOMA-B) and insulin resistance 
(HOMA-IR) will be derived from fasting glucose, c-peptide and insulin. Only glucose and c-peptide will be 
measured serially after surgery (given high likelihood of exposure to exogenous insulin).
Analysis: We will integrate analyses from Aims 1 and Aims 2 to evaluate the role of dulaglutide on metabolites, 
metabolic pathways and biomarkers. We will use univariate and multivariate statistical methods, such as linear 
mixed effects models with post-hoc Tukey tests, LIMMA, and multilevel sparse Partial Least Squares 
Discriminant Analysis (msPLSDA), as described in Aim 1.
Expected outcomes in Aim 2: In Aim 2.1 we expect to observe a decrease in the number of patients with 
stress-hyperglycemia with low risk of hypoglycemia with dulaglutide therapy. We expect to find a least an 18 
mg/dl (1 mmol/l) mean difference in BG between groups during ICU stay. In Aim 2.2 we don’t expect to find 
differences in hospital outcomes. In Aim 2.3 We expect to observe differential changes in up or down 
regulation of metabolic pathways in response to dulaglutide compared to placebo. 
Potential Pitfalls, and Possible Solutions, Alternative Consideration: Recruitment and retention of patients 
are important challenges in RCTs; however, Emory University and affiliated hospitals serve as cardiovascular 
referral center to a large population in the city of Atlanta, with over 1,000 major cardiac surgeries performed 
yearly. In our previous trial we recruited 340 patients over 3 years, therefore we expect to have enough time 
during the award period to complete enrollment (please see research timeline). It is possible that dulaglutide 
does not have an effect on the prevention of hyperglycemia. This information will help us understand the 
contribution of the incretin pathway to glucose metabolism during surgical stress. 
E. Risks to Human Subjects
E.1.1 Human Subjects Involvement, Characteristics, and Design

Description and justification for proposed involvement of human subjects: 
Extensive data from observational and prospective randomized controlled trials (RCT) in hospitalized 
patients have reported a strong association between stress hyperglycemia and poor clinical outcome, 
such as increased mortality, morbidity, hospital length of stay (LOS), infections and overall 
complications. This relationship is well established, and a dose response is consistently observed. This 
association is more robust among non-diabetic subjects compared to patients with diabetes or 
normoglycemia. Millions of cardiac surgeries are conducted globally and there is an urgent need to 
understand the mechanisms that lead to hyperglycemia during stress conditions and strategies to 
improve meaningful clinical outcomes. Cardiac surgery, in particular coronary artery bypass graft 
(CABG), is a unique human model for the study of metabolic changes during surgical stress. In our own 
study we have shown a reduction in a composite score of complications in subjects without diabetes 
undergoing CABG surgery randomized to a more intensive glycemic target. Our current approach to 
treat hyperglycemia, however, is reactive, it demands high resource utilization (staff needs to monitor 
glucose levels hourly and adjust intravenous insulin doses frequently), and if not done carefully is 
associated with a very high risk of iatrogenic hypoglycemia (up to 35%), which also carries a high risk 
of complications. This novel, exploratory study will characterize metabolic signatures during stress 
hyperglycemia, integrate findings with clinically meaningful biomarkers, and provide preliminary 
estimates of the effect of a long acting GLP-1 receptor agonist on the prevention of stress 
hyperglycemia. 

Study Population Characteristics: Clinically stable adults scheduled to undergo coronary artery 
bypass graft surgery (CABG) will be studied. We expect that a total of 90 subjects will complete this 
project. A proportion of patients will be derived from the placebo arm of the randomized trial. This 
design will allow efficient recruitment from our cohort of CABG patients to allow substantial savings in 
cost and time. For Aim 1 a total of 50 patients will be included. In Aim 2 patients will be randomly 
assigned to dulaglutide (N=30) or placebo (N=30) one to three days before surgery. For both aims 
subjects must meet the inclusion and exclusion criteria listed below: 


