Clinical trial NCT02556918
Conditions: Hyperglycemia
Keywords: Coronary artery bypass graft surgery (CABG) Type 2 Diabetes
Sponsor: Emory University
Start date: 2016-01-01; Completion date: 2018-11-06
Enrollment: 202 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether treatment with sitagliptin reduces the frequency and severity of high blood sugar (hyperglycemia) after cardiac surgery and to determine whether treatment with sitagliptin is effective in maintaining blood sugar control in patients with type 2 diabetes (T2D).

Detailed description:
The purpose of this study is to determine whether treatment with sitagliptin reduces the frequency and severity of high blood sugar (hyperglycemia) and the need for continuous intravenous insulin infusion (CII) in the intensive care unit (ICU) in patients with type 2 diabetes (T2D) undergoing coronary artery bypass graft (CABG) surgery. In addition, the study seeks to determine whether treatment with sitagliptin is effective in maintaining glycemic control and in preventing the need for subcutaneous (SC) insulin therapy in patients with T2D during the transition from intensive care unit (ICU) to regular floor in cardiac surgery patients with T2D.

Arms: arm 1: Subjects undergoing cardiac surgery with type 2 diabetes (T2D) will be randomized to receive one tablet of sitagliptin once a day.Subjects with stress hyperglycemia (defined as a blood glucose (BG) greater than 180 mg/dL) in the intensive care unit (ICU) will continue to receive sitagliptin and will be started on continuous intravenous insulin (Regular Human Insulin) adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Additionally, once moved to the regular floors and out of ICU, the subjects can receive insulin glargine, insulin lispro, and/or insulin aspart depending on the blood glucose level.

Interventions:

Drug: Sitagliptin Drug: Regular Human Insulin Drug: Insulin glargine Drug: Supplemental insulin (Insulin lispro) Drug: Supplemental insulin (Insulin aspart) arm 2: Subjects undergoing cardiac surgery with type 2 diabetes will be randomized to receive one tablet of placebo once a day.Subjects with stress hyperglycemia (defined as a blood glucose (BG) greater than 180 mg/dL) in the intensive care unit (ICU) will continue to receive a placebo and will be started on continuous intravenous insulin (Regular Human Insulin) adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Additionally, once moved to the regular floors and out of ICU, the subjects can receive insulin glargine, insulin lispro, and/or insulin aspart depending on the blood glucose level.

Interventions:

Drug: Placebo Drug: Regular Human Insulin Drug: Insulin glargine Drug: Supplemental insulin (Insulin lispro) Drug: Supplemental insulin (Insulin aspart)
Interventions: intervention 1: Sitagliptin intervention 2: Placebo intervention 3: Regular Human Insulin intervention 4: Insulin glargine intervention 5: Supplemental insulin (Insulin lispro) intervention 6: Supplemental insulin (Insulin aspart)
Intervention descriptions: intervention 1: Subjects will take one pill daily starting one day prior to surgery until discharge from the hospital. Sitagliptin will be dispensed orally at 100 mg/day for patients with a glomeruler filtration rate (GFR) greater than or equal to 50. Patients with a GFR between 30-49 will receive 50 mg/day. intervention 2: One pill daily starting one day prior to surgery until discharge from the hospital. intervention 3: Continuous intravenous insulin given to intensive care unit (ICU) patients with a blood glucose (BG) greater than 180 mg/DL and will be started on Regular Human Insulin adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol.Intravenous insulin infusion will be continued until the patient is able to eat and/or is transferred to non-ICU service. In previous studies, average length of insulin infusion in patients with stress hyperglycemia was 16.9±19 hours and the amount of IV insulin requirement was 18.6±24.3 U/day. intervention 4: Patients that required continuous insulin infusion (CII) at a rate \>1U/h will be transitioned to basal insulin (glargine/detemir). Calculate total daily dose (TDD) of insulin from the average CII rate during the last four hours of infusion (example, if the average rate is 2 U/hr., the TDD is 48 U/day) Give 50% of calculated dose as basal (glargine/detemir) insulin every day. Basal insulin will be given approx. 4 hours before discontinuation of CII.

The total daily insulin dose will be adjusted as follow:

Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change Fasting and pre-meal BG between \>180-240 mg/dl: increase basal dose by 10% every day Fasting and pre-meal BG \>241 mg/dl: increase basal dose by 20% every day Fasting and pre-meal BG \<100 mg/dl: stop basal intervention 5: Insulin lispro will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at blood glucose (BG) greater than 240 mg/dL will be given. For the subjects receiving supplemental insulin lispro with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows:

* BG between 181-220 mg/dL; 2-4 units of insulin lispro
* BG between 221-260 mg/dL; 3-5 units of insulin lispro
* BG between 261-300 mg/dL; 4-6 units of insulin lispro
* BG between 301-350 mg/dL; 5-7 units of insulin lispro
* BG between 351-400 mg/dL; 6-8 units of insulin lispro
* BG greater than 400 mg/dL; 7-9 units of insulin lispro intervention 6: Insulin aspart will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at blood glucose (BG) greater than 240 mg/dL will be given. For the subjects receiving supplemental insulin aspart with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows:

* BG between 181-220 mg/dL; 2-4 units of insulin aspart
* BG between 221-260 mg/dL; 3-5 units of insulin aspart
* BG between 261-300 mg/dL; 4-6 units of insulin aspart
* BG between 301-350 mg/dL; 5-7 units of insulin aspart
* BG between 351-400 mg/dL; 6-8 units of insulin aspart
* BG greater than 400 mg/dL; 7-9 units of insulin aspart

Protocol documents:
Prot_SAP_000.pdf: 
 
 
IRB00082180 
 
NCT02556918 
 
 
 
Sitagliptin for the Prevention and Treatment of Hyperglycemia in Patients with Type 2 Diabetes 
Undergoing Cardiac Surgery (SITA-CABG DM TRIAL) 
 
 
Principal Investigator:       Guillermo E. Umpierrez, MD, CDE, FACP, FACE 
 
 
10/05/2018 
 


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Sitagliptin for the Prevention and Treatment of Hyperglycemia in Patients with Type 2 Diabetes 
Undergoing Cardiac Surgery (SITA-CABG DM TRIAL)  
 
Emory University: 
 
Principal Investigator:       Guillermo E. Umpierrez, MD, CDE, FACP, FACE  
                                           Professor of Medicine 
                                           Department of Medicine/Endocrinology 
                                           Emory University School of Medicine 
 
Co-Investigators: 
 
Department of Medicine: 
Francisco Pasquel, MD., Priyathama Vellanki, MD, Sonya Haw, MD, Sol Jacobs, MD, and Saumeth Cardona, 
MD 
 
Department of Surgery: 
Vinod Thourani, MD 
 
School of Public Health (Statistical analysis) 
Limin Peng, PhD 
 
 


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I. 
RESEARCH OBJECTIVES AND SPECIFIC AIMS 
    
   More than 500,000 patients undergo coronary artery bypass graft surgery (CABG) each year in the United 
States.1 Nearly 30% to 40% of patients undergoing cardiac surgery have diabetes mellitus (DM).2,3 More than 
90% of patients with DM and ~80% of patients without DM will develop hyperglycemia (defined as a BG >140 
mg/dl) after surgery.4-7 Several cohort studies have reported that hyperglycemia; in patients with and without DM, 
is an independent risk factor of morbidity and mortality after cardiac surgery.8-12 Patients with DM have higher 
rates of deep sternal wound infections,11,13 acute renal failure,6 longer hospital stay,9,14 and perioperative 
mortality14,15 when compared to those without DM. Despite ongoing debate about the optimal glucose target, 
there is strong agreement that improvement in glycemic control reduces complications and inpatient mortality.16-
18 In the GLUCO-CABG trial,19 we reported lower, but not significant differences in a composite of complications 
between intensive and conservative regimens in patients with DM; however, we observed a reduction in hospital 
complications in non-DM patients with stress hyperglycemia treated with intensive glucose control (see 
preliminary results).  
 
