Linagliptin Inpatient Trial: A Randomized Controlled Trial on the Safety and Efficacy of Linagliptin (Tradjenta®) Therapy for the Inpatient Management of General Surgery Patients With Type 2 Diabetes
Phase: PHASE4
Conditions: Type 2 Diabetes
Sponsor: Emory University

Linagliptin Inpatient_07.19.2016 
 
IRB00066548 NCT02004366 
 
Linagliptin Inpatient Trial: A Randomized Controlled Trial on the Safety and Efficacy of Linagliptin 
(Tradjenta®) Therapy for the Inpatient Management of General Surgery Patients with Type 2 
Diabetes  
 
Principal Investigator: Guillermo E. Umpierrez, M.D. Emory University School of Medicine 
 
Date: 07/19/2016  
 
1 

Linagliptin Inpatient_07.19.2016 
 
Title:   
Linagliptin Inpatient Trial: A Randomized Controlled Trial on the Safety and Efficacy of Linagliptin 
(Tradjenta®) Therapy for the Inpatient Management of General Surgery Patients with Type 2 Diabetes  
 
Principal Investigator: 
 
Guillermo E. Umpierrez, M.D. 
Professor of Medicine 
 
 
 
 
Department of Medicine/Endocrinology 
Emory University School of Medicine 
 
 
Sites/Investigators: 
 
Grady Memorial Hospital: Priyathama Vellanki, M.D. 
Emory University Hospital: Francisco Pasquel, M.D. 
 
Centers for consideration: 
 
Boston Medical Center: Sara Alexanian, M.D. (Site PI)  
Rush University: David Baldwin, M.D. (Site PI)  
 
University of Colorado: Neda Rasouli, M.D. (Site PI) 
 
Statistical Support:  
Limin Peng, Ph.D. 
Associate Professor 
Rollins School of Public Health 
Emory University 
 
 
 
 
 
 
 
 
2 

Linagliptin Inpatient_07.19.2016 
 
I. 
RESEARCH OBJECTIVES AND SPECIFIC AIMS 
 
A. 
Introduction: 
The association between hyperglycemia and poor clinical outcomes in patients with and without 
diabetes is well established (1-5). Extensive data from observational and prospective randomized controlled  
trials in hospitalized patients have reported a strong association between hyperglycemia and poor clinical 
outcome, such as mortality, morbidity, length of stay (LOS), infections and overall complications (1, 4, 6-8).  
Most clinical trials in critically ill and general medicine and surgery patients have reported that improvement 
of glycemic control reduces LOS, risk of multiorgan failure and systemic infections (9-11), as well as short- 
and long-term mortality (6, 11) in patients with hyperglycemia and diabetes.   
 
Clinical guidelines from professional organizations (12-14) recommend the use of subcutaneous (SQ) 
insulin as the preferred therapy for glycemic control in general medical and surgical patients with T2D.  The 
two most common SQ insulin regimens for inpatient glycemic management are sliding scale regular insulin 
(SSRI) and basal bolus insulin therapy in combination with correction insulin scale (15, 16).  The use of 
basal bolus regimen results in better glycemic control and in lower rate of hospital complications compared 
to sliding scale regular insulin (SSRI) (16-19).  The basal bolus regimen; however, requires multiple insulin 
daily injections and is associated with a significant risk of hypoglycemia reported in up to 32% of non-ICU 
patients with T2D (16, 18, 19).   
 
We recently completed a randomized two-center pilot open label trial aiming to determine differences 
in glycemic control between treatment with sitagliptin (Januvia) alone or in combination with glargine 
compared to a standard basal bolus regimen in general medicine and surgery patients with T2D (see 
preliminary result section). We found no differences in mean daily BG, number of BG readings within target, 
frequency of hypoglycemia, LOS and hospital complications.  We also found that patients treated with 
sitagliptin alone required less insulin dose (p<0.001) and lower number of insulin injections per day 
(p<0.001) compared to treatment with basal bolus regimen. These results suggest that treatment with a DPP-
4 inhibitor is safe and effective for the management of hyperglycemia in patients with T2D.  These results 
are of great clinical importance and may represent a major improvement in management of hospitalized 
patients with T2D; however, they need to be confirmed by a large multicenter RCT.  Accordingly, we 
propose to determine the safety and efficacy of DPP-4 inhibitor therapy for in-hospital and post-discharge 
management of general medicine and surgical patients with T2D. 
 
B. 
Hypothesis: 
We hypothesize that treatment with linagliptin (Tradjenta®) once daily plus correction 
(supplemental) doses with a rapid-acting insulin analog before meals will result in a similar glycemic control 
than treatment with glargine (Lantus) once daily plus rapid-acting insulin before meals in general surgery 
patients with T2D.   
 
C. 
Specific Aims: 
Specific Aim 1: To determine whether in-hospital glycemic control, as measured by mean daily blood 
glucose concentration and frequency of hypoglycemic events, is different between treatment with 
linagliptin (Tradjenta®) plus correction doses with a rapid-acting insulin analog before meals and a 
basal bolus regimen with glargine once daily and rapid-acting insulin analog before meals in general 
surgery patients with T2D.  Surgery patients with T2D treated with diet, oral antidiabetic agents (OAD) or 
with low total daily dose insulin therapy (≤0.5 unit/kg/day) will be randomized to receive linagliptin (group 
1) or basal bolus insulin regimen (group 2).  If needed, patients in both groups will receive supplemental 
(correction) doses of rapid-acting insulin (lispro, aspart or glulisine) before meals for BG > 140 mg/dl.   
 
Specific Aim 2:  To determine the efficacy and safety of an HbA1c based discharge algorithm in controlling 
BG after discharge in surgery patients with T2D.  Patients who participate in the in-hospital arm (Aim 1) will 
 
3 

Linagliptin Inpatient_07.19.2016 
 
be invited to enroll in this open label prospective outpatient study.  The total duration of the study is 3 
months.  Patients with an admission HbA1c <7% will be discharged on their same outpatient antidiabetic 
regimen or linagliptin 5 mg once daily. Patients with an HbA1c between 7% and 9% will be discharged on 
their outpatient treatment plus linagliptin once daily.  Patients with an admission A1C ≥ 9% will be 
discharged on a combination of metformin plus linagliptin and 50% of basal insulin used in the hospital stay. 
 
II. 
BACKGROUND AND CURRENT STATUS OF WORK IN THE FIELD. 
A large body of evidence suggests that in hospitalized patients with and without diabetes, the 
presence of hyperglycemia is associated with poor clinical outcomes (1-6, 20-23).  Evidence from 
observational studies indicates that hyperglycemia is associated with an increased risk of complications and 
mortality, a longer hospital stay, a higher admission rate to the ICU, and a higher likelihood that transitional 
or nursing home care after hospital discharge will be required (1, 2, 6, 24-28).  Prospective randomized trials 
in critical care patients have shown that glycemic control reduces short- and long-term mortality, multiorgan 
failure and systemic infections, length of hospital and ICU stay [7, 9-11], and to lower total hospitalization 
cost (29).  Similarly, attainment of targeted glucose control in the setting of cardiac surgery is associated 
with a significant reduction in deep sternal wound infections and mortality rate (9, 30, 31). Based on these 
observational and interventional studies, improved glycemic control is recommended in patients with critical 
illness (3, 6, 23, 26, 28, 32).  
 