Version 6 July 30, 2020
14
Inclusion criteria: 1) Males or females between the ages of 40 and 80 years and BMI ≥25kg/m2 
undergoing elective CABG surgery; no previous history of diabetes or hyperglycemia. 
Exclusion criteria: 1) Hyperglycemia (BG>125 mg/dl or HbA1c > 6.5%) or previous treatment with 
antidiabetic agents; 2) Severely impaired renal function (GFR < 30 ml/min) or clinically significant 
hepatic failure; 3) Subjects with gastrointestinal obstruction expected to require gastrointestinal suction; 
4) patients with clinically relevant pancreatic (including history of pancreatitis) or gallbladder disease; 5) 
treatment with oral or injectable corticosteroid; 6) mental condition rendering the subject unable to 
understand the possible consequences of the study; 7) Pregnant female subjects or breast feeding at 
time of enrollment. 
•
Sampling Plan: Potential study subjects will be identified and pre-screened among patients scheduled 
for CABG at Emory University affiliated hospitals. Enrollment will be coordinated with cardiovascular 
surgeons. Dr. Halkos, Scientific Director, of the Cardiothoracic Surgery Center for Clinical Research 
(CCR) will facilitate enrollment in the study. A study coordinator will conduct informed consent in eligible 
subjects prior to any study procedures. Screening and recruitment reports will be generated monthly 
that include actual and expected recruitment statistics.  Strategies to address potential problems with 
recruitment will include biweekly communications between Dr. Pasquel, Dr. Umpierrez, and Dr. Halkos. 
After informed consent, baseline and post CABG blood sampling will be performed. Samples will be 
stored at Clinical Research Network (CRN) sites of the NIH-funded Georgia Clinical and Translational 
Science Alliance (CTSA).  
•
Special Populations: This study does not involve special vulnerable populations. It will, however, 
include elderly subjects with ages between 65 and 80 years of age, who are more likely to have 
advanced cardiovascular disease and require CABG surgery. Older patients are also more likely to 
develop hyperglycemia during surgery. 
•
Group Assignment / Case Definition: Clinically stable adults scheduled to undergo coronary artery 
bypass graft surgery (CABG) will be studied. For logistic purposes recruitment will favor assignment to 
the clinical trial in the beginning of the award period (Aim 2, N=60). We expect a total of 30 subjects will 
be randomized to each group (dulaglutide or placebo). Thirty patients assigned to placebo in the clinical 
trial will contribute to the cohort of patients to be included in the nested case-control study. Cases and 
controls will be categorized prospectively on arrival to the surgical intensive care unit (SICU) (Cases are 
defined as BG >140mg/dL on ICU arrival). To further avoid selection bias, 25 age-matched controls will 
be selected for comparison. Once the number of cases is completed, additional potential controls will 
be selected (+/- 3 years) based on the characteristics of the population of cases. If additional patients 
develop stress hyperglycemia no further samples will be collected.  This design will allow for efficient 
recruitment from our cohort of CABG patients to allow substantial savings in cost and time. 
•
Research Sites: All human subjects’ research will be performed on the campus of Emory University, 
Atlanta, GA, and at Emory Affiliated Hospitals. Sites include Clinical Research Units (CTSA) where 
samples will be stored. Data collected are kept confidential and protected as per HIPAA regulations. 
Data collected at each facility will be shared only with the study team.
E.1.2. Study Endpoints and Sources of Materials: 

In the case control study (Aim 1) we will compare metabolic and hormonal profiles between subjects 
that develop stress hyperglycemia compared to controls. In an open-label format (Aim 2) we will assess 
whether exposure to dulaglutide is associated with a reduction in the frequency of stress hyperglycemia 
compared to placebo (primary endpoint). Prospectively, we will assess the association of candidate 
metabolites and metabolic pathways with the onset of stress hyperglycemia. Potential mechanisms 
underlying these associations will be explored by examining whether the associations of exposure to 
dulaglutide and prevention/improvement of glycemic control can be explained by changes in metabolic 
pathways (and key metabolites within these pathways) measured in plasma that occur between 3 days 
prior to surgery (baseline) and during the perioperative period. Addressing these research questions 


Version 6 July 30, 2020
15
will be possible using innovative ultra-high resolution mass spectrometry (HRMS) with liquid 
chromatography (LC) and gas chromatography (GC) and advanced data extraction algorithms. LC-
HRMS will also measure >2000 metabolomic intermediates in plasma at the time of surgery and at 
follow-up, providing coverage of >85% of human metabolic pathways. The overall hypotheses are 
that candidate metabolites such as: ceramides, acylcarnitines, and branched-chain amino acids 
(BCAAs) are associated with incident stress hyperglycemia, and that hyperglycemia leads to changes 
in path-specific biomarkers related to CV risk. In addition, exposure to an agent associated with low risk 
of hypoglycemia can positively affect the trajectory of metabolic changes during acute surgical stress. 
Baseline measurements: Samples will be collected up to seven days prior to scheduled CABG surgery. 
Blood samples will be processed by the CRN Laboratory and stored at −80°C until ready for batch 
analysis. Fasting plasma metabolomics analysis will be performed using high-resolution metabolomics 
(HRM) methods established in Co-mentor Dean Jones’ laboratory. Samples for measurement of 
biomarkers, glucose, cortisol, glucagon, insulin and c-peptide will also be collected. Indexes of insulin 
sensitivity/insulin resistance: will be derived from glucose, insulin and c-peptide values. Indexes of 
insulin secretion: pancreatic β-cell insulin secretion capacity will be assessed with HOMA-B. 
Sources of materials: Research material will include medical history, demographic information, and 
complications obtained both from subjects, medical record, and study blood samples. 
Data collected: Data to be collected is detailed in Table 1 below, along with the source of the data. 
Baseline and daily information will be entered by Dr. Pasquel or a study coordinator into data collection 
paper forms and into an electronic database (REDCap) provided by the Emory Research Information 
Technology Department. 
Table. Data to be collected and source
Data Item
Source 
-Vitals (e.g. blood pressure, pulse, temperature)
Medical Exam
-Height, weight, BMI
Manual stadiometer and digital scale
-Demographic Information (e.g. age, race)
Self-report and medical records
-Medical history (e.g., comorbidities, surgeries)
Self-report and medical records
-Social history (e.g., education, smoking, alcohol use)
Self-report and medical records
-Indexes of insulin secretion, resistance and sensitivity
serial blood draws
-Plasma metabolomics, biomarkers, hormones 
-Dates of hospitalization and operation
-Daily laboratory results (e.g. blood glucose, creatinine, eGRF)
-Treatment (IV or SC insulin dosage, use of corticosteroids)    
Blood draw
Medical records
Medical records
Medical records 
-Complications and adverse events (defined below) 
-Length of ICU and hospital stay
Self-report and medical records 
Medical records
Data Collection on Complications 
o
Surgical wound infection (superficial and deep sternal wound infection).
o
Pneumonia (CDC criteria).
o
Acute kidney injury defined as an increment in serum creatinine ≥ 0.3 mg/dL from baseline or  
≥1.5 times baseline creatinine (KDIGO) 
o
Acute myocardial infarction (AMI): (1) typical increase and gradual decrease (troponin) or (2) 
more rapid increase and decrease (creatine kinase MB) of biochemical markers of myocardial 
necrosis with at least one of the following: (a) ischemic symptoms, (b) development of 
pathologic Q waves on the electrocardiogram, (c) electrocardiographic changes indicative of 
ischemia (ST-segment elevation or depression), or (d) coronary artery intervention (e.g., 
coronary angioplasty). 