   Clinical guidelines from professional organizations recommend treatment with continuous intravenous insulin 
infusion (CII) for treatment of hyperglycemia in cardiac surgery patients with DM and hyperglycemia.7,20-22 
Although effective and widely utilized 16,18,23, the use of CII is labor intensive, requiring hourly BG testing and 
insulin drip adjustment, and is associated with a significant risk of hypoglycemia, reported in 5 – 32% of patients 
in the ICU.24-27 Hypoglycemia after cardiac surgery has been independently associated with increased risk of 
complications, longer length of hospital stay, and increased mortality.28-30 Recently, the inpatient therapy with 
dipeptidyl peptidase-4 [DPP-4] inhibitors has been shown to be an effective alternative to insulin therapy in 
improving glycemic control with low risk of hypoglycemia.31 In addition, our preliminary studies indicate that 
the use of sitagliptin is effective in maintaining glucose control and in preventing the need for subcutaneous 
insulin therapy during the transition period from the ICU to regular floors in cardiac surgery patients with stress 
hyperglycemia (see preliminary data). 
 
We hypothesize that treatment with sitagliptin (Januvia®), by reducing glucagon-mediated hepatic glucose 
production and by stimulating insulin secretion in a glucose-dependent fashion, will prove to be a safe and 
effective for the prevention and treatment of hyperglycemia during the perioperative period in cardiac surgery 
patients with type 2 diabetes.  
 
I.1.   Specific Aims 
 
Aim 1.  To determine whether treatment with sitagliptin reduces the frequency and severity of 
hyperglycemia and need for CII in the ICU compared to placebo in patients with type 2 diabetes 
undergoing CABG surgery. In this prospective, randomized, blinded, placebo-controlled study, patients with 
type 2 diabetes (T2D) treated with diet, oral antidiabetic drugs (OADs), and/or insulin will be randomized to 
receive sitagliptin or placebo starting the day prior to surgery and continue once daily in the ICU. 
Hypothesis: Treatment with sitagliptin will significantly reduce the severity of hyperglycemia and the need for 
CII during the perioperative period in T2D patients undergoing CABG.  
 
Aim 2. To determine whether treatment with sitagliptin is effective in maintaining glycemic control and in 
preventing the need for subcutaneous (SC) insulin therapy in patients with T2D during the transition from 
ICU to telemetry unit in patients with T2D undergoing CABG. In this study, patients randomized to sitagliptin 
or placebo in Aim 1 will continue treatment after transition from ICU to regular wards. 
Hypothesis: Treatment with sitagliptin will be effective in maintaining glucose control avoiding the need for SC 
insulin therapy after transition from ICU to regular wards in T2D undergoing CABG surgery.  
 
I.2. 
Overall Design and Study Interventions 
   This prospective, randomized, blinded pilot clinical trial will be conducted in patients with T2D undergoing 
CABG surgery. Subjects will be consented prior to surgery at the surgery-anesthesia pre-hospitalization 
assessment or on admission to the hospital.  Subjects will be randomized to receive sitagliptin or placebo starting 
one day prior to surgery and continued daily in the ICU (Aim 1) to determine if hyperglycemia (BG > 180 mg/dl 


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in the ICU) could be prevented or ameliorated with the use of a DPP4-inhibitor.  Treatment with sitagliptin or 
placebo (Aim 2) will be continued during transition to regular floors to confirm our preliminary data that treatment 
with DPP4-inibitors facilitates the management of hyperglycemia avoiding the use of SC insulin after stopping 
insulin infusion. Study patients who develop hyperglycemia during the hospital stay (BG > 180 mg/dl in non-
ICU areas) will be managed following our institution standard insulin protocols.  
 
The dose of study drug will depend on the patient’s GFR at time of randomization. Patients with a calculated 
GFR≥50 mL/min/1.73m2 will receive study drug 100mg daily. Patients with calculated GFR between 30-49 
mL/min/1.73m2 will receive study drug 50mg daily. If the calculated GFR drops below 30 mL/min/1.73m2, 
patients will receive study drug 25mg daily. If the calculated GFR changes after randomization, study drug will 
be adjusted accordingly.  
 
 
I.3. 
Background and Significance 
 
I.3.1. Diabetes and Coronary Heart Disease. The prevalence of diabetes mellitus is rising at an alarming rate 
and it currently affects ~200 million people worldwide and 29 million in the United States.32 The adverse 
microvascular and macrovascular consequences of diabetes are well recognized, as is the accompanying 
accelerated rate of atherosclerosis that predisposes patients to coronary artery disease and to higher rates of 
myocardial infarction and death.33-35 Coronary heart disease causes much of the serious morbidity and mortality 
in patients with diabetes, who have a 2- to 4-fold increased risk of myocardial infarction, 36,37 and 3 times as many 
deaths as people without diabetes.33,38   
 
I.3.2. Diabetes and CABG surgery. More than 500,000 patients undergo CABG surgery each year in the 
United States.1 The national prevalence of diabetes among patients undergoing CABG is about 30%.39-41 Patients 
with diabetes who undergo CABG surgery have increased perioperative mortality and morbidity and more 
recurrent episodes of angina.3,9,17,42. Similarly, long-term survival after surgical revascularization is significantly 
reduced in diabetics compared to nondiabetic subjects.43,44 In the BARI trial, diabetics had significantly lower 5-
year survival rates (73.3% vs. 91.3%) than nondiabetic subjects.45 Most deaths after CABG are attributable to 
cardiac causes in ~ two-thirds of patients (ischemia due to graft failure, left ventricular failure and 
dysrhythmia),11,41,46,47 as well as increased neurologic complications,48 renal dysfunction,49 and infectious 
complications.11,50   
 
I.3.3. Glycemic control in cardiac surgery patients with T2D and Hyperglycemia. Hyperglycemia during 
the perioperative period is reported in >90% of patients with T2D and in ~80% of patients without a history of 
DM.4-6 Large cohort studies have identified hyperglycemia, in patients with and without DM as an independent 
risk factor of poor outcome after cardiac surgery compared to patients with normoglycemia, specifically higher 
perioperative mortality,14,15 deep sternal wound infections,11,13 renal failure,6 postoperative strokes,9,51 longer 
hospital stays,9,14 and higher health care resource utilization.52-54  
 
   The results of several clinical trials in critically ill and surgery patients indicate that improvement of glycemic 
control reduces length of stay (LOS), risk of multi-organ failure and systemic infections,13,16,23 as well as mortality 
in patients with stress hyperglycemia and diabetes.16,55 The Portland Diabetic Project, a prospective, non-
randomized study of diabetic patients who underwent CABG13 reported that the use of CII to achieve a BG target 
between 150-200 mg/dl compared with SQ regular insulin resulted in a lower mortality rate (2.5% vs. 5.3%) and 
reduced rate of deep sternal wound infection by 66%.56 The Leuven trial, 16 a prospective RCT of intensive insulin 
therapy in diabetic and non-diabetic surgical ICU patients treated to target glucose between 80 and 110 mg/dl 
reduced hospital mortality by 34%. A subgroup analysis by Van den Berghe et al57 of surgical and medical ICU 
patients reported that while glucose lowering effectively reduced mortality in those without a previous history of 
diabetes, no significant benefit from treatment was observed in patients with diabetes. Similarly, in the GLUCO-
CABG trial (see preliminary results) we found a lower, but non-significant reduction in a composite of 
complications between intensive and conservative regimens in patients with DM; however, we observed a 
reduction in hospital complications in patients with stress hyperglycemia treated with intensive glucose control.19  
 