The importance of hyperglycemia also applies to adult patients admitted to general surgical and 
medical wards.  In such patients, the presence of hyperglycemia is associated with prolonged hospital stay, 
infection, disability after hospital discharge, and death (1, 4, 6).  Over the short-term, hyperglycemia can 
adversely affect fluid balance and immune function, and it can promote inflammation (26, 33).  Our research 
group reported that inpatient hyperglycemia (defined as a fasting blood glucose ≥ 126 mg/dl or random 
blood glucose ≥ 200 mg/dl on two or more occasions) in subjects with and without history of diabetes was 
associated with longer length of hospital stay and increased hospital mortality (1).  In general surgical 
patients, a serum glucose > 220 mg/dL on postoperative day one has been shown to be a sensitive predictor 
of the later development of postoperative nosocomial infection (4).  In patients with hyperglycemia (BG > 
220 mg/dL) on postoperative day one, the infection rate was 2.7 times that observed (31.3% versus 11.5%) in 
diabetic patients without hyperglycemia.  These data strongly indicate that hyperglycemia from any etiology 
is a predictor of poor outcome in hospitalized patients in critical care units or in general medicine or surgical 
services, and that improvement in outcomes can be achieved with improved glycemic control.     
 
Recent prospective, randomized multi-center trials have shown that basal bolus insulin regimens 
result in improved glycemic control and reduce the rate of hospital complications compared to sliding scale 
regular insulin (SSRI) in general medical and surgical patients with T2D (16, 18, 19).  In the Rabbit-2 
medicine trial (34), insulin naïve patients with T2D were randomized to receive glargine once daily and 
glulisine before meals or SSRI four times daily.  Patients treated with glargine + glulisine had greater 
improvement in blood glucose control than SSRI (19).  The Rabbit Surgery trial compared the safety and 
efficacy of a basal bolus insulin regimen with glargine once daily and glulisine before meals to SSRI in 
patients with T2D undergoing general surgery.  We observed a lower mean daily glucose concentration after 
the 1st day and a reduction in the frequency of hospital complications with basal bolus as compared with 
SSRI treatment (19).  These results indicate that basal/bolus insulin regimen is a preferred regimen over 
SSRI alone in the hospital management of patients with T2D.  The use of basal bolus approach; however, is 
labor intensive requiring multiple daily insulin injections (4 to 6), and have a significant risk of 
hypoglycemia (19, 35) reported in up to 32% of hospitalized patients with T2D in general wards.   
 
We recently completed the first pilot study on the safety and efficacy of treatment with sitagliptin 
(Januvia) alone or in combination with basal insulin in general medicine and surgery patients with T2D 
(see preliminary result section).  In this study, 90 patients with T2D randomized to sitagliptin once daily, 
 
4 

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Linagliptin Inpatient_07.19.2016 
 
In summary, our preliminary studies indicate that 1) treatment with basal bolus regimen results in better 
metabolic control and in a lower rate of hospital complications than treatment with SSRI in patients with 
T2D, and 2) the use of a DPP-4 inhibitor alone or in combination with basal insulin may represent effective 
alternatives to basal bolus insulin regimen for the management of hospitalized patients with T2D.   
 
 
IV. 
EXPERIMENTAL PLAN. 
 
Specific Aim 1: To determine whether in-hospital glycemic control, as measured by mean daily glucose 
concentration and frequency of hypoglycemic events, is different between treatment with linagliptin 
(Tradjenta®) plus correction doses with a rapid-acting insulin analog before meals and a basal bolus regimen 
with glargine once daily and rapid-acting insulin analog before meals in general surgery patients with T2D.   
 
IV.a. Rationale. 
The result of several observational and interventional studies indicate that 
hyperglycemia is associated with poor hospital outcomes including prolonged hospital stay, increase rate of 
wound and systemic infections, disability after hospital discharge, and death (1, 26).  Previous studies have 
shown that basal bolus regimens in patients with T2D result in a significant improvement in glycemic control 
and in lower rate of hospital complications compared to SSRI in patients with T2D (40-42). In our 
preliminary study, the use of sitagliptin alone or in combination with basal insulin was proven to be as 
effective in improving glycemic control compared to basal bolus insulin regimen.   
Linagliptin has a unique pharmacokinetic and pharmacodynamic profile that makes it an attractive agent for 
the treatment of inpatients with T2D including its rapid-onset of action in improving glycemic control, low 
risk of hypoglycemia when used as monotherapy, large volume of distribution into tissues, and lack of 
relevant alterations in linagliptin pharmacokinetics in patients with renal or hepatic impairment. Linagliptin 
is a new orally active small-molecule inhibitor of DPP-4, licensed in the US in 2011 to improve glycemic 
control in adults with T2D (36). Based on our preliminary experience and the proven efficacy of linagliptin 
in improving glycemic control, safety and excellent tolerance, we believe that linagliptin may represent an 
excellent alternative to basal bolus treatment in subjects with T2D.   
 
IV.b. STUDY DESIGN AND METHODS 
A total of 280 randomized (300 patients consented to account for screen failures) general surgery 
patients with T2D treated with diet, oral hypoglycemic agents, or low-dose (≤ 0.5 units/kg/day) insulin 
therapy prior to admission will be included in this prospective, randomized, open label trial to compare the 
safety and efficacy of linagliptin once daily versus basal bolus regimen with glargine once daily plus rapid-
acting insulin before meals. Both treatment groups will receive corrective doses of rapid-acting insulin 
analogs (aspart, lispro or glulisine) before meals for BG > 140 mg/dl. 
 
Study Outcomes: 
The primary outcome of the study is to determine differences in glycemic control as measured by mean daily 
BG concentration between linagliptin and basal bolus therapy.    
Secondary outcome is to compare differences between treatment groups in any of the following measures:  
1. Number of hypoglycemic events (<70 mg/dl) and severe hypoglycemic events (<40 mg/dl). 
2. Number of episodes of hyperglycemia (BG > 300 mg/dl) after the first day of treatment. 
3. Total daily dose of insulin. 
4. Length of hospital stay. 
5. Need for ICU care (transfer to ICU) 
6. Differences between groups on a composite of hospital mortality and perioperative complications 
including wound infections (deep and superficial), bacteremia, respiratory failure, acute renal 
failure, and major cardiovascular events (acute myocardial infarction, congestive heart failure, 
and cardiac arrhythmias).   
 
7 

Linagliptin Inpatient_07.19.2016 
 
7. Acute renal failure defined as a clinical diagnosis of acute renal failure with documented new-
onset abnormal renal function (serum creatinine >2.2 mg/dL or an increment >0.5 mg/dL from 
baseline). 
8. Hospital mortality.  Mortality is defined as death occurring during admission.    
 
IV.c. Overall Design and Study Interventions 
 
This multicenter randomized clinical trial will include male or female subjects with known history of 
diabetes between 18-80 years of age admitted to general surgery (non-ICU) service.  Due to the design of 
this study (i.e. enrollment of subjects in need of acute care), there will be no run-in period.  Upon arrival to 
the Emergency Department or surgery service, subjects will be screened for the study.  Patients with a known 
history of T2D treated with diet alone, any combination of oral hypoglycemic agents or low-dose insulin 
therapy (≤0.5 unit/kg/day) prior to admission will be considered potential candidates in this study.  The goal 
of therapy is to maintain fasting and pre-meal BG < 140 mg/dL while avoiding hypoglycemia.  Treatment 
assignment will be coordinated by a research pharmacist at each institution following a computer-generated 
block randomization table.  Diabetic patients with a BG > 140 mg/dL and < 400 mg/dL without ketosis will 
be randomized consecutively (using a randomization table) to receive: 
 
• Group 1.  Linagliptin once daily*  
• Group 2.  Basal bolus regimen with glargine once daily and lispro, aspart or glulisine before meals*  
 
* Supplemental (correction) doses rapid-acting insulin analog (lispro, aspart or glulisine) will be given for 
BG > 140 per sliding scale if needed.  Rapid-acting insulin may vary at different institutions. 
 