Version 6 July 30, 2020
16

Clinical Management Guidelines: The primary care team will provide care regarding the use of 
vasopressors, ventilator support, sedation, antibiotics, and treatment of co-morbid conditions.  
a.
Assessment and monitoring of BG concentration.  Information on BG measurements both at 
bedside by glucose meter and by hospital laboratory will be collected.  BG will be measured every 
1-2 hour during continuous insulin infusion (CII) in the ICU, and before meals and at bedtime after 
transition to regular wards.  Hypoglycemia is the main adverse event and safety concern in the 
study. The number of mild (≤70 mg/dL) and severe hypoglycemia (≤ 40 mg/dL) and clinical 
consequences (neurological and cardiovascular) will be compared between groups. 
b.
Assessment and monitoring of hospital mortality.  Investigators will follow study subjects daily and 
the date and presumed cause of death will be recorded.  Information on the attending physician’s 
summary of events surrounding subject’s demise will also be documented.
c.
Assessment and monitoring of wound infections.  The investigators will review each subject’s 
records daily from Monday to Friday regarding potential new infections.  Data from the weekends 
will be collected the following Monday.  Definitions: Deep Sternal Wound Infection (DSWI): chest 
wound infection involving the sternum or mediastinal tissues, including mediastinitis; Superficial 
Sternal Wound Infection (SSWI) (not involving the sternal bone or wires): chest wound infections 
involving the skin or subcutaneous tissues, or both. 
d. Assessment and monitoring of nosocomial infections.  The following daily information will be 
collected for nosocomial infection surveillance: 1) temperature curve; 2) white blood cell counts; 3) daily 
progress notes; 4) daily clinical microbiology laboratory data; 5) all relevant radiographic reports; 6) 
orders for antimicrobial agents; 7) communication, as needed, with primary physicians and site 
infectious disease consultants; 8) use of the CDC guidelines for diagnosis of specific nosocomial 
infections. 
e. Assessment and monitoring of days on mechanical ventilation.  The need for mechanical ventilation 
will be monitored daily. The day the subject is weaned from the ventilator will be recorded.
f. Assessment and monitoring of length of SICU and hospital stay.  The morning location of the study 
subject (in either the SICU or surgical ward) and date of hospital discharge will be recorded daily. 
g. Assessment and monitoring of renal function.  Acute kidney injury - new-onset abnormal renal 
function is defined as an increment of creatinine level above 50% from baseline.  
h. Cerebrovascular accident (CVA).  Defined as central neurologic deficit persisting more than 72 hours 
(permanent stroke), transient ischemic attack, deficit resolving within 24 hours, or deficit lasting more 
than 24 hours but less than 72 hours (reversible ischemic neurologic deficit).
   Data collection and data entry.  Study members will enter baseline and daily data for this study into 
data collection paper forms and into an electronic database provided by the Emory Research 
Information Technology Department. Baseline data will include demographics/history form (subject 
gender, date of birth, ethnicity, dates of hospitalization and operation, history of diabetes, and comorbid 
conditions, body weight, BMI, smoking status, type of surgery, APACHE score. Daily information will be 
collected on treatment (insulin IV or SC and dosage, antibiotics, use of corticosteroids), nutrition 
support, BG and laboratory values, hospital complications and adverse events, and length of ICU and 
hospital stay.
E.1.3. Potential Risks

Potential Risks/Discomforts: 
a.
Venipuncture: There is some minor discomfort and risk of mild bruising during venipuncture. 
Standard sterile techniques will be used during phlebotomy; thus, infection is unlikely. Disposable 
pre-sterilized needles and syringes will be used for all blood drawing in this study; needles and 
syringes will not be reused. Discomforts associated with venipuncture are rapidly reversible. 
Approximately 40 mL of blood will be obtained for all the blood measurements proposed.