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1.3.4. Stress hyperglycemia: mechanisms and consequences.  The ADA/AACE and Endocrine Society 
guidelines on inpatient hyperglycemia defined hyperglycemia or hospital-related hyperglycemia as any BG 
concentration >140-180 mg/dl. Acute illness, surgery, and trauma raise levels of counterregulatory hormones 
such as glucagon, epinephrine, cortisol, and growth hormone. The counterregulatory response results in a number 
of alterations in carbohydrate metabolism, including insulin resistance, increased hepatic glucose production, 
impaired peripheral glucose utilization, and relative insulin deficiency.58,59 The development of hyperglycemia 
leads to generation of reaction oxygen species (ROS), lipid peroxidation, and elevated inflammatory markers. It 
also increased pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and 
IL-1, which ultimately alter the immune system, 60-63 as well altered hemostasis, increased platelet activation, 
adhesion and aggregation,64 reduced plasma fibrinolytic activity and increased plasminogen activator inhibitor-1 
(PAI-1) activity.65   
 
1.3.5. Hospital Use of DPP-4 Inhibitors. We recently completed a randomized two-center open label pilot trial 
determined the safety and efficacy of treatment with sitagliptin alone or in combination with basal insulin in 
general medicine and surgery patients with T2D.31 In this pilot study, 90 general medicine and surgery patients 
with a BG between 140-400 mg/dl treated with diet, oral antidiabetic drugs or low-dose insulin were randomized 
to sitagliptin once daily, sitagliptin and basal insulin, or basal bolus insulin. All groups received correction doses 
of lispro before meals and bedtime for BG >140 mg/dl.  Patients in the sitagliptin group received a single daily 
dose of 50-100 mg based on kidney function. The use of sitagliptin alone or in combination with basal insulin 
was well tolerated and resulted in no significant differences in daily BG, frequency of hypoglycemia or in the 
number of treatment failures compared to basal bolus regimen. DPP4 therapy is associated with low-risk of 
hypoglycemia, and these agents are ideal for the management of hyperglycemia and diabetes in the hospital 
setting.  In a different uncontrolled pilot trial we treated a group of 22 patients with stress hyperglycemia requiring 
insulin infusion in the ICU with sitagliptin. Patients were treated with sitagliptin 100 mg/day at discontinuation 
of CII (as an alternative to the SQ insulin) and at transition to regular floor. The use of sitagliptin was well 
tolerated and patients remained in good metabolic control avoiding transition to SQ insulin after discontinuation 
of IV insulin drip (see preliminary results).    
 
1.3.6. Significance and Innovation.   
Significance.  Most cardiac surgery patients, with or without history of T2D, develop significant hyperglycemia 
and require CII during the perioperative period.6,16,66 There is strong evidence to indicate that hyperglycemia is 
an independent risk factor of morbidity and mortality after cardiac surgery.8-12 Clinical guidelines recommend 
treating patients with hyperglycemia with CII in the ICU; 7,20,21 however; CII is labor intensive, costly, and 
associated with a high rate of hypoglycemia (5–32%).24-27 Hypoglycemia after cardiac surgery has been 
independently associated with increased risk of complications and mortality28-30. The concerns regarding 
complications associated with insulin therapy has led to the search of alternative treatment regimens. Our 
preliminary studies have shown that treatment with DPP4-inhibitors represent an alternative treatment to insulin 
therapy in improving glycemic control with low risk of hypoglycemia in a general inpatient population31 and in 
preventing the need for subcutaneous insulin therapy after stopping CII in cardiac surgery patients with stress 
hyperglycemia. 
 
Innovation.  This proposal will test 2 major innovative areas: 1) can hyperglycemia, which is present in more 
than 90% of patients with T2D after CABG surgery, be prevented or ameliorated with the use of a DPP4-
inhibitors? And 2) can DPP4-inhibitors facilitate the management of patients with T2D avoiding the use of 
subcutaneous basal bolus insulin therapy during the transition from ICU to regular floors? These are two important 
clinical questions that may facilitate care of millions of patients with T2D undergoing cardiac surgery. More 
importantly, if treatment with sitagliptin is proven effective in reducing the severity of hyperglycemia during the 
perioperative period, and in reducing the rate of hyperglycemia and hypoglycemia during the transition from ICU 
to regular wards, it is possible that these agents will reduce the number of perioperative complications in patients 
with T2D undergoing CABG surgery.    
 
 
 


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2. 
PRELIMINARY RESULTS: 
Our research team has extensive clinical and research experience in inpatient management of hyperglycemia and 
has published several randomized controlled trials in medical/surgery patients in ICU and non-ICU settings.19,31,67-
71 Emory University and affiliated hospitals serve as cardiovascular referral center including cardiac surgery to a 
large population based in the city of Atlanta and the state of Georgia. More than 1000 major CV surgeries (CABG, 
aortic and valve surgery) procedures are performed every year at the 3 participating institutions (Emory 
University, Midtown Hospital and Grady Hospital).   
 
2.1. 
RABBIT 2 Surgery Trial.  
This multicenter RCT compared the efficacy and safety of 
a basal/bolus regimen to sliding scale insulin (SSI) in non-
ICU patients undergoing general surgery. Study outcomes 
included differences in daily BG levels and a composite of 
hospital complications including postoperative wound 
infection, pneumonia, respiratory failure, acute renal 
failure, and bacteremia. A total of 211 patients were 
randomized to glargine once daily + glulisine before meals 
or to SSI given 4 times/day. The mean daily glucose 
concentration after the 1st day of basal bolus and SSI was 
145±32 mg/dl and 172±47 mg/dl, respectively, p<0.01. There were reductions with basal bolus as compared with 
SSI in the composite outcome (24.3% and 8.6%, OR: 3.39 (95% CI: 1.50-7.65); p=0.003). SSI had higher number 
of wound infection (2.9% vs. 10.3%), pneumonia (0% vs. 2.8%), and acute renal failure (3.8% vs. 10.3%) than 
basal bolus regimen. We concluded that treatment with basal bolus improved glycemic control and reduced 
hospital complications compared to SSI in surgery patients with T2D.  
  
2.2. Sitagliptin Inpatient Pilot Study.31   In a two-center 
open label randomized pilot trial we recently determined 
differences in glycemic control between sitagliptin alone or in 
combination with basal insulin and basal bolus regimen in 
medicine and surgery patients with T2D.  In this study, 90 
patients with a BG between 140-400 mg/dl treated with diet, 
OAD or low-dose insulin (≤ 0.4 U/kg/day) were randomized 
to sitagliptin once daily (n=30), sitagliptin and basal insulin 
(n=30) or to a basal bolus (n=30) regimen. Patients in the 
sitagliptin group received a daily dose of 100 mg or 50 mg as 
per renal function. Those in the sitagliptin plus glargine 
received sitagliptin and glargine starting at 0.25 U/kg once 
daily. Patients in the basal bolus group were started at 0.5 
U/kg, given half as glargine once daily and half as lispro before meals.  All groups received correction doses of 
lispro before meals and bedtime for BG >140 mg/dl.  We found that treatment with sitagliptin alone or in 
combination with glargine resulted in similar glycemic control compared to basal bolus regimen (Figure 2). 
There were no differences in mean daily BG, number of BG readings within target, hypoglycemia, frequency of 
treatment failures, hospital LOS or complications.  In 
addition, treatment with sitagliptin had less daily insulin 
requirements and lower number of insulin injections, both, 
p<0.001. The study shows that use of a DPP4 inhibitor is a 
safe and effective for treatment of inpatient 
hyperglycemia. 
 