 
The primary medical team (PMT) will decide on the treatment for the surgical and other medical problem(s) 
for which patients are admitted.  The PMT will also decide patient’s discharge orders for the treatment of 
their primary diagnosis.  At discharge, patients will be followed by their primary care physician, surgery 
team, and the diabetes research team.   The recommended insulin therapy at discharge will be based on the 
degree of glycemic control (HbA1c level) as described in Aim 2. After discharge, a member of the diabetes 
research team will contact patients via telephone call every 2 weeks for a total of 3 months.  In addition, 
patients will be asked to attend an outpatient clinic visit within one month and after 3 months of hospital 
discharge to assess level glycemic control (fasting and premeal BG levels, presence of hypoglycemia), and to 
determine the presence of complications after discharge (wound or systemic infection, hospital readmission, 
cardiac events, etc).     
 
IV.e. Treatment Groups: 
 
           
 
          Glargine once daily plus rapid-acting insulin before meals (n=140) 
  
  
 N= 280  
Linagliptin once daily plus correction doses of rapid-acting insulin (n=140) 
 
 
8 

Linagliptin Inpatient_07.19.2016 
 
GROUP 1.  Linagliptin Group.  
 
• Discontinue oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, pioglitazone), 
insulin and non-insulin injected antidiabetic medication (pramlintide, exenatide) on admission. 
 
• Linagliptin 5 mg once daily  
 
• Supplemental (correction) insulin.  Supplemental (lispro, aspart or glulisine) insulin will be 
administered following the “supplemental/sliding scale” protocol (Table 1).   
• If a patient is able and expected to eat all or most of his/her meals, supplemental (lispro, 
aspart or glulisine) 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 (lispro, aspart or glulisine) insulin will be 
administered every 6 hours (6-12-6-12) following the “sensitive” dose of the sliding scale. 
 
• Insulin adjustment.  The supplemental (lispro, aspart or glulisine) insulin dose will be adjusted as 
follow:  
• If the fasting and pre-meal plasma glucose are persistently >140 mg/dl in the absence of 
hypoglycemia, the supplemental (lispro, aspart or glulisine) insulin scale could be increased 
from sensitive to usual, or from usual to resistant scale.   
• If a patient develops hypoglycemia, the supplemental (lispro, aspart or glulisine) insulin 
should be decreased from insulin resistant to usual scale or from usual to sensitive scale.   
• The attending physician may consider using the total supplemental insulin dose, patient’s 
nutritional intake, and results of blood glucose testing to adjust insulin regimen.    
• Blood glucose monitoring.  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.   
 
 
 
9 

Linagliptin Inpatient_07.19.2016 
 
GROUP 2.  Basal Bolus Regimen with Glargine and Rapid-acting Insulin (Lispro, Aspart or Glulisine)  
 
• Discontinue oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, pioglitazone), 
insulin and non-insulin injected antidiabetic medication (pramlintide, exenatide) on admission.  
 
• Starting total daily insulin dose:  
• Patients with BG between 140-200 mg/dL= 0.4 units per kg weight per day.  
• Patients with BG between 201-400 mg/dL= Total insulin dose 0.5 units per kg  
• If GFR<45 ml/min reduce total daily dose by half (0.2 to  0.25 units per Kg per day 
• Half of total daily dose will be given as glargine and half as lispro, aspart or glulisine.   
• Glargine insulin will be given once daily, at the same time of the day.   
• Patients will receive the full-dose of glargine insulin (even if NPO).     
• Prandial insulin (lispro, aspart or glulisine) will be given in three equally divided doses within 30 
minutes before/after each meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose 
of lispro, aspart or glulisine will be held.  
• Insulin adjustment.  The total daily insulin dose will be adjusted as follow:  
• 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%.   
• The attending physician may consider using the total supplemental insulin dose, patient’s nutritional 
intake, and results of blood glucose testing to adjust insulin regimen. 
 
 
• Supplemental insulin.  Supplemental (lispro, aspart or glulisine) insulin will be administered 
following the “supplemental/sliding scale” protocol (Table 1).   
• If a patient is able and expected to eat all or most of his/her meals, supplemental (lispro, aspart or 
glulisine) 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 (lispro, aspart or glulisine) insulin will be administered 
every 6 hours (6-12-6-12) following the “sensitive” dose of the sliding scale. 
• Blood glucose monitoring.  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.   
 
 
10 

Linagliptin Inpatient_07.19.2016 
 
V. Specific Aim 2:  To determine the efficacy and safety of an A1C based discharge algorithm in 
controlling BG after discharge in patients with T2D.   
Patients who participate in the in-hospital arm (Aim 1) will be invited to enroll in this open label prospective 
outpatient study.  The total duration of the study is 3 months.   
 
V.a. 
Rationale.  Few studies have addressed the efficacy of insulin or oral antidiabetic agents after 
hospital discharge. In a recent pilot study we assessed the efficacy of an HbA1c based algorithm for the 
management of patients with T2D (see preliminary results section, Fig. 5). Patients with a high HbA1c were 
discharged on a combination of OADs and basal insulin or on a basal bolus regimen. 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). 
These data indicate that the admission HbA1c is beneficial in designing the discharge treatment algorithm 
after discharge in non-ICU patients with T2D.  Linagliptin has a unique pharmacokinetic and pharmaco-
dynamic profile that makes it an attractive agent for the treatment of with T2D including its rapid-onset of 
action in improving glycemic control without weight gain and the low risk of hypoglycemia. Based on our 
preliminary experience and the proven efficacy of linagliptin in improving glycemic control, we believe that 
linagliptin may represent an excellent alternative to insulin therapy after discharge in subjects with T2D.   
 
IV.a. Study Outcomes: 
The primary outcome of the outpatient arm is to explore the safety and efficacy of linagliptin after hospital 
discharge.  Differences from baseline (hospital admission) in HbA1c concentration will be assessed at 4 
weeks and 12 weeks after discharge.    
 
Secondary outcome will include: 
1. Fasting and postprandial BG concentration 
2. Number of hypoglycemic events (<70 mg/dl) and severe hypoglycemic events (<40 mg/dl). 
3. Number of patients with HbA1c <7.0%  
4. Total daily dose of insulin. 
5. Number of emergency room visits and hospital readmissions 
6. Number of complications: wound infection, pneumonia, acute renal failure and mortality.    
 
IV.b. STUDY DESIGN AND METHODS 
The trial is a 12-week, open label trial investigating the efficacy and safety of linagliptin as add-on to 
existing oral antidiabetic drug (OAD) or insulin therapy in patients T2D after hospital discharge.   
 
 
 
V.a. 
Inhospital Diabetes Education.  Prior to discharge, participants will be trained on: 
1. Diabetes education if not received within 1 year of admission or if discharge on insulin therapy.   
2. ADA targets for fasting and premeal BG between 90 to 130 mg/dL. 
3. Use of glucose meters for home glucose self-monitoring (meters may vary at different institutions).   
4. Keeping BG records, and will receive a log-book to record glucose tests results. 
5. Hypoglycemia recognition and management (see VI.B.) 
6. Insulin administration (if needed). 
 
V.b. 
Follow-up Care: 
• Insulin therapy is the standard of care at discharge, therefore, glargine or rapid-acting insulin analogs 
will not be provided to participants. The choice of rapid-acting analogs will be based on formulary 
availability at each institution. 
• Patients to be discharged on linagliptin will receive 1-month supply by the research hospital 
pharmacy.  
 