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b.
Hypoglycemia: In our previous ICU studies, we observed that <10% of cardiac surgery subjects 
during CII and 20-30% during SC insulin experienced hypoglycemia. No episodes of severe 
hypoglycemia were observed during CII in our study. The use of insulin in combination with GLP1-
RA may increase the risk of hypoglycemia.  The number of mild (≤70 mg/dL) and severe 
hypoglycemia (≤ 40 mg/dL) and clinical consequences (neurological and cardiovascular) will be 
compared between groups. Treatment of hypoglycemia: hypoglycemia, defined as a BG <70 mg/dL 
will be treated by a standard hypoglycemia protocol available at each hospital.
c.
Hyperglycemia: it is very likely that a high proportion of patients randomized to placebo develop 
hyperglycemia. All subjects with hyperglycemia (in both groups) will be treated by standard 
protocols in the ICU units at each hospital. We expect that ~50-60% of subjects randomized to 
placebo will experience one or more episodes of hyperglycemia. The frequency of severe 
hyperglycemia will be analyzed statistically.  
d.
Gastrointestinal adverse effects: include nausea and vomiting, which are more common in patients 
treated with dulaglutide compared to placebo. The frequency of nausea and vomiting is reported in 
up to 10% of patients receiving dulaglutide in combination to oral agents compared to 3.5% in 
patients receiving placebo plus oral agents. If a participant developed nausea during hospitalization 
the research team will perform a phone call visit on post-discharge day 2 to ensure safety. There 
have been few reported events of acute pancreatitis with the use of GLP1-RA (typically reported 
among patients at higher risk of pancreatitis).  Subjects should be informed of the characteristic 
symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, 
potentially suspect medicinal products should be discontinued. Patient will receive a single 0.75mg 
dose of dulaglutide. If the investigator suspects acute pancreatitis, all suspected drugs should be 
discontinued until confirmatory test have been conducted and appropriate treatment should be 
initiated. Subjects diagnosed with acute pancreatitis (as a minimum 2 of 3: characteristic abdominal 
pain, amylase and/or lipase >3xUNR or characteristic findings on CT scan/ MRI) should be 
withdrawn from the study.

Alternative treatments: The alternative is for a participant to not participate in the trial.
E.1.4 Adequacy of Protection Against Risks
a.
Recruitment and Informed Consent

Recruitment and Informed consent: Potential study subjects will be identified and pre-screened among 
patients undergoing CABG surgery at Emory affiliated hospitals. 

Dr. Pasquel or the study coordinator will conduct informed consent in eligible subjects prior to any 
study procedures. Screening and recruitment reports will be generated monthly that include actual and 
expected recruitment statistics.  

Description of informed consent process: A written and signed informed consent will be obtained in 
person in a private area. After identification of a person as potentially eligible for the study, approved 
study personnel will explain the study in detail in the consent form as well as verbally. Potential 
participants will be informed of the purpose of the study, the study protocol, and the routine and 
potential risks associated with the study procedures. All risks, costs, and benefits will be discussed.  
Participants will be assured of their right to withdraw at any time without prejudice to their care. They 
will be assured of confidentiality in maintaining records and reporting of results. A separate consent 
will also be obtained for permission to store biological samples for future studies. Any additional 
information regarding questions or concerns from potential or confirmed study participants will be 
provided. Participants will have ample time to call the study team with questions/concerns and make 
an informed decision about their participation in the study. 
An Institutional Review Board (IRB) approved study designee will provide verbal and written consent. 
The study is discussed thoroughly with each potential participant, and he/she will be encouraged to 
ask questions regarding the study and her participation. If the potential participant decides to enroll, 
he/she will sign the written informed consent, as will the study team member conducting informed 
consent. A copy of the signed consent form will be provided to enrolled study participants. The 


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consent process will be documented using a template provided by the Emory IRB in the "Consent 
Clinical Trial Tools" section of the Emory IRB website.
Subjects must be able to read, write and understand the consent documents. Study personnel will 
subjectively assess the capacity to give informed consent through the use of questions to ensure 
understanding and comprehension of the study. Only adults will participate in this study.

Waivers: We will request a partial HIPAA waiver to be able to access medical records for screening.
b.
Protections Against Risk

Protections against risks: Adverse events are expected to be uncommon and not pose more than 
minimal risk to the study participants. 
o
Subject identification and screening for eligibility: Our strict inclusion and exclusion criteria for 
entry (outlined above) will help to minimize potential risks. All subjects will be monitored closely 
by frequent clinical assessments and review of safety laboratory tests by experienced 
clinicians. In addition, we will carefully monitor capillary BG at the bedside using the hospital 
certified meter, b) only experienced nurses/or phlebotomist will draw blood samples, c) patients 
will be closely monitored in the ICU, d) no patients with history of significant pancreatic, renal 
or hepatic failure will be recruited in this study.  
o
Blood sampling: Experienced research nurses will use aseptic techniques for all study blood 
draws. Participants will be asked to stay hydrated with water the day before the study visit. 
Universal precautions will be employed in all instances involving human specimens and all 
blood processed under at least BSL2 conditions. Discomforts associated with venipuncture are 
rapidly reversible. During surgery trained personnel will collect the blood samples. 
o
Hyperglycemia: All patients that develop hyperglycemia will be treated by standard insulin 
protocols in the ICU and non-ICU units available at each hospital. 
o
Hypoglycemia: In our previous ICU studies, we observed that <10% of cardiac surgery 
subjects during CII and 20-30% during SC insulin experienced hypoglycemia. No single 
episode of severe hypoglycemia was observed during CII in our study in CABG patients. The 
use of insulin in combination with GLP1-RA may increase the risk of hypoglycemia.  The 
number of mild (≤70 mg/dL) and severe hypoglycemia (≤ 40 mg/dL) and clinical consequences 
(neurological and cardiovascular) will be compared between groups. Any episode of 
hypoglycemia (BG <70 mg/dL) will be treated by a standard hypoglycemia protocol available at 
each hospital.
o
Privacy/Confidentiality: The subjects’ extracted medical records and data from the study 
will be initially stored on paper prior to transfer to electronic format. The encrypted 
electronic record will remain on the principal investigator’s password protected computer 
in his locked office. Confidentiality will be assured by the use of subject codes rather than 
personal identifiers. The master list connecting the subject codes to identifying information 
will be secured in the Emory’s computerized database. All paper subject records will be 
kept in locked file cabinets in the PI’s research office and will be accessible only to the PI 
and the investigative team. Only institutional review board (IRB)-approved study 
personnel will have access to individually identifiable information about human subjects. 
This may include the study PI, co-investigators, research coordinators, and other 
approved study personnel. All information and materials will be obtained for research 
purposes only and the data will be kept in strict confidence for use in this proposed 
research only.
o
Other: Since the proposed tests are not inherently hazardous, hazard is likely to occur 
only as the result of impaired participant confidence or sudden unwillingness to complete 
a test. To avoid this possibility, study personnel will thoroughly explain all tests to potential 
participants prior to them signing the consent form. Potential participants will have the 
opportunity to see all test equipment and facilities before giving consent or undergoing 
testing. Every effort will be taken to prevent injury or distress that may result from this 