2.3. GLUCO-CABG TRIAL19 
This randomized controlled trial aimed to determine 
whether intensive BG control (intensive, target: 100-140 
mg/dl) reduces perioperative complications compared to 


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conservative BG control (conservative, 141-180 mg/dl) in hyperglycemic patients undergoing CABG. After 
ICU care, subjects were transitioned to a single treatment regimen targeting a BG<140 mg/dl before meals 
during the hospital stay and 90 days post discharge. The primary outcome was differences in a composite score 
of complications including mortality, wound infection, 
pneumonia, bacteremia, respiratory failure, acute renal 
failure, and major cardiovascular events. A total of 302 
patients were randomized to intensive (n=151) or 
conservative (n=151) glucose control following a 
computerized insulin infusion algorithm. 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). There were no differences in 
the composite or on individual complications in patients 
with DM (Figure 3); however, the composite of complications was lower in non-DM patients with stress 
hyperglycemia (Fig 4) in the intensive compared to the conservative group (p=0.008). 
 
2.4. Sitagliptin after discontinuation of CII in patients 
with stress hyperglycemia. 
In an uncontrolled open label pilot study, we treated a group 
of 22 non-DM patients with stress hyperglycemia in the 
ICU with sitagliptin 100 mg/day at discontinuation of CII 
(as an alternative to the standard SQ insulin) and at 
transition to regular floor (Fig. 5). The use of sitagliptin was 
well tolerated and patients remained in good control with a 
mean daily BG < 140 mg/dl during days 1 and 4 after 
transition to regular floor. The sitagliptin therapy was 
discontinued the day before discharge and all patients were 
successfully discharged home without insulin injections.  
 
Transition of Care after Discharge.  In a recent preliminary 
study we assessed the efficacy of an HbA1c based algorithm 
for the management of 224 non-ICU patients with T2D (Fig. 
6). Patients with an admission HbA1c < 7% were discharged 
on their same outpatient antidiabetic regimen (OADs and/or 
insulin).  Patients with an HbA1c between 7% and 9% will be 
discharged on a combination of OADs and basal (glargine) 
insulin at 50% of total daily hospital dose. Patients with an 
admission HbA1c ≥ 9% were discharged on a combination of 
oral agents and basal insulin at 80-100% of total daily hospital 
dose or on a basal bolus regimen at the same hospital dosage. 
The admission HbA1c on admission of 8.75% decreased to 
7.9% and 7.35% after 4 and 12 weeks of hospital discharge 
(p<0.01). We concluded that the admission HbA1c 
concentration is beneficial in designing the discharge treatment algorithm after discharge in patients with T2D. 
 
In summary, during the past decade our group has provided novel and important information to guide health care 
providers in the hospital management of patients with hyperglycemia and diabetes. Our preliminary studies 
indicate that hyperglycemia is common and associated with increased rate of complications in medicine and 
surgery patients with T2D.  The proposed studies will determine if DPP4 agents are effective in the prevention 
and management of hyperglycemia in patients with T2D undergoing CABG surgery.  
Fig 5 


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3.  EXPERIMENTAL PLAN. 
 
3.1. Rationale: More than 90% of patients with T2D undergoing cardiac surgery will develop hyperglycemia 
(BG>140-180 mg/dl) and require treatment with CII during the perioperative period.6,7,16,66 There is strong 
evidence to indicate that hyperglycemia is an independent risk factor of morbidity and mortality after cardiac 
surgery.8-12 Clinical guidelines recommend treatment with intravenous insulin infusion (CII)7,20,21, that is labor 
intensive, costly, and associated with increased risk of hypoglycemia24-27. The rate of severe hypoglycemia (BG 
< 40 mg/dl) in the ICU after cardiac surgery has ranged between 5% and 19% in previous clinical trials.16,17,26,72 
Most patients with T2D who are treated with CII in the ICU require transition to SC insulin (basal or basal bolus 
approach) when transferred to regular wards19,73. In such patients, daily insulin dose adjustments are needed to 
prevent hypoglycemia once the stress abates 2 to 5 days after surgery. The basal bolus approach is labor intensive 
requiring multiple injections per day and is associated significant risk of hypoglycemia reported in 10% to 30% 
of patients in non-ICU setting.68,71,74-76 Hypoglycemia after cardiac surgery has been independently associated 
with increased risk of complications and increased mortality.28-30 Our preliminary studies indicate that the use of 
sitagliptin is effective in achieving glucose control in patients with T2D,31 and in preventing the need for SC 
insulin therapy after stopping CII in cardiac surgery patients with hyperglycemia. 
 
3.2.  STUDY DESIGN and METHODS 
   This randomized, placebo-controlled, intent-to-treat trial will include subjects between 18-80 years of age, with 
a history of T2D undergoing CABG surgery. Patients with T2D treated with diet, oral antidiabetic drugs, will be 
randomized to receive sitagliptin or placebo (see, 3.2.a).  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 to rule out 
pregnancy before participating in the study.   
 
 
3.2.a.  Treatment Groups: 
 
 
 
 
 
 
 
 
 
 
3.2.b. Intervention: 
   A total of 220 patients with T2D will be consented and randomized prior to surgery. For patients consented in 
the outpatient setting their antidiabetic treatment will be modified as follows: 
• Oral treatment: Insulin secretagogues (sulfonylureas and glinides), DPP-4 inhibitors will be 
discontinued 24 hours prior to surgery. SGLT-2 inhibitors will be discontinued 48 hours prior to surgery. 
All other oral antidiabetic agents will be continued until the day prior to surgery. 
•  GLP-1 receptor agonists: short-acting (liraglutide, exenatide) will be held 48 hours prior to surgery. 
Long-acting (exenatide ER, albiglutide, dulaglutide) will be held at least one week before surgery. 
• Insulin: Pre-prandial insulin will be continued until the day prior to surgery. Basal (glargine, detemir, 
degludec) and NPH insulin dose is recommended to be decreased by 20%, the day prior to surgery. 


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Patients will receive sitagliptin or placebo starting the day before surgery and continue daily during the hospital 
stay.  The day of surgery, antidiabetic therapy will be held and subjects will receive study drug. The dose of 
study drug will depend on the patient’s GFR at time of randomization. Patients with a calculated GFR ≥45 
mL/min/1.73m2 will receive study drug 100mg daily. Patients with calculated GFR between 30-44 
mL/min/1.73m2 will receive study drug 50mg daily. If the calculated GFR drops below 30 mL/min/1.73m2, 
patients will receive study drug 25mg daily If the calculated GFR changes after randomization, the study drug 
will be adjusted accordingly.  
 