11 

Linagliptin Inpatient_07.19.2016 
 
• After discharge, a member of the diabetes research team will contact patients via telephone call every 
2 weeks for a total of 3 months.   
• Patients will be asked to attend an outpatient clinic visit within one month of hospital discharge.  
During this visit, patients will receive a 2 month supply of linagliptin and will be asked to return to 
clinic 2 months later (3 month after discharge visit).  
• Recommendation on insulin adjustment will be provided to patients and their PCP after each 
telephone contact and clinic visit by a license physician (fellow or study physician) (see section Vf).     
 
V.c. 
During follow up we will collect the following information:   
1. Glycemic control: 
a. Mean daily fasting and premeal blood glucose levels 
b. A1C at 3 months of discharge 
c. Hypoglycemic events (BG < 70 mg/dl and < 40 mg/dl) 
d. Hyperglycemic events (BG > 300 mg/dl) 
2. Diabetes treatment: 
a. Number of patients receiving insulin and linagliptin therapy 
b. Use of linagliptin and other oral agents 
c. Protocol adherence by PCP (diabetes clinic versus PCP) 
3. Clinical Outcome: 
a. Hospital readmissions 
b. Emergency room visits 
c. Postoperative complications 
 
V.d. 
Treatment recommendations at discharge: 
 
V.d.1. Admission A1C < 7%:  
 
• Discharge on same pharmacologic regimen (oral agents, insulin therapy) or linagliptin 5 mg/day.  
• If contraindication to OADs, discharge on linagliptin once daily.  
 
V.d. 2. Admission A1C between 7% and 9%:   
  
•  V.d.2.a.  Patients receiving no pharmacologic agents prior to admission: 
• Assure there are no contraindications to metformin therapy. 
•    If no contraindication to metformin, discharge on the combination of linagliptin daily and 
metformin twice daily.  
•    If contraindication to metformin, discharge patient on linagliptin once daily.  
•   
V.d.2.b.Patients treated with OADs prior to admission: 
•    Assure there are no contraindications to metformin therapy. 
•     If no contraindication to metformin, discharge on linagliptin daily and metformin 500 mg 
twice daily. If patients were on metformin 1000 mg twice a day prior to admission, may 
restart on the same dose if A1C>8%. May use previous OADs, but consider stopping or 
reducing dose of sulfonylureas. 
• If contraindication to metformin, discharge patient on linagliptin once daily plus previous 
OADs. May consider linagliptin plus basal if HbA1c >8% as follows: 
 If in basal bolus group during the inpatient arm, can start basal insulin at 50% of 
hospital dose. 
 If in the linagliptin group during the inpatient arm, can start basal insulin at 0.2 
units/kg/day   
 
12 

Linagliptin Inpatient_07.19.2016 
 
 
  
V.d.2.c. Patients treated with insulin (with or without OADs) prior to admission: 
•   Assure there are no contraindications to metformin therapy. 
•   If no contraindications to metformin, discharge patient on linagliptin daily and metformin 
500 mg twice daily and basal insulin as follows: 
 If in the basal bolus group during the inpatient arm, can start basal insulin at 50% of 
hospital dose. 
 If in the linagliptin group during the inpatient arm, can start basal insulin at 0.2 
units/kg/day  
• If contraindication to metformin, discharge on linagliptin once daily and basal insulin as 
follows: 
 If in the basal bolus group during the inpatient arm, can start basal insulin at 0.2 
units/kg/day. 
 
 
V.d.3. Admission A1C ≥ 9%:   
V.d.3.a. Patients receiving no treatment or on OADs treatment prior to admission: 
• Assure there are no contraindications to metformin therapy. 
• If no contraindications to metformin, discharge patient on linagliptin daily and metformin 500 
mg twice daily and basal insulin as follows: 
 If in the basal bolus group in the inpatient arm, can start basal insulin at 80% of 
hospital dose.  
•  If in the linagliptin group in the inpatient arm, can start basal insulin at 0.2 units/kg/day If 
contraindication to metformin, discharge on linagliptin once daily and basal insulin as 
follows: 
 If in the basal bolus group in the inpatient arm, can start basal insulin at 80% of 
hospital dose.   
  If in the linagliptin group in the inpatient arm, can start basal insulin at 0.2 
units/kg/day. 
•  Consider stopping or reducing dose of sulfonylureas 
 
•                  Alternative:  Discharge on basal bolus regimen at same inpatient total daily insulin dose.   
 Basal insulin once daily and rapid-acting insulin before meals.  
 
 
V.d.3.b. 
Patients treated with insulin (with or without OADs) prior to admission: 
 Assure there are no contraindications to metformin therapy. 
 If no contraindications to metformin, discharge patient on linagliptin daily and 
metformin 500 mg twice daily and basal insulin as follows: 
• If in the basal bolus group during the inpatient arm, can start basal insulin at 
80% of daily hospital dose.  
• If in the linagliptin group during the inpatient arm, can start basal insulin at 0.2 
units/kg/day. 
 If contraindication to metformin, discharge on linagliptin once daily and basal insulin 
as follows: 
• If in the basal bolus group during the inpatient arm, can start basal insulin at 
80% of hospital dose.   
• If in the linagliptin group during the inpatient arm, can start basal insulin at 0.2 
units/kg/day. 
 
13 

Linagliptin Inpatient_07.19.2016 
 
o Alternative:  Discharge on basal bolus regimen at same inpatient total daily insulin dose. 
Basal insulin once daily and rapid-acting insulin before meals.  
  
 
 
 
 
V.e. 
Primary care physicians will be provided with the following algorithm for outpatient glargine 
insulin dose adjustment: 
 
Insulin Glargine 
If mean FBG > 180 mg/dL for the last 
2 consecutive days and no episodes of 
hypoglycemia (BG <70 mg/dL) 
Increase daily dose by 4 IU 
If mean FBG > 140 mg/dL for the last 
2 consecutive days and no episodes of 
hypoglycemia (BG <70 mg/dL) 
Increase daily dose by 2 IU 
If mean FBG between 100 to 140 mg/dL for 
the last 2 consecutive days and no episodes of 
hypoglycemia (BG <70 mg/dL) 
No Change 
If any FBG between 70 – 99 mg/dl 
Decrease by 4 IU or 10% of total daily dose 
If any FBG or RBG < 70 mg/dl 
Decrease by 8 IU or 20% of total daily dose 
If any FBG or RBG < 40 mg/dl 
Decrease total daily dose by 30% 
 
V.f. 
Primary care physicians will be provided with the following algorithm for the outpatient 
prandial (lispro, aspart or glulisine) insulin dose adjustment (Basal Bolus regimen): 
 
Prandial insulin (lispro, aspart or glulisine) 
Mealtime Dose, U 
BG 70 – 100 mg/dl* 
BG 141-180 mg/dl** 
≤ 10 U 
Decrease by 1 U 
Increase by 1 U 
>11- 19 U 
Decrease by 2 U 
Increase by 2 U 
≥ 20 U 
Decrease by 3 U 
Increase by 3 U 
 
 
 
Mealtime Dose, U 
BG 40-70 mg/dl 
BG 180-240 mg/dl 
≤ 10 U 
Decrease by 2 U 
Increase by 2 U 
>11- 19 U 
Decrease by 3 U 
Increase by 3 U 
≥ 20 U 
Decrease by 4 U 
Increase by 4 U 
 
 
 