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study. Dr. Pasquel, or a study physician will be on call for support. A qualified physician 
will have primary responsibility for inpatient care.
o
Data and Safety Monitoring: A senior faculty Safety Officer, with expertise in randomized 
controlled clinical trials will be designated as the Safety Officer for this study. He/she will 
review semi-annual reports created by Dr. Pasquel and make recommendations regarding the 
continuation of study. Dr. Pasquel will review this protocol on a continuing basis for subject 
safety and include the results of the review in semi-annual reports to the Safety Officer and 
annual progress reports submitted to the IRB. A full Data and Safety Monitoring Plan (DSMP) 
is provided in a separate document. 

Medical intervention: If a participant suffers from distress during a procedure, the procedure will 
be discontinued. The participant will then be managed in the Emory affiliated Hospital surgical suite 
or in the CRN unit, which, if applicable or warranted, have immediate access to EKG monitoring, 
cardiac resuscitation equipment and are located in close proximity to Emergency Departments. 

Every effort will be taken to prevent injury or distress that may result from this study. A study 
physician will be on call for support. A qualified physician will have primary responsibility for 
inpatient care.
E.1.5   Potential Benefits of the Proposed Research to Human Subjects and Others

Potential Benefits: There may be no specific health benefit to patients’ participation in the study. 
However, participants will receive information on their blood glucose levels during the hospital stay, 
which they may use to inform their own health decisions/activities. 

Risk/Benefit Assessment: The risks incurred are minimal relative to the potential benefit of gaining 
information about individuals’ health. Our group has extensive experience in glycemic control in the 
hospital and we will follow closely all patients for timely and appropriate management of 
hyperglycemia and hypoglycemia. 
E.1.6. Importance of the Knowledge to be Gained
•
Importance of Knowledge: The long-term goal of this study is to identify underlying 
mechanisms that lead to hyperglycemia and their association with established biomarkers 
known to predict risk of death in patients with coronary disease. This study has the potential to 
identify clinically meaningful metabolites to guide the development of important biomarkers (to 
be assessed in independent cohort studies) that can help to stratify patients at risk for hospital 
complications. The findings that arise from this research will also inform scientists in developing 
new technologies and designing future therapies to better understand and treat metabolic 
derangement during acute stress. We also aim to prevent hyperglycemia with an agent 
associated with lower risk of iatrogenic hypoglycemia. If our hypothesis is correct, such 
information could guide future clinical trials aimed at preventing hyperglycemia with the goal of 
impacting meaningful endpoints (cost, hospital complications, and mortality). 

Risk/Importance Assessment: The anticipated benefits of the proposed research study outweigh the 
potential risks to participating subjects. The potential for serious adverse effects is small and the 
potential benefit to society is high enough for the studies to proceed. 
E.1.7 Data and Safety Monitoring Plan (DSMP): Please see DSMP provided as a separate document. 
E.1.8 ClinicalTrials.gov Requirement: This clinical trial will be registered on ClinicalTrials.gov. Final 
results will be published on this site. 
E.1.9 Statistical Considerations 


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Sample Size Calculation and Power Analysis: with a Wilcoxon test, for an effect size >1 at alpha=0.05 and 
power=0.80, the proposed sample size of N=50 for this experiment will be more than adequate for the main 
objective of identifying differentially expressed metabolites and pathways in Aim 1, as shown in previous 
studies.134,138 For Aim 2 we assumed N=60. No preliminary data on prevention of hyperglycemia is available. 
Assuming an effect size of ~0.50 on hyperglycemia prevention with X2 goodness of fit for contingency tables, 
power 80%, alpha=0.05, a total of 52 patients would be needed. In on our previous RCT (GLUCO-CABG4) 
non-DM patients in the conservative group had a mean BG 143mg/dl vs. 127mg/dl in the intensive group. This 
difference was associated with a lower composite score of complications in the intensive group. It is 
reasonable to assume the standard deviation of the mean BG is bounded around 40 mg/dl. With two-sample t 
tests or Wilcoxon tests, alpha=0.05, 25 subjects for each arm would be needed to ensure 80% power to reject 
the hypothesis that the mean BG in patients treated with dulaglutide is not 16 mg/dl lower compared to 
placebo. Accounting for ~15% attrition rate this leads to a final total sample size estimate of 60 patients for 
both considerations. This study is not powered to assess differences in hospital complications between groups. 
E.1.10 Confidentiality 

Access: Only institutional review board (IRB)-
approved study personnel will have access to 
individually identifiable information about human 
subjects. This may include the Emory study 
Investigators who are directly involved with human 
subjects (Francisco J. Pasquel, Guillermo E. 
Umpierrez, Michael Halkos), and other approved 
study personnel (e.g. research coordinators).