Recommendations to manage hospitalized patients prior to surgery: 
• Starting total daily insulin dose:  
• Insulin naïve patients (oral agents or no therapy) 
• Patients with BG between 140-200 mg/dL= 0.3 units per kg weight per day.  
• Patients with BG between 201-400 mg/dL= 0.4 units per kg weight per day. 
• The starting insulin TDD will be reduced to 0.25 units per kg in patients ≥ 70 years of age and/or 
with a GFR < 50 ml/min. 
• Subjects treated with insulin prior to admission will receive 80% of the outpatient dose (basal or basal 
plus prandial) insulin dose. 
• Half of total daily dose will be given as basal (glargine or Levemir) and half as rapid-acting 
insulin analogs   
• Basal (Glargine/Levemir) insulin will be given once daily, at the same time of the day.   
• Rapid-acting insulin (lispro, aspart or glulisine) will be given in three equally divided doses 
before each meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose will be held.  
• Insulin adjustment.  The total daily BASAL insulin dose will be adjusted as follows:  
• Fasting and pre-meal BG between 100-140 mg/dl without hypoglycemia the previous day: no 
change  
• Fasting and pre-meal BG between 141-180 mg/dl: increase glargine dose by 10% every day 
• Fasting and pre-meal BG >180 mg/dl: increase glargine dose by 20% every day  
• Fasting and pre-meal BG between 70-99 mg/dl: decrease glargine dose by 10% every day 
• If a patient develops hypoglycemia (BG <70 mg/dL), decrease glargine dose by 20%.   
• If a patient develops hypoglycemia (BG <40 mg/dL), decrease glargine dose by 30-40%.   
 
•  Supplemental insulin.  Supplemental (lispro,aspart or glulisine) insulin will be administered following 
the “sliding scale” protocol by Primary Care Team.   
• If a patient is able and expected to eat all or most of his/her meals, supplemental  insulin will be 
administered before each meal and at bedtime following the “usual” dose of the sliding scale 
protocol. 
• If a patient is not able to eat, supplemental insulin will be administered every 6 hours (6-12-6-12) 
following the “sensitive” dose of the sliding scale chosen by the Primary Care Team or healthcare 
facility. 
If determined by the investigator or co-investigator that patient is insulin resistant, it would be to his/her 
medical discretion to adjust doses of basal and rapid acting insulin based on patient’s needs. 
 
3.2.b.1   ICU Stay:  The study drug will be given once daily in a blinded fashion during the ICU and hospital 
stay. Study patients with hyperglycemia in the ICU (defined as a BG >180 mg/dL) will continue to receive the 
study drug (sitagliptin or placebo) and will be started on intravenous CII in the ICU adjusted to achieve and 
maintain a BG target between 110 - 180 mg/dl in the ICU.  
 
Patients with hyperglycemia who require CII in the ICU will be started on the institution’s insulin infusion 
protocol in the ICU.  Below is the Emory insulin drip protocol: 
 


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3.2.b.2. Transition from Insulin Drip to Subcutaneous Insulin  
The study drug will be given once daily in a blinded fashion until completion of 10 days of study treatment.  
• Patients who didn’t require CII or a rate <1 U/h: 
• Insulin naïve patients: 
o  BG <180 mg/dL: Transition to SSI  
o BG>180 mg/dL: Start basal weight based at 0.2 U/kg plus SSI. 
• Patients with prior insulin treatment: 
o Start basal at pre-surgery dose plus SSI, or 
o Start basal weight based at 0.2 U/kg plus SSI. 
 


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• Patients that required continuous insulin infusion (CII) at a rate ≥1U/h will be transitioned to basal insulin 
(glargine/detemir).  Calculate total daily dose (TDD) of insulin from the average CII rate during the last four 
hours of infusion (example, if the average rate is 2 U/hr., the TDD is 48 U/day)   
o Give 50% of calculated dose as basal (glargine/detemir) insulin every day. Basal insulin will be 
given approx. 4 hours before discontinuation of CII. 
o Monitor BG AC and HS, if BG > 180 mg/dl x 2, start prandial (lispro / aspart) insulin at same 
basal dose divided in 3 equal doses before meals and coverage with sliding scale insulin for BG 
>180 mg/dl, see table 3.2.c.1. 
 
 
• After transition to regular floor, patients not transitioned to basal insulin will continue to receive sitagliptin or 
placebo along with a supplemental sliding scale outlined in Table 3.2.c.1. During this period, if patients have 2 
consecutive fasting and/or premeal BG >180 mg/dl, or with average daily BG >180 mg/dl, 180 mg/dL), rescue 
therapy will be initiated. Rescue therapy with subcutaneous insulin (see 3.2.c.2) 
 
 
 
 
Supplemental (correction) insulin.  Supplemental (lispro or aspart) insulin will be administered following the 
“sliding scale” protocol (Table 3.2.c.1.).   
Table 3.2.c.1., Supplemental Sliding Scale Insulin (number of units) - Add to scheduled insulin dose before 
meals.   
Blood Glucose  
  
(mg/dL) 
                  Sensitive 
           Usual 
 
     Resistant             
 
181-220 
 
 
2 
 
   3 
 
 
4 
221-260 
 
 
3 
 
   4 
 
 
5 
261-300 
 
 
4 
 
   5 
 
 
6 
301-350 
 
 
5 
 
   6 
 
 
7 
351-400 
 
 
6 
 
   7 
 
 
8 
> 400  
 
 
7 
 
   8 
 
 
9 
______________________________________________________________ 
** Check appropriate column below and cross out other columns 
 
At bedtime, give Sliding Scale Insulin starting at BG >240 mg/dl. 
Blood Glucose  
  
(mg/dL) 
                  Sensitive 
           Usual 
 
     Resistant             
 
241-280 
 
 
1 
 
   2 
 
 
3 
281-320 
 
 
2 
 
   3 
 
 
4 
321-360 
 
 
3 
 
   4 
 
 
5 
361-400 
 
 
4 
 
   5 
 
 
6 
> 400  
 
 
5 
 
   6 
 
 
7 
______________________________________________________________ 
** Check appropriate column below and cross out other columns 
 
 
The numbers in each column indicate the number of units of aspart or lispro insulin per dose. If a patient is able 
and expected to eat all or most of his/her meals, supplemental insulin will be administered before each meal 
following the “usual” column dose.  Supplemental insulin at bedtime = insulin dose at BG > 240 mg/dl.  If a 
patient is not able to eat (NPO), supplemental insulin will be administered every 6 hours (6-12-6-12) following 
the “sensitive” column dose.  
 
 
 
 


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3.2.c.2 Inpatient Rescue Therapy with Basal Bolus Insulin regimen: 
Patients with persistent hyperglycemia (fasting and premeal BG > 180 mg/dl) while receiving basal plus 
correction regimen will be changed to basal bolus insulin regimen, calculated to give 50% of basal (glargine or 
detemir) insulin once daily and 50% or premeal rapid-acting insulin (lispro or aspart) before meals.  
 
Basal Bolus Regimen: Starting total daily insulin dose:  
 
• Starting total daily insulin dose (TDD) = 0.4 units per kg weight per day. 
• Half of total daily dose will be given as basal and half as rapid-acting insulin analogs   
• Basal insulin will be given once daily, at the same time of the day.   
• Patients will receive the full-dose of basal insulin (even if NPO).     
• Rapid-acting insulin (lispro, aspart) will be given in three equally divided doses before each meal.  To 
prevent hypoglycemia, if a subject is not able to eat, the dose of lispro will be held.  
 