Mealtime Dose, U 
BG < 40 mg/dl*** 
BG > 240 mg/dl 
≤ 10 U 
Decrease by 4 U 
Increase by 3 U 
>11- 19 U 
Decrease by 6 U 
Increase by 4 U 
≥ 20 U 
Decrease by 8 U 
Increase by 5 U 
* If > ½ of the pre-prandial BG values for the week were below target 
**If > ½ of the pre-prandial BG values for the week were above target 
*** Decrease by 30-40% in the event of severe hypoglycemia (pre-prandial BG < 40 mg/dl) 
 
 
 
VI. 
Methods and Procedures Applied to Human Subjects: 
 
a. Subject Population: 
 
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Linagliptin Inpatient_07.19.2016 
 
 
 
This will include 280 randomized general surgery patients with a known history of T2D, age 18-80, 
treated with diet alone, oral antidiabetic agents: sulfonylureas, repaglinide, nateglinide, or metformin, 
pioglitazone as monotherapy or in combination therapy (excluding DPP4 inhibitors), or on low-dose insulin 
therapy (TDD ≤0.5 unit/kg/day).  Patients included within this study will be determined by the set of 
inclusion and exclusion criteria. 
 
b. Inclusion Criteria: 
 
1. Males or female surgical non-ICU patients ages between18 and 80 years  
2. A known history of T2D > 1 month, receiving either diet alone, oral antidiabetic agents: 
sulfonylureas and metformin as monotherapy or in combination therapy (excluding DPP-4 inhibitors) 
or low-dose (≤ 0.5 units/kg/day) insulin therapy.  
3. Subjects with a BG >140 mg and < 400 mg/dL without laboratory evidence of diabetic ketoacidosis 
(serum bicarbonate < 18 mEq/L or positive serum or urinary ketones) at randomization. 
 
c. Exclusion Criteria:  
 
1. Age < 18 or > 80 years.  
2. Subjects with increased BG concentration, but without a history of diabetes (stress hyperglycemia). 
3. Subjects with a history of type 1 diabetes (suggested by BMI < 25 requiring insulin therapy or with a 
history of diabetic ketoacidosis and hyperosmolar hyperglycemic state, or ketonuria) (43).  
4. Treatment with DPP4 inhibitor or GLP1 analogs during the past 3 months prior to admission. 
5. Acute critical illness or CABG surgery expected to require admission to a critical care unit. 
6. Subjects with gastrointestinal obstruction or adynamic ileus or those expected to require 
gastrointestinal suction. 
7. Patients with clinically relevant pancreatic or gallbladder disease.  
8. Patients with previous history of pancreatitis 
9. Patients with acute myocardial infarction, clinically significant hepatic disease or significantly 
impaired renal function (GFR < 30 ml/min). 
10. Chronic use of steroid with total daily dose (prednisone equivalent) >5 mg/day  
11. Mental condition rendering the subject unable to understand the nature, scope, and possible 
consequences of the study. 
12. Pregnancy or breast-feeding at time of enrollment into the study. 
13. Patients who received supplemental sliding scale insulin >72 hours prior to randomization 
14. Patients who received basal insulin > 48 hours prior to randomization 
 
 
VII. 
Study Sites: This study will be performed at Grady M. Hospital: Guillermo Umpierrez, M.D. 
(Principal investigator), Dawn Smiley, M.D.,  
Emory University Hospital: Francisco Pasquel, M.D. (Site PI); University of Colorado: Neda Rasouli, M.D. 
(Site PI); Boston University, Boston, MA (Site PI: Marie McDonnell); and Rush University, Chicago, IL 
(site PI: David Baldwin, MD). 
 
VIII. CLINICAL MANAGEMENT GUIDELINES 
 
 
VIII.a.  Admission Laboratory Studies 
 
Standard of care laboratory studies including glucose, HbA1c, chemistry, hematology, and urine will be 
measured on admission and as determined by the treating physician.   
 
 
VIII.b. Treatment of Hypoglycemia (BG <70 mg/dL) 
 
15 

Linagliptin Inpatient_07.19.2016 
 
Hypoglycemia, defined as a blood glucose level < 70 mg/dL will be treated following standard 
hypoglycemia protocols available at both institutions.  Patients with hypoglycemia will be treated as per 
protocol: For blood glucose < 70 mg/dL, follow hypoglycemic orders below: 
• If patient is alert and can tolerate oral intake, give 20 grams of fast-acting carbohydrate (6 oz. fruit juice 
or regular soda, crackers). 
• If patient not alert and cannot tolerate oral intake, give1ampule (50 mL) of D50. 
• Check finger stick BG q 15 minutes and repeat above treatment until BG > 100 mg/dL. 
• Once BG > 100 mg/dL, repeat finger stick BG 1 hour later and treat as follows: 
o If BG < 70 mg/dL, call MD and follow y hypoglycemia orders (above) 
o If BG 70 – 100 mg/dL, give snack/scheduled meal and check BG q1 h until BG >100 mg/dl 
o If BG > 100, no further treatment needed. 
 
VIII.c.    Assessment and Monitoring of Hospital Mortality  
All study subjects will be followed daily by the investigators 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.    
VIII.d.  
Assessment and Monitoring of Nosocomial Infections  
Nosocomial infections will be diagnosed based on standardized CDC criteria (44).  New nosocomial 
infections will not be diagnosed until 48 hr after study initiation to minimize the chance that the infection 
was actually present (but undiagnosed) prior to study initiation.   
The investigators will review each subject’s records regarding potential new infection diagnosis daily on 
each weekday from Monday to Friday. Data from the weekends will be collected on the following Monday.  
The coded infection diagnosis and the presumed causative microorganism will be determined daily on a 
Monday to Friday basis, with weekend data entered on the following Monday by the coordinators.   
 
IX. 
STATISTICAL ANALYSIS  
This study is randomized multicenter, open-label controlled trial. The overall hypothesis is that in non-ICU 
patients with T2D, treatment with linagliptin once daily will result in a similar improvement in glycemic 
control and in a lower frequency of hypoglycemic events than treatment with basal bolus insulin regimen 
with basal bolus insulin regimen.   
 
IX.a. Sample Size and Power Calculations: The primary endpoint in this study is glycemic control 
measured by mean daily BG concentration between treatment groups. To show the non-inferiority of 
linagliptin to basal bolus in terms of glycemic control, we set the equivalence margin as 18mg/dl, from a 
view that a BG difference less than 18 mg/dl is usually not considered as clinically significant. Based on the 
preliminary data from Rabbit medicine and Rabbit Surgery trials, it may be reasonable to assume the 
standard deviation of mean daily BG is bounded above by 50 mg/dl. With two-sample t tests or Wilcoxon 
tests, one sided, alpha=0.05, 121 subjects for each treatment arm would be needed to ensure 80% power to 
reject the hypothesis that the mean daily BG in patients treated with linagliptin is no more than 18 mg/dl 
higher than that in patients treated with Basal Bolus.  In our calculation, we applied Bonferroni correction to 
adjust for multiple comparisons across four time points during follow-up. Accounting for 10-15% attrition 
rate, we would need 140 patients per treatment group. This leads to a final total sample size estimate of 280 
randomized patients. 
 