Protection and Management of data: All 
information and materials will be obtained for research purposes only and the data will be kept in strict 
confidence for use in this proposed research only. Confidentiality will be assured by the use of subject 
codes rather than personal identifiers on questionnaires, blood collection and storage tubes. All subject 
paper records will be kept in locked file cabinets and will be accessible only to the investigative team. 
The master list connecting the subject codes to identifying information (name, birth date, phone 
number, address, clinic visit dates, study dates) will be secured in a computer database (REDCap). All 
data maintained in computerized databases will be accessible only with a login and protected 
password. After the study is completed, all data will be kept according to NIH and FDA regulations in a 
locked file.
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Schmeltz LR, DeSantis AJ, Schmidt K, O'Shea-Mahler E, Rhee C, Brandt S, Peterson S, 
Molitch ME. Conversion of intravenous insulin infusions to subcutaneously administered insulin 
glargine in patients with hyperglycemia. Endocr Pract. Nov-Dec 2006;12(6):641-650. 
137.
Lund A, Knop FK, Vilsboll T. Glucagon-like peptide-1 receptor agonists for the treatment of 
type 2 diabetes: differences and similarities. Eur J Intern Med. Jun 2014;25(5):407-414. 
138.
Deo RC, Hunter L, Lewis GD, Pare G, Vasan RS, Chasman D, Wang TJ, Gerszten RE, Roth 
FP. Interpreting metabolomic profiles using unbiased pathway models. PLoS computational biology. 
Feb 26 2010;6(2):e1000692. 2829050

ICF_000.pdf: 
Informed Consent Form 
 
 
TITLE: Metabolic Phenotyping During Stress Hyperglycemia in Cardiac 
Surgery Patients 
 
 
NCT NUMBER: NCT03743025 
 
 
IRB APPROVAL DATE: June 21, 2023 
 


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You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom.
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used.
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., time commitment, unfamiliar words, specific procedures, etc.) 
4. If there will be medical treatment, know which parts are research and which are 
standard care.
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: Metabolic Phenotyping During Stress Hyperglycemia in Cardiac Surgery Patients
Ancillary protocol: Use Of Continuous Glucose Monitoring Technology to Characterize Stress Hyperglycemia in Cardiac
Surgery Patients
Principal Investigator: Francisco Pasquel, MD, MPH
            Assistant Professor of Medicine
            Department of Medicine/Endocrinology
                                         Emory University School of Medicine
Co- Investigator:           Georgia M. Davis, MD 
            
             Assistant Professor of Medicine
           
            Department of Medicine/Endocrinology
                                         Emory University School of Medicine
Co- Investigator:           Michael Halkos, MD, MSc 
            Associate Professor of Surgery, 
            Division of Cardiothoracic Surgery, Department of Surgery, 
            
            Emory University School of Medicine
Co- Investigator:           Guillermo Umpierrez, MD, CDE 
            Professor of Medicine
           