Insulin adjustment.  The total daily insulin dose will be adjusted as follow:  
• Fasting and/or pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change  
• Fasting and/or pre-meal BG between >180-240 mg/dl: increase basal dose by 10% every day 
• Fasting and/or pre-meal BG >241 mg/dl: increase basal dose by 20% every day  
• Fasting and/or pre-meal BG <100 mg/dl: Decrease basal by 10% 
•    If a patient develops hypoglycemia (BG <70 mg/dL), the insulin TDD (basal and prandial) should be 
decreased by 20%.   
 
Supplemental (correction) insulin.  Supplemental (lispro or aspart) insulin will be administered following the 
“sliding scale” protocol (Table 3.2.c.1.).   
Blood glucose monitoring in non-ICU.  Blood glucose will be measured before each meal and at bedtime (or 
every 6 hours if a patient is not eating) using a glucose meter.  In addition, blood glucose will be measured at 
any time if a patient experiences symptoms of hypoglycemia or if requested by the treating physician.   
If determined by the investigator or co-investigator that patient is insulin resistant, it would be to his/her 
medical discretion to adjust doses of basal and rapid acting insulin based on patient’s needs. 
 
 
3.2.b.3.    Treatment recommendations at discharge: 
 
• Admission A1C < 7.5%:  
• Discharge on same pharmacologic regimen (oral agents, insulin therapy).  
• Assure there are no contraindications to OAD (i.e., TZDs and heart failure; metformin and renal 
failure). 
• If contraindication to OADs, discharge patient on sitagliptin once daily.  
 
• Admission A1C between 7.5% and 9%:   
 Patients receiving OAD treatment prior to admission: 
• If no contraindications to OAD discharge on metformin in combination to sitagliptin. 
• If contraindication to metformin, discharge on sitagliptin in combination to basal at 50% of total 
daily hospital dose.  
• If contraindication to metformin in a patient who did not receive basal in the hospital, discharge 
on sitagliptin once daily and basal at 0.15 unit/kg/day.  
 Patients receiving OAD and insulin combination prior to admission: 
• If no contraindications to OAD discharge on metformin in combination to sitagliptin. 
• If contraindication to metformin, discharge on sitagliptin in combination to basal at 50% of daily 
hospital dose.  


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• If contraindication to metformin in a patient who did not receive basal insulin in the hospital, 
discharge on sitagliptin once daily and basal insulin at 0.15 unit/kg/day.  
 
 
 
 Patients receiving insulin treatment prior to admission: 
• Discharge on sitagliptin in combination with basal insulin at 50% of total daily hospital dose.  
 
 
 
• Admission A1C ≥ 9%:   
 Patients receiving OAD treatment prior to admission: 
• If no contraindications to OAD discharge on metformin plus sitagliptin in combination to basal 
once daily at 80% of daily hospital. 
• If contraindication to metformin, discharge on sitagliptin in combination to basal at 80% of daily 
hospital dose.  
• If contraindication to metformin in a patient who did not receive basal in the hospital, discharge 
on sitagliptin once daily and basal at 0.15 unit/kg/day.  
 
 Patients receiving OAD and insulin combination prior to admission: 
• If no contraindications to OAD discharge on metformin plus sitagliptin in combination to basal 
insulin once daily at 80% of total daily hospital. 
• If contraindication to metformin, discharge on sitagliptin in combination with basal insulin at 
80% of total daily hospital dose.  
• If contraindication to metformin in a patient who did not receive basal insulin in the hospital, 
discharge on sitagliptin once daily and basal insulin at 0.15 unit/kg/day. 
 
 Patients receiving insulin treatment prior to admission: 
• If no contraindications to OAD discharge on metformin plus sitagliptin in combination to basal 
insulin once daily at 80% of total daily hospital. 
• If contraindication to metformin, discharge on sitagliptin in combination to basal insulin at 80% 
of total daily hospital dose.  
• If contraindication to metformin in a patient who did not receive basal in the hospital, discharge 
on sitagliptin once daily and basal insulin at 0.15 unit/kg/day 
 
• Alternative:  Discharge on basal bolus regimen at same inpatient total daily insulin dose.   
 Basal insulin (glargine or detemir) once daily, at the same time of the day.   
 Rapid-acting insulin (lispro, aspart, glulisine) before meals.  
 
 
 
 
 
3.3. 
Primary and Secondary Research Outcomes: 
Primary Outcome: 
3.3. a Aim 1: To determine differences in the frequency of stress hyperglycemia (% patients with BG >180 
mg/dl) in the ICU after CABG surgery between patients treated with sitagliptin or placebo.  
3.3. b. Aim 2:  To determine differences between groups on the number of patients with persistent 
hyperglycemia (2 consecutive fasting and/or premeal BG > 180 mg/dl, or with average daily BG >180 mg/dl) 
who require rescue therapy with SC insulin after discontinuation of CII. 
 
Secondary outcome is to compare differences between treatment with sitagliptin and placebo on: 


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1. Need for CII for treatment of hyperglycemia  
2. Mean ICU BG concentration  
3. Mean insulin dose during ICU (insulin infusion per hour  (unit/hour) and per day) 
4. Duration of CII (hours on CII) 
5. Number of patients requiring SC insulin after discontinuation of CII (transition ICU to floor) 
6. Days of SC insulin after discontinuation of CII 
7. Mean non-ICU BG concentration 
8. Amount of SC insulin in ICU and non-ICU stay  
9. Hyperglycemic events (BG > 200 mg/dL) in ICU and non-ICU 
10. Hypoglycemic events (BG < 70 mg/dl; severe hypoglycemia (BG < 40 mg/dl) in ICU and non-ICU. 
11. Composite of perioperative complications including: hospital mortality, sternal wound infection 
(deep and superficial), bacteremia, pneumonia, acute renal failure, and acute myocardial infarction.   
a. Surgical wound infection (superficial and deep sternal wound infection) 
b. Pneumonia (CDC criteria) 
c. Acute renal injury (new-onset increment serum creatinine level > 50% from baseline)   
d. 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) 77.   
12. Duration of ventilatory support.  
13. ICU and hospital length of stay, and ICU readmissions 
14. Cerebrovascular events (permanent stroke and reversible ischemic neurologic deficit).  
15. Hospital readmission and need for Emergency room visit after discharge (a short visit will be 
conducted at the time of their post-op visit or via telephone). 
 
4. 
CLINICAL MANAGEMENT GUIDELINES  
The primary care team will provide care concerning the use of pressors, ventilatory support/weaning, sedation, 
antibiotics, and treatment of co-morbid conditions.   
4.1. 
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 CII 
in the ICU, and before meals and at bedtime after transition to regular wards.  Hypoglycemia is the main 
adverse event and safety issue in the study. The number of mild (BG ≤70 mg/dL) and severe hypoglycemia (BG 
≤ 40 mg/dL) and clinical consequences (neurological and cardiovascular) will be compared between groups.    
4.2. 
Assessment and monitoring of hospital mortality.  Investigators daily will follow study subjects and 
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.    
 
4.3. 
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.  Deep Sternal Wound Infection (DSWI): chest wound infection involving the sternum or 
mediastinal tissues, including mediastinitis; and Superficial Sternal Wound Infection (not involving the sternal 
bone or wires): chest wound infections involving the skin or subcutaneous tissues, or both.  
 
4.4. 
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, 4) all relevant radiographic reports, 5) orders for 
antimicrobial agents, 6) communication, as needed, with primary physicians and site infectious disease 
consultants, 7) use of the CDC guidelines for diagnosis of specific nosocomial infections.78 
 


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4.5. 
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 as a ventilator day. 
 