Secondary outcomes of major interest in this study are outcomes on hypoglycemia (BG<70 mg/dl) and the   
composite of hospital mortality and perioperative complications. The assessment of group difference in 
hypoglycemia will mainly be based on the comparison of proportions of patients who have any 
hypoglycemia event during the study between the two treatment groups. Based on the Rabbit Surgery trail, 
23% of patients that received Basal Bolus had at least one hypoglycemia episode. Assuming the same rate of 
hypoglycemia in the Basal Bolus group in this study, given the sample size of 121subjects per treatment 
 
16 

Linagliptin Inpatient_07.19.2016 
 
group, based on a two sided Fisher’s exact test with alpha=0.05, we would have 80% power to detect an odds 
ratio in hypoglycemia rate of 0.33 in linagliptin group (versus Basal Bolus group), which corresponds to a 
smaller difference in hypoglycemia rate than that observed in Rabbit Surgery study. In the following table, 
we give the estimated power under different assumed group differences in hypoglycemia rate, represented by 
four hypothesized odds ratios. 
 
Table: Estimated power with 121 subjects per group (after attrition) and the anticipated hypoglycemia rate of 
23% based on two-sided Fisher’s exact test with alpha=0.05. 
 
Odds Ratio 0.1 
0.2 
0.3 
0.4 
Power 
>0.99 0.96 0.85 0.67 
   
For the composite outcome of hospital mortality and perioperative complications, we consider complications 
including wound infection, bacteremia, acute renal failure, respiratory failure, and major cardiovascular 
events. Based on the Rabbit Surgery trial, the rate of the composite outcome is about 10% in the Basal Bolus 
group. Assuming the same rate for patients receiving Basal Bolus in this study, we would have 80% power to 
detect an odds ratio in the composite outcome of 0.09 in linagliptin group (versus Basal Bolus group).   
IX.b. Analysis of Primary Endpoint: 
The primary endpoint in this study is glycemic control measured by mean daily BG concentration. We will 
first perform cross-sectional analyses using one-way ANOVA, followed by repeated measures ANOVA to 
estimate and test the difference between the two treatment groups while simultaneously examining mean 
daily BG across multiple days during treatment. A mixed effect model may be used to further account center 
effect or other potential confounders for the BG outcome. 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 will be applied to examine the fit of the developed models. 
 
IX.c. Analysis of Secondary Endpoints: 
Secondary endpoints in this study include rate of hypoglycemia, number of hypoglycemia events, number of 
episodes of severe hyperglycemia, length of hospital stay, hospital mortality and differences between groups 
on a composite of hospital mortality and perioperative complications including wound infections (deep and 
superficial), bacteremia, respiratory failure, acute renal failure, and major cardiovascular events (acute 
myocardial infarction, congestive heart failure, and cardiac arrhythmias).  For hypoglycemia outcomes, we 
will first conduct nonparametric comparisons of the rate of hypoglycemia based on a two-sided Chi-square 
test (or Fisher’s exact test in the presence of low incidence rates), followed by the Cochran-Mantel-Haenszel 
test which adjusts for the potential center effect. Univariate Poisson regression (or Negative Binomial 
regression) will be performed to assess whether there is any difference in the number of hypoglycemia 
events between the two treatment groups. We will further conduct multivariate Logistic regression, Poisson 
regression (or negative binomial regression) to estimate the difference in the rate and frequency of 
hypoglycemia while adjusting for relevant covariates.  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 models. Similar analyses will be conducted to severe hyperglycemia, 
composite of hospital mortality and perioperative complications. For continuous outcomes, such as length of 
hospital stay, we will use two-sample t-tests or nonparametric Wilcoxon tests to compare them between the 
intensive BG control group and the conventional BG control group. 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 other relevant covariates. We 
will use standard model selection and model checking procedures for linear regression to decide the final 
models and assess their fits to the data. 
 
 
 
17 

Linagliptin Inpatient_07.19.2016 
 
X. 
Potential Risks to the Subject: 
Hypoglycemia.    It is possible that following the proposed protocol, patients receiving basal bolus insulin 
regimen or linagliptin in combination to insulin may develop hypoglycemia (BG < 70 mg/dL).  The risk of 
hypoglycemia in non-ICU patients treated with subcutaneous insulin in previous RCT has varied between 
4% and 32%.  We expect that approximately 10-20% of subjects treated with basal bolus protocol will 
experience one or more episodes of hypoglycemia.  The frequency of hypoglycemia in patients with T2D 
treated with linagliptin is similar to placebo, thus, we expect to have a frequency of hypoglycemia similar to 
that reported during SSRI alone (< 5%).   
 
The number of reports of hypoglycemia will be analyzed statistically.  For the purpose of this 
analysis, hypoglycemia is defined as a capillary and/or laboratory BG < 70 mg/dL.  Severe hypoglycemia is 
defined as an event with symptoms consistent with hypoglycemia in which the subject required the 
assistance of another person and blood glucose less than 40 mg/dL. 
 
Hyperglycemia.    In the Rabbit Trial, 14% of patients treated with SSRI remained with blood glucose of > 
240 mg/dL despite increasing the SSI dose to the maximal or insulin resistant scale.  In such patients, 
glycemic control rapidly improved in all of the SSI failure subjects after starting basal bolus insulin, and the 
glucose target of < 140 mg/dL was achieved within 4 days of initiating basal bolus insulin therapy.  Queale 
et al (15) reported that more than 25% had more than 1 episode of hyperglycemia during the first 4 days of 
hospitalization.  We expect that approximately < 20% of subjects treated with insulin glargine or with 
linagliptin plus lispro, aspart or glulisine insulin will have severe hyperglycemia.  The number of reports of 
severe hyperglycemia will be analyzed statistically.  For the purpose of this analysis, severe hyperglycemia is 
defined as a capillary and/or laboratory BG >300 mg/dL.   
 
Blood samples will be taken.  Risks associated with drawing blood are pain, bruising at the site of the 
needle stick, bleeding, and on rare occasions, fainting, light-headedness and infection.   
 
XI. 
Protection against Risks: 
 
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor capillary 
blood glucose at the bedside using a hand-held glucose meter, b) only experienced nurses/or phlebotomist 
will draw blood samples, and c) women of reproductive age who are sexually active will undergo a urine 
pregnancy tests prior to participation in the study.  To prevent significant clinical events that may result with 
the use of insulin, no patients with significant liver and renal impairment will be recruited in this study.    
 
Hypoglycemia:  We expect that approximately 20% of subjects treated with basal bolus insulin will 
experience one or more episodes of hypoglycemia and less than 5% of linagliptin patients will experience 
hypoglycemia.  Hypoglycemia will be treated with dextrose infusion.  Dextrose 50% solution will be given 
for glucose values < 70 mg/dl.  If the patient is awake, 25 ml (1/2 amp) will be given IV.  If the patient is not 
awake:  50ml (1 amp) will be given STAT.  Blood glucose levels will be repeated in 15 minutes and dextrose 
administration will be repeated as needed for values < 70 mg/dl.  If a patient develops hypoglycemia, the 
total daily insulin dose will be decreased by 10% to 30% in the basal bolus group and by moving to a less 
sensitive supplemental insulin column (see appendix 3).   
Hyperglycemia:  supplemental insulin will be given up to 4 times daily to cover for BG >140 mg/dl (see 
appendix 2).  Patients with persistent hyperglycemia (≥ 2 glucose readings ≥ 400 mg/dl, ≥ 3 consecutive glucose 
readings >240 mg/dl, or with a mean daily blood glucose concentration ≥240 mg/dl) will be considered as 
failure and discontinued from the study.  Patients receiving linagliptin therapy will be switched to basal bolus 
insulin or continuous insulin infusion.  Dose of insulin will be adjusted and if needed, patients treated with 
basal/bolus insulin will be started on continuous insulin infusion.   
 