            Department of Medicine/Endocrinology
                                         Emory University School of Medicine
Study Supporter: NIH National Institute of General Medical Sciences
Study Supporter to Ancillary Protocol: DexCom, INC.
Introduction
We are asking you to be in a medical research study. This form will 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.
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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.
What is the purpose of this study?
The purpose of this study is to compare dulaglutide (diabetes injection medication) and placebo (saline injection) for the 
prevention of high blood glucose (sugar) during surgery and to find out what are the causes of high blood sugars after 
cardiac (heart) surgery. About 60% of patients (6 out of 10) develop high sugar levels after heart surgery. High sugar is 
related to an increased risk of hospital complications. High sugar increases the risk of wound infection, kidney failure and 
death. Patients with high sugar are treated with insulin given through an arm vein or by frequent insulin injections under 
the skin. This study will determine if dulaglutide can prevent the development of high sugars after heart surgery. 
Dulaglutide is a diabetes injection approved by the Food and Drug Administration (FDA) to treat patients with diabetes. 
Dulaglutide has been shown effective in improving glucose control in patients with diabetes in the hospital. It is not known; 
however, if dulaglutide can prevent the development of high blood sugars in the hospital in patients at high risk. 
We will also measure levels of certain blood tests related to blood sugar metabolism and use a continuous glucose (sugar) 
monitoring (CGM) device to look at the characteristics of high blood sugar in a high-risk population (patients undergoing 
CABG surgery), including its timing, duration, severity.
A total of 150 subjects from Grady Memorial Hospital, Emory University Hospital at Midtown, and Emory University 
Hospital will participate in this study. We will analyze the samples collected from patients participating in the 
intervention trial (Placebo group) in an observational study. We will follow you for the total length of your hospital 
(inpatient) stay and up to thirty (30) days after you leave the hospital. 
A) Clinical trial:  If you are older than 40 years and have a body mass index (BMI) of 25 or higher we would like to invite 
you to participate in an intervention study aiming at improving sugar levels during surgery (the intervention includes 
a single dose of dulaglutide or placebo).* 
B) Observational study:  If you are younger than 40 years and have a BMI less than 25 we would like to invite you to 
participate in an observational study (we will only monitor glucose levels continuously (CGM) and will collect blood 
samples)
*Note: You may also choose to participate in the observational study only.   
For both options: 
Blood samples in either option will be taken as described below:   
Baseline samples before your heart surgery and at two (2), twenty-four (24), seventy-two (72) to ninety six (96) hours after 
your surgery, and about thirty (30) days after your heart surgery. This will help understand what can cause high blood 
sugars after heart surgery.
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. 
Continuous Glucose Monitoring (CGM):
The Dexcom G6 Pro System (Figure 1) includes a transmitter, sensor, receiver and mobile app. The transmitter is about 
the size of a thumbprint.  The sensor probe is thicker than a strand of a 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 10 days. The 
sensor continuously measures your blood sugar levels.  The transmitter snaps onto the sensor pod and collects and 
stores blood sugar information.  A receiver will not be used in this study. 
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What will I be asked to do?
Patients with no history of diabetes and with normal blood glucose (sugar) who are scheduled to have heart surgery will 
be considered as candidates in this study. 
1)
You can choose to participate in the intervention part (we will give you study medication as described below), we 
will place one (1) CGM in your belly before surgery and one on your arrival to the intensive care unit (ICU) after 
heart surgery) and blood samples will be taken.
If you are a woman who is able to get pregnant, you will receive a pregnancy test one time prior to enrollment in the 
trial. 
The type of treatment you receive while in the hospital will be decided randomly (by chance or like flipping a coin).  
You will receive a single dose of either 1) dulaglutide injection, or 2) placebo (saline) injection up to three days 
before your surgery. This is a blinded study (you will not know if you received dulaglutide or placebo).
2)
You can choose to be in the observation part only, in this option we will place one (1) CGM in your belly before 
surgery and one once you arrive to ICU after heart surgery and collect blood samples only.
Study (both options):
The study will be carried out as follows: 
•
We will place a Dexcom G6 device in your abdomen (belly) before your heart surgery and another Dexcom G6 on the 
opposite side of your belly (after you arrive to ICU after your heart surgery)  with the display-off for up to 10 days or 
leaving the hospital (whichever comes first), you will continue to have to blood sugar checked by fingersticks by the 
nursing staff (1-2 hours in the intensive care unit or before each meal and at bedtime once you start eating). Display-
off means you and/or nursing staff will not see sugar values on the mobile application. We will continue to manage 
your high sugars and adjust insulin based on your fingerstick sugar readings. Prior to leaving the hospital, study staff 
will remove the hospital CGM.
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•
Before surgery, we will collect 12 ml (about 3 teaspoons) of blood to measure markers of blood sugar control. We 
will also collect blood samples four (4) times after surgery at 2, 24, and 72-96 hours after your heart surgery and at 
about 1 month (30 days) after your heart surgery when you return for follow up with your heart surgeon.  The cost 
of all research visits and samples will be covered by the study funds.  You may have additional blood draws for your 
regular care if requested by your primary care team.
•
After surgery, if your blood sugar is greater than 140 mg/dl in the intensive care unit (ICU), you will receive insulin to 
treat this. This is the standard or usual care for patients who develop high sugars after heart surgery in the hospital. 
•
You will receive intravenous insulin (in one of your arm veins) while you are in the ICU or until you are stable and 
able to eat. Then, you may receive subcutaneous insulin (under the skin) shots if your blood sugar levels are still 
high. 
•
In the ICU, nursing staff will measure your blood sugar levels at the bedside using a glucose meter every one or two 
hours. Once you are able to eat, we will measure your blood sugar before meals and at bedtime. 
•
The nurse will prick your finger with a small needle and place a drop of blood on a special strip. This strip measures 
how much sugar is in your blood. 
•
We will use your blood sugar levels to determine if you need insulin to control your blood sugar. 
•
We will call you on day 2 after discharge if you developed nausea during hospitalization. 
•
We will also conduct a short visit at the time of your post-operative visit with your heart surgeon to draw blood and 
collect information on any visits to the emergency room or admissions to the hospital since your discharge after 
your heart surgery. 
If you choose to participate in the OBSERVATIONAL PART ONLY:
You will not receive any study medication and you will wear CGM devices and blood samples will be collected as 
described above to study the potential causes of high sugars.
How will my medicine be provided? 
If you choose to participate in the intervention part, 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. We will administer the study medication up to three (3) days 
before your heart surgery. 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. If you are admitted to the hospital: your treating nurse will give the study 
medication to you.
Who owns my study information and samples?
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 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:
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 low blood sugars.  Symptoms of low blood glucose 
include sweating, nervousness, confusion, agitation, sleepiness and even coma (loss of awareness).  If it occurs, low 
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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 those receiving placebo develop higher sugars 
than those receiving dulaglutide, however, all patients with high blood sugars will receive insulin to control it. 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.
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 heartbeat, sweating and a drop in blood pressure. 