4.6. 
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.  
 
4.7. 
Assessment and monitoring of renal function.  Acute kidney injury is defined as an increment level > 
50% from baseline. 
 
4.8. 
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). 
 
4.9.  
APACHE II Scoring.  APACHE score will be calculated on arrival to ICU.  The APACHE II score will 
be entered into the initial screening form following completion of CABG. 
 
4.10.    Data collection and data entry.  The study coordinators 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, type of treatment of diabetes and comorbid 
conditions, body weight, BMI, type of surgery, and 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. All data will be entered 
electronically in Redcap by participating sites. Sponsor site expects data to be entered in Redcap within 10 days 
of discharge, phone call or outpatient visit. 
 
 
 
 
5. 
HUMAN SUBJECTS 
5.1. 
Study population.   
5.1. a. Inclusion criteria:   
1. Males or females between the ages of 18 and 80 years undergoing any CABG surgery.   
2.   Patients with T2D treated with diet, oral, injectable agents, and/or insulin.  
5.1. b. Exclusion criteria:  
1. Patients with Type 1 Diabetes  
2. Patients with history of diabetic ketoacidosis and/or hyperosmolar, hyperglycemia syndrome. 
3. Severely impaired renal function (GFR < 30 ml/min) or clinically significant hepatic failure. 
4. Moribund patients and those at imminent risk of death (brain death or cardiac standstill).  
5. Subjects with gastrointestinal obstruction or adynamic ileus or those expected to require gastrointestinal 
suction. 
6. Patients with clinically relevant pancreatic or gallbladder disease.  
7. Treatment with oral or injectable corticosteroid. 
8. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of 
the study, 
9. Female subjects are pregnant or breast-feeding at time of enrollment into the study. 
 
5.2. Inform consent and randomization.   All patients scheduled to undergo cardiac surgery will be 
considered potential candidates in this study. Patients will be consented during the preoperative evaluation on 
admission to the surgical service at least 24 hours prior to scheduled surgery. The investigators or study 
coordinators will review and explain the contents of the informed consent document to the eligible patient.  The 
potential subject will be informed of the purpose of the study, the randomization procedure, and the risks and 


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benefits of participation.  The potential subject will also be informed that he/she may refuse to participate, and 
that even if he/she consents to participate he/she may withdraw from the study at any time.  
5.3. 
Study Sites. This study will be conducted at Emory University Hospitals and Grady Memorial  
 
6. STATISTICAL ANALYSIS  
The proposal is a two-arm, three-center, randomized placebo-controlled clinical trial. The primary hypothesis is 
that treatment with sitagliptin will prove to be a safe and effective for the prevention and treatment of 
hyperglycemia during the perioperative period cardiac surgery patients.  
 
6. a. 
Analysis of Primary Endpoint: The primary endpoints in this study are to determine differences 
between sitagliptin and placebo treatment on: 1) frequency of hyperglycemia in the ICU after cardiac surgery, 
and 2) number of patients with persistent hyperglycemia who require rescue therapy with SC insulin after 
discontinuation of CII. We will first use two-sided Chi-square test or Fisher’s exact test to compare the primary 
endpoint between the treatment group and the control group. Next, we will perform multivariate logistic 
regression to estimate the difference in the occurrence rate of the primary endpoint while adjusting for other 
relevant covariates such as age and gender.  Stepwise, backward, or forward model selection strategy will be 
adopted to determine the variables to be included in the final model. Standard diagnostic and model checking 
procedures, such as deviance residual plot and Hosmer-Lemeshow test, will be applied to examine the fit of the 
developed predictive model. We will use two-sample t-tests or nonparametric Wilcoxon tests to compare them 
between the two study groups. Transformations will be applied if normality violation is detected.  Multivariate 
linear regression will be further conducted to assess the difference in continuous secondary outcomes between 
the two groups while accounting for other potential confounders. We will also apply standard model selection 
and diagnostic procedures to determine and assess the final multivariate linear model. 
 
6. b. 
Analysis of Secondary Endpoints: The secondary outcomes of interest can be a binary outcome (e.g. 
indicator for whether CII is needed in ICU), or a count outcome (e.g. number of perioperative complications), 
or a continuous outcome (e.g. mean daily BG concentration). We will adopt the same strategy proposed for the 
primary endpoint to analyze any binary or continuous secondary outcomes. For secondary endpoints measured 
as counts, we plan to use nonparametric tests such as Krustal-Wallis tests to compare them between the two 
study groups. 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 taken into account. We will use standard model selection and model checking procedures for 
Poisson regression (or Negative Binomial regression) and linear regression to decide the final models and assess 
their fits to the data. 
 
6. c. 
Sample Size Calculation and Power Analysis: We have performed sample size and power calculations 
based on our prior studies. In the GLUCO-CABG trial, 91% of DM subjects had stress hyperglycemia in ICU. 
In this study, we assume the same rate of hyperglycemia in the control (placebo) group. We anticipate that 
sitagliptin will reduce the rate of hyperglycemia by 20-25% (corresponding to odds ratio (OR) in the range of 
0.264-0.213). We calculate the sample size based on the OR estimate of 0.264 and provide the power for the 
larger treatment effects represented by OR=0.25, 0.20, and 0.15 (see Table). More specifically, conservatively 
using two-sided Fisher’s exact test, two-sided, with alpha=0.05, the sample size required for 80% power to 
detect the conjectured treatment effect of OR=0.264 (i.e. 91% vs 73%) would be 77 patients per study group. 
Accounting for 15-20%% attrition rate, recruiting ~95 patients we need to be recruited in each group.  A total of 
200 randomized patients (100 patients per group) will be recruited in this study. 
 
We also consider the statistical power for the primary endpoint for Aim 2 and important secondary endpoints. 
Based on the GLUCO-CABG trial, 98% of T2D subjects required SQ insulin post-transition. We assume the 
same rate for the placebo group in the proposed study, and expect 20-25% reduction in the rate of requiring SC 
insulin post-transition, which corresponds to OR in the range of 0.074-0.057. Given 77 patients per group (after 
attrition), we would have 97.8% power when the OR in this endpoint is 0.074. . We also calculate the power for 


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OR=0.07, 0.06, and 0.05 (Table). In in the GLUCO-CABG data, the standard deviation (SD) of mean daily BG 
for T2D subjects is bounded above by 36 mg/dl. Assuming the same upper bound for the BG SD in this study, 
given 77 patients per group (after attrition), we would have over 80% power to detect a mean daily BG 
difference of 16.6 mg/dl between the two study groups, based on a two-sample, two-sided t-test, with 
alpha=0.05. Our calculations suggest that the proposed study is well powered for the primary endpoint as well 
as the secondary endpoints of major interests.   
 
 
Table. Power computed based on two-sided Fisher’s exact test with alpha=0.05 and the proposed sample, 56 
patients per group after attrition. 
  