 
18 

Linagliptin Inpatient_07.19.2016 
 
Acute renal failure: the total daily dose of insulin will be adjusted as per serum creatinine concentration.  The 
total daily insulin dose will be reduced to 0.3 unit/kg in patients with creatinine >2.0 mg/dl.  The dose of 
linagliptin does not need to be adjusted in patients with renal dysfunction.     
XII.  DATA handling and record keeping: 
Data collection records with personal identifiers will be stored in locked file cabinets.  Blood samples drawn 
and stored in conjunction with this study will not be labeled with information that could directly identify 
study subjects.  Blood samples will be stored at Dr Umpierrez Research Laboratories in the Grady Diabetes 
Clinic.  Presentation of the study results at regional or scientific meetings or in publications will not identify 
subjects.  Access to research and confidential records will be limited to clinical investigators, research 
coordinators, and the IRB at Emory University. 
 
XIII. Study drugs and materials: 
Clinical trial materials will be labeled and should be handled and stored according to the respective 
hospital’s regulatory requirements.  After discharge, patients will be re-started on their pre-admission OADs 
(except for DPP4-inhibitors, GLP-1, and selected drugs in the presence of contraindication, i.e., metformin 
and renal failure).  
 
Storage and Drug Accountability of Study Medication(s) 
Linagliptin will be stored and dispensed by the research pharmacy at each institution.  Linagliptin will be 
dispensed to each subject as required according to treatment group. The research/clinical staff will perform 
drug accountability by asking patients to return all unused, partly used and unused at each visit.   
 
Stock bottles of linagliptin will be stored at the hospital research pharmacy at a controlled room temperature 
between 59 to 86o Fahrenheit.  A daily room temperature will be documented (Monday - Friday) s well as 
the minimum and maximum daily temperature reached.  The minimum and max temperatures during 
weekends will be recorded on Monday morning.   
 
Study drug will be stored at the Investigational Drug Office inside the hospital pharmacy, and will be kept 
locked when not in use.  For the inpatient trial, unit-dose bottles would be stored in a pharmacy Pyxis.  The 
room temperature is also captured for drug kept in the pharmacy pyxis.   
 
Drug received for investigational use will be logged by Lot number specific log per study.  All drug received 
and dispensed will be recorded on the study specific / drug specific / lot specific log. 
 
XIV. Randomization and Blinding 
This is an open label randomized controlled trial.  Patients will be randomized consecutively using a 
computer generated randomization table provided by Dr. Limin Peng at the Emory School of Public Health.  
The randomization table will be mailed to the research pharmacist at each institution who will be in charge 
of the randomization and group assignment.  
 
XV. 
Adverse events: 
XV.a. 
Definitions of adverse events 
An adverse event (AE) is defined as any untoward medical occurrence, including an exacerbation of a pre-
existing condition, in a patient in a clinical investigation who received a pharmaceutical product. The event 
does not necessarily have to have a causal relationship with this treatment. 
 
XV.b. Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately life-threatening, 
results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a 
congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical 
 
19 

Linagliptin Inpatient_07.19.2016 
 
event when based upon appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definitions. 
Patients may be hospitalised for administrative or social reasons during the study (e.g. days on which 
infusion takes place, long distance from home to site,). These and other hospitalisations planned at the 
beginning of the study do not need to be reported as a SAE in case they have been reported at screening visit 
in the source data and have been performed as planned. 
XV.c. Adverse Events of Special Interest 
Based on regulatory recommendation that is based on the experience with other compounds in the 
DPP-4 inhibitor class, the following events should be defined as adverse events of special interest. 
• Hypersensitivity reactions such as angioedema, angioedema-like events, and anaphylaxis 
• Skin lesions such as exfoliative dermatitis, and exfoliative rash 
• Renal adverse events (e.g. renal failure, >=2x increase of creatinine from baseline) 
• Pancreatitis 
• Hepatic adverse events such as hepatitis, liver injury, and increased liver enzymes. Hepatic injury is 
defined by the following alterations of liver parameters: For patients with normal liver function (ALT, 
AST and bilirubin within normal limits) at baseline an elevation of AST and/or ALT >3 fold ULN 
combined with an elevation of bilirubin >2 fold ULN measured in the same blood draw sample.  
 
Refer to the appendix 1 for a list of prefered terms (PT’s) that are considered as AEs of Special Interest. 
 
Protocol-specified significant events are to be reported in an expedited manner similar to Serious Adverse 
Events, even if they do not meet any of the seriousness criteria. 
 
XV.d. Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
• Mild: Awareness of sign(s) or symptom(s) which is/are easily tolerated 
• Moderate: Enough discomfort to cause interference with usual activity 
• Severe: Incapacitating or causing inability to work or to perform usual activities 
 
XV.e. Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant factors, including 
pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. Assessment of causal relationship should 
be recorded in the case report forms.  
Yes: There is a reasonable causal relationship between the investigational product administered and the AE.  
No: There is no reasonable causal relationship between the investigational product administered and the 
AE.  
 
XV.f. Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S) AE in the 
(e) CRF. 
 
XV.g. Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S) AE 
in the (e) CRF, if they are judged clinically relevant by the investigator. 
XV.h. Responsibilities for SAE reporting 
The Sponsor shall report (i.e., from signing the informed consent onwards through the trialdefined follow-up 
period)  all SAEs and non-serious AEs occurring at the same time and/or which are medically related to the 
 
20 

Linagliptin Inpatient_07.19.2016 
 
SAE and Adverse Events of Special Interest by fax or other secure method to the BI Unique Entry Point in 
accordance with timeline specified in the pharmcovigilance agreement 
 
For each adverse event, the investigator will provide the onset date, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug. The investigator will determine the 
expectedness of the investigational drug to the AEs as defined in the Listed Adverse Events section of the 
Boehringer Ingelheim’s (BI’s) Investigator Brochure for the Product or BI Drug Information e.g. Summary 
of Product Characteristics (SmPC) or Product Information (PI) for the authorised Study Drug provided by 
BI. 
 
XVI. Ethics 
XVI.a.   Informed Consent.  
After identification of eligible patients these individuals will be provided basic information regarding the 
study and, if interested, a member of the research staff using inclusion/exclusion criteria delineated 
elsewhere in the protocol will then screen patients.  Informed consent will be obtained before any trial 
related procedures including screening procedures. The consent form, potential risks and benefits, and the 
rights of research participants will be explained to the participant by the investigators or research 
coordinator.  Individuals will be asked if they have questions, and a member of the research staff will answer 
questions.  The principal investigator will also be available at all times to answer questions that participants 
may have during the consent procedure or during the time a participant is enrolled in the study.  The consent 
form will be completed in accordance with the IRB guidelines of Emory University.  A signed copy of the 
consent form will be provided to the participant and a copy will be placed in the file that is maintained for 
each participant in the study office.   
 
Informed consent will follow the procedure of Emory University Institutional Review Board.   Every 
potential participant will be informed in writing and verbally with the important and key points of the study.   
One of the investigators or research coordinators will obtain a witnessed informed consent prior to inclusion 
of a patient into the study.   
 
The study will be conducted in accordance with the Declaration of Helsinki and will be conducted in 
accordance with the ICH GCP guidelines. The sponsor-investigator will comply with all applicable 
regulatory and legal requirements, ICH GCP guidelines and the Declaration of Helsinki in obtaining and 
documenting the informed consent. 
 
XVI.b. Potential Benefits to the Subject:  We believe that all subjects will benefit greatly from this study.  
Intensified blood glucose monitoring and blood glucose control may significantly reduce hospital 
complications associated with hyperglycemia and hypoglycemia.   
 