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 rare complication associated with 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 an adequate 
method of birth control or abstinence for the duration of the study.  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.
Risks of Wearing the CGM System 
When the sensor is inserted you should expect to feel a feeling like a needle-stick. After insertion, you may feel some 
tenderness, but you should not feel any large amount 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 
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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.
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.
Pregnancy (While Wearing a CGM System)
If you think that you have become pregnant while being in the study, you must contact the study staff immediately.  It is 
unknown whether the use of the study device and the intensive testing performed during the study pose a risk during 
pregnancy.  As a precaution, if you are female and of child-bearing age, you will have to take a pregnancy testing before 
entering the study. You will not be allowed to be in the study if you are pregnant. 
This study may include risks or side effects that are unknown at this moment.
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. Your stress hyperglycemia (high sugars) may improve while you are in 
this study but it may not, and it may even get worse. This study is designed to learn more about preventing high sugars 
in patients without diabetes that undergo cardiac surgery. We will use the study results to help others in the future.
Will I be compensated for my time and effort?
You will receive fifty dollars ($50.00) in compensation for your time, trouble, and inconvenience, for your visit before 
your heart surgery, fifty dollars ($50.00) for wearing the Dexcom G6 CGM; fifty dollars ($50.00) prior to discharge 
(leaving the hospital) and fifty dollars ($50.00) at the time of your last visit at approximately 1 month after leaving the 
hospital . If you decide to stop study procedures before it is over, you will receive $10.00 per day to a maximum of 
$50.00 during the hospital stay. Total compensation if you complete all the visits will be two hundred dollars ($200.00)
What are my other options?
If you decide not to enter this study, there is care available to treat your stress hyperglycemia (high sugars) outside of 
this research. You should know that there are other types of insulins available at Grady and Emory Hospitals to treat 
high blood sugars. 
The study doctor will discuss these with you. You do not have to be in this study to receive treatment for high blood 
sugars after cardiac 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?
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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 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 may be shared with the research community at large to advance science and health. 
Data from this study 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.
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.  The results of all 
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: metabolomics (blood sugar metabolism samples).
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. Also, if you decide to be in this study, it is up to you to let your other health 
providers know. 
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In Case of Injury
If you get ill or injured from being in the study, Emory and Grady Health System will help you get medical treatment.   
Emory and Grady Health System and the sponsor 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 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. Francisco Pasquel at telephone 
number 
. You should also let any health care provider who treats you know that you are in a research 
study. 
Costs
There will be no costs to you for participating in this study, other than basic expenses like transportation. You will not be 
charged for any of the research activities. If the study procedures result in any medical complications that would not fall 
under “injury” as discussed above, the cost of treatment for those complications may be charged to you or your 
insurance.  
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
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 study in which you may choose to 
participate.
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:  
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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 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. c
•
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.
•
 Dr. Francisco Pasquel is the Sponsor of the study.  DexCom, Inc. is providing funding for the study. The 
Sponsor and DexCom, Inc. 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 and DexCom, Inc. may disclose your 
PHI to other people and groups like study monitors to help conduct the study or to provide oversight for 
the study.  
•
The research team and the Sponsor may use and disclose your PHI, including disclosure to insurance 
carriers to administer payment for subject injury. 
•
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:  Office for Human Research 
Protections; Food and Drug Administration.
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.
Storage of Data/Specimens for Future Research: 
PHI That Will be Used/Disclosed for Storage of Data/Specimens: 
The PHI that we will use and/or disclose (share) for the optional storage and future research use of your                
PHI includes: blood samples from before and after surgery. 
Purposes for which your PHI will be Used/Disclosed for Optional Study: 
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We will use and disclose your PHI for the conduct and oversight of the optional storage and future 
research use of your PHI. 
Authorization for This Use of PHI is Required to Participate in Optional Storage of Data/Specimens, 
but Not in Main Study: 
You do not have to authorize the use and disclosure of your PHI. If you do not authorize the use and 
disclosure of your PHI for the optional storage and future research use, then you may not participate in 
the option for storage and future research use of your PHI. You can still be in the main research study 
even if you don’t participate in the option for storage and future research use of your PHI. 
People Who Will Use/Disclose Your PHI for Optional Storage of Data/Specimens: 
The same people and groups who will use and disclose your PHI for the main study will also do so in 
connection with the optional storage and future research use of your PHI.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
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. Francisco Pasquel at:
At that point, the researchers would not collect any more of your PHI.  But they may use 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 study. 
As long as it is possible to find your samples, the Sponsor will remove your consent to use them for future biomedical 
research. One way it might not be possible to find your samples is if the code linking them to the Sponsor’s records has 
been destroyed at the study site. Any data that has been created from your samples before your request to leave this 
sub-study will not be deleted. If you leave, you will not lose any benefits, medical treatment or legal rights. 
Leaving the main study does not mean you have also stopped being a part of this sub-study. To stop being a part of this 
sub-study, you will have to make a separate request.
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. 
IRB00097963
IRB Approved
6/21/2023


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IRB Form 12152017
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.  
IRB00097963
IRB Approved
6/21/2023


Page 13 of 13
Metabolic Phenotyping & CAD - Version 6 Date: July302020
IRB Form 12152017
Contact Information
Contact 
•
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, concerns or complaints about the research
Contact the Emory University 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.
•
if you have questions, concerns or complaints about the research.
•
You may also let the IRB know about your experience as a research participant through our Research Participant 
Survey at http://www.surveymonkey.com/s/6ZDMW75.
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 Study/Studies:  
Please initial below if you opt to participate in and authorize use and disclosure of your PHI in the optional study/studies 
previously described:
_____I agree to participate in the Intervention, CGM, and Collection & Storage of Blood Samples Study ________Initials
_____I agree to participate in the observational CGM and Sample Collection & Storage Only   ____________Initials 
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in the main study. 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
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
Signature of Person Conducting Informed Consent Discussion
Date              Time
IRB00097963
IRB Approved
6/21/2023