 
 
 
 
 
 
 
 
 
 
 
 
7.        Data and Safety Monitoring Board (DSMB): 
The Data and Safety Monitoring Board (DSMB) will review unblended data on safety, treatment compliance, 
and evaluate the efficacy of the intervention being studied in this clinical trial. The DSMB will meet at 6-month 
intervals and report on study progress to the IRB.  
8. 
Interim Analysis and Stopping Rules:  We plan to perform one interim analysis on the primary 
endpoint every 6 months and when half of the subjects have been randomized.  The trial will be stopped if there 
is evidence beyond a reasonable doubt of a difference in the rate of death and hospital complications (two-sided 
alpha level, <0.01) between the treatment groups.  
 9.       ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation subject administered an investigational (medicinal) product and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all adverse events 
(AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more AEs.) 
Effect Size: 
Odds ratio  
0.264 
0.25 
0.20 
 
0.15 
Primary endpoint: Stress hyperglycemia in ICU (placebo 96% event rate) 
Event rates 
91% vs. 73% 
91% vs. 72% 
91% vs. 67% 
91% vs. 60% 
Power  
80.3% 
84.3% 
95.3% 
>99% 
Secondary endpoint: Need for SC insulin post-transition (placebo 98% 
event rate) 
Effect Size: 
Odds ratio  
0.074 
0.07 
0.06 
 
0.05 
Event rates  
98% vs. 78% 
98% vs. 77% 
98% vs. 75% 
98% vs. 71% 
Power 
97.8% 
98.5% 
>99% 
>99% 


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9.1. Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize 
the subject or may require intervention [e.g. medical, surgical] to prevent one of the other serious outcomes 
listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization.)  
Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via the study drug is an SAE.  
NOTE:  
The following hospitalizations are not considered SAEs:  
− a visit to the emergency room or other hospital department < 24 hours, that does not result in admission 
(unless considered an important medical or life-threatening event) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy) 
− medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases 
− admission encountered for another life circumstance that carries no bearing on health status and requires 
no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason). 
9.2. Serious Adverse Event Collection and Reporting 
The collection of AEs will start after the signing of the informed consent.  All SAEs, whether related or not related 
to study drug, must be collected, including those thought to be associated with protocol-specified procedures. An 
SAE report should be completed for any event where doubt exists regarding its seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of 
the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should 
be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS (or designee) within 
24 hours. SAEs must be recorded on an SAE Report Form or similar form (e.g. CIOMS, MedWatch); If only 
limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports should 
include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, 
a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used 
for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 


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9.3. Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
The collection of nonserious AE information should begin at initiation of study drug. Nonserious AE information 
should also be collected from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the subjects.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. 
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of study drug and for 
those present at the end of study treatment as appropriate. All identified nonserious AEs must be recorded and 
described on the nonserious AE page of the CRF.  
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that are 
reported/identified during the course of the study. 
9.4. Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. All occurrences of overdose must be reported as an SAE. 
 
9. 
Risk associated with participation: 
9.1. 
Hypoglycemia.    Hypoglycemia is the main adverse event and safety issue in the study. In our previous 
ICU studies, we observed that <10% of cardiac surgery subjects during CII and 20-30% during SC insulin 
experienced hypoglycemia. The use of insulin in combination with DPP4 inhibitors may increase the risk of 
hypoglycemia during the hospital stay.  The number of mild (BG ≤70 mg/dL) and severe hypoglycemia (BG ≤ 
40 mg/dL) and clinical consequences (neurological and cardiovascular) will be compared across treatment arms.    
9.2. 
Treatment of hypoglycemia.  Hypoglycemia, defined as a BG <70 mg/dL will be treated by a standard 
hypoglycemia protocol available at each hospital.  In brief, insulin infusion will be turn off in the ICU or total 
daily dose of SC insulin will be reduced by 20-40% in non-ICU settings. In the ICU, subjects will receive 
Dextrose 50% solution (D50W) IV push based on the formula cc of D50W IV push = (100-BG) x 0.4, or 
alternative D50W IV push dose:  patient awake:  25 ml (1/2 amp), patient not awake (i.e. sedated):  50ml (1 
amp).  Blood glucose will be rechecked every 20 minutes and repeat 25ml of D50W IV if < 60 mg/dL. Insulin 
infusion will be restarted once blood glucose is >140 mg/dL.  In non-ICU patients will be treated with oral 
glucose if alert or with IV Dextrose (as above) if comatose. 
 
9.3. 
Hyperglycemia.    It is possible that following the proposed protocol, patients randomized to the 
conventional treatment arm will develop higher numbers of hyperglycemic events (BG >200 mg/dl) which may 
lead to increased risk of complications.  We expect that ~20% of subjects will experience one or more episodes 
of hyperglycemia.  The frequency of severe hyperglycemia will be analyzed statistically.   
 
9.4. 
Protection against risks.   Our strict inclusion and exclusion criteria for entry will help to minimize 
risks. 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, and 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, e) study subjects will receive rescue therapy with insulin in the event of hyperglycemia.     
 
10. 
Potential benefits to the subject.  
We believe that all subjects will benefit from this study.  
Intensified blood glucose monitoring and blood glucose control has been shown to significantly reduce hospital 
complications associated with hyperglycemia and hypoglycemia.   
 
11. 
Inclusion of women.  We anticipate that ~50% of the study subjects will be female.  No patients under 
the age of 18 and no pregnant women will be included in the study.   
 
12. 
Inclusion of minorities.     Patients will not be excluded based on race or ethnic origin.  We anticipate 
that half of the patients will be African Americans or Hispanics, and the rest Caucasians.   
 


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13. 
Inclusion of children.     No patients under the age of 18 will be recruited in this study. 
 
14. 
Confidentiality.     Informed consent will follow the procedure of Emory University Institutional 
Review Board.   Every participant will be informed in writing and verbally with the important and key points of 
the study.   The investigators or the research coordinators will obtain a witnessed informed consent prior to 
inclusion into the study.  Data collection records with personal identifiers will be stored in locked file cabinets.  
All data maintained in the computerized database will be accessible only with a login and protected password. 
After the study is completed, all data will be kept in a locked file. Presentation of the study results at regional or 
scientific meetings or in publications will not identify subjects.   
 
15. 
Payment for participation.    Participation in this study is voluntary.  Patients will receive one 
hundred dollars ($100.00) prior to discharge.  If a participant should stop participation before completion, the 
payment will be prorated at $20.00 per day.  
 
16. 
Financial conflict of interests.     This study receives support from Merck. Dr. Umpierrez, Dr. Pasquel, 
and Dr. Vellanki serve as a consultant to Merck and receives compensation for these services. The terms of this 
arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest 
policies. 
 
17. 
Study time line: More than 1200 major cardiac surgeries are performed every year at Emory University 
Hospital, Midtown Hospital and Grady Memorial Hospital.  We anticipate that >80% of patients without a 
history of DM will experience stress hyperglycemia (BG>140 mg/dl) after surgery, giving 4 to 6 potential 
candidates per week.  Historically we averaged 8-12 subjects/week requiring insulin infusion 
at the 3 institutions.  We anticipate recruiting 2 or 3 patients per week (one per 
institution) for a total recruitment period of approximately 12 months.  
 
18. RESPONSIBILITIES OF THE SPONSOR   
Emory University will serve as Sponsor of this Clinical Trial.  The sponsor is responsible to Health Authorities for 
taking all reasonable steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial 
Protocol compliance, and integrity and validity of the data recorded. As the Monitoring Team, we will help the 
Investigators in maintaining a high level of ethical, scientific, technical and regulatory quality in all aspects of the 
Clinical Trial.  
 
At regular intervals during the Clinical Trial, a member of the Monitoring Team to review study progress, Investigator 
and patient compliance with Clinical Trial Protocol requirements and any emergent problems will contact all research 
sites, through letters or telephone calls. These monitoring contacts will include but not be limited to review of the 
following aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, 
AEs with pre-specified monitoring documentation and reporting, AE documentation, patient compliance, 
concomitant therapy use and quality of data.  


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