XVI.c. Potential Benefits to Society:  This study will provide important information on the benefits of oral 
antidiabetic agents (linagliptin) in the inpatient management of patients with type 2 diabetes.  We will 
determine whether glycemic control is different among insulin and linagliptin therapy. 
 
XVI.d.   Risk/Benefit Assessment:  Insulin therapy is the mainstay of diabetes management in hospitalized 
patients with diabetes.   There are no prospective, randomized studies to assess the efficacy and safety of oral 
antidiabetic agents for the inpatient management of diabetes.  Most patients with type 2 diabetes are treated 
with a sliding scale or basal bolus insulin therapy.  This study will test the efficacy of the inpatient use of 
oral antidiabetic agents and to determine whether glycemic control is different between linagliptin and basal 
bolus regimen in surgical patients with type 2 diabetes.    
 
 
21 

Linagliptin Inpatient_07.19.2016 
 
XVI.e. Therapeutic Alternatives:   Patients can be treated with other insulin formulations (regular insulin, 
NPH, glargine, lispro, aspart or glulisine currently available at Grady Hospital, Emory University Hospital 
and other Medical centers for the treatment of T2D.   
 
XVI.f. 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.  Absence of pregnancy must be 
demonstrated by blood or urine testing prior to randomization (in female of child bearing potential only).   
 
XVI.g. Inclusion of minorities:  Patients will not be excluded based on race or ethnic origin.  We anticipate 
that half of patients will be African Americans, 10% Hispanics, and the rest Caucasians.   
 
XVI.h. Inclusion of children:  No patients under the age of 18 will be recruited in this study. 
 
XVII. Confidentiality 
Informed consent will follow the procedure of Emory University Institutional Review Board.   Every 
potential participant will be informed in writing and verbally with the important and key points of the study.   
One of the investigators or research coordinators will obtain a witnessed informed consent prior to inclusion 
of a patient into the study.  Data collection records with personal identifiers will be stored in locked file 
cabinets.  Blood samples drawn and stored in conjunction with this study will not be labeled with 
information that could directly identify study subjects.  Blood samples will be stored at Dr Umpierrez 
Research Laboratories in the Grady Diabetes Clinic.  Presentation of the study results at regional or scientific 
meetings or in publications will not identify subjects.  Access to research and confidential records will be 
limited to clinical investigators, research coordinators, and the IRB at Emory University. 
 
XVIII. 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 
$10.00 per day to a maximum of one hundred dollars ($100.00).  Patients participating in the discharge study 
(Aim 2) will also receive seventy-five dollars ($75.00) after each clinic visit at 1 and 3 months after 
discharge.  Total compensation for participation in the study is two-hundred and fifty ($250.00). 
 
XIX. Financial Obligation. 
 
No additional cost to patients or to the institution will be incurred for research purposes.  
Research studies will be performed at no cost to study subjects.  Linagliptin tables will be provided by 
Boehringer Ingelheim Pharmaceuticals, Inc.   
 
XX. 
Research Injuries. 
 
If a patient is injured because of taking part in this study, Dr. Umpierrez and investigators, along with 
the medical facility will make medical care available to the patient at patient’s own cost.  Financial 
compensation for such things as lost wages, disability or discomfort due to an injury related to the study is 
not available.   
 
XXI.  Financial Conflict of Interests. 
 
None of the investigators in this study have any outside activities that may represent a conflict of 
interest.  None of the investigators have an economic interest in an outside entity, or act as officers, directors, 
employees or consultants with such an entity, whose financial interest may be affected by this research study. 
 
XXII. Informed Consent.  
After identification of eligible patients these individuals will be provided basic information regarding 
the study and, if interested, they will then be screened by research staff using the inclusion/exclusion criteria 
delineated elsewhere in this protocol.  The consent form, potential risks and benefits, and the rights of 
research participants will be explained to the participant by the investigators or research coordinator.  
 
22 

Linagliptin Inpatient_07.19.2016 
 
Individuals will be asked if they have any questions, and these questions will be answered by research staff.  
The principal investigator will also be available at all times to answer questions that participants may have 
during the consent procedure or during the time a participant is enrolled in the study.  The consent form will 
be completed in accordance with the IRB guidelines of Emory University.  A signed copy of the consent 
form will be provided to the participant and a copy will be placed in the file that is maintained for each 
participant in the study office.   
 
XXIII.   Medical Device Research.  
 
Not applicable. 
 
XXIV. DSMB and Monitoring. 
All adverse events (AEs) will be graded as to their attribution (unrelated to protocol, or possibly, probably, 
or definitely related to protocol).  Any AE that is reported to either the PI or her designated research 
associates by a study subject or medical staff will document caring for the subject and which meets the 
criteria as such.  This study will be entered into the Emory GCRC computerized database system to permit 
tracking of adverse events.  This system will then be used by all investigators to report “expected” AEs 
(predefined AEs which will be monitored over the course of the trial – see below), “observed” AEs (AEs 
which occur but which may or may not have been anticipated), and all serious adverse events (SAEs, see 
below); this system will be used in this trial.  Serious adverse events are predefined as:  any experience that 
suggests a significant hazard, such as events which: a) are fatal, b) are life threatening, c) result in permanent 
disability, d) require inpatient hospitalization, or e) involve cancer, a congenital anomaly, or drug overdose.   
 
Any AEs will be reported to the Emory GCRC Research Safety Advocate (RSA), within 15 days of the event 
and any SAEs will be reported to the RSA and the Emory IRB within 24-48 hours of the event.  The standard 
Emory IRB reporting guidelines for AE and SAE reporting will also be followed.  The investigators and staff 
will enter all AEs into the RSA database, and evaluate the SAEs, in close coordination with the Emory IRB.  
The IRB annual report from the P.I. will also be transmitted to the RSA and stored both in the RSA database 
and as a hard copy file.  The P.I. will also personally discuss the study and any observed AEs or SAEs on a 
regular basis with the RSA (at least once a year and more often as indicated).  
 
The Emory PI will be monitoring all sites (including non-Emory sites). The Emory PI and Emory study team 
will have a teleconference at the beginning to introduce the protocol, specific aims, plan and methods, and 
statistical analysis.  
The PI will ensure that each site will have a regulatory binder that contains the following documents and 
forms; 
Contact info, and CVs of all the study members. 
Delegation of authority form 
Financial disclosure form 
Recruitment plans, and study procedure forms 
Key inclusion/exclusion criteria checklist 
Attendance log / Informed Consent Procedure  
Randomization / Data Collection (CRF) 
Electronic Data Capture (Red Cap)  
Protocol deviation log 
DSMP activities 
Investigational product (package insert) 
 
 
 
23 

Linagliptin Inpatient_07.19.2016 
 
The PI will also have a weekly teleconference with the sites to monitor the study process, recruitment and 
adverse events. 
 
 
 
24 

Linagliptin Inpatient_07.19.2016 
 
XXIV. References 
 
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independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol 
Metab. 2002;87(3):978-82. 
2. 
Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. 
Jama. 2003;290(15):2041-7. 
3. 
Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, et al. Outcome 
benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care 
Med. 2003;31(2):359-66. 
4. 
Pomposelli JJ, Baxter JK, 3rd, Babineau TJ, Pomfret EA, Driscoll DF, Forse RA, et al. Early 
postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J Parenter 
Enteral Nutr. 1998;22(2):77-81. 
5. 
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al. Randomized trial of 
insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute 
myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 
1995;26(1):57-65. 
6. 
Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, et al. Management of 
diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-97. 
7. 
McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J, Marrie TJ. The relation between 
hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired 
pneumonia. Diabetes Care. 2005;28(4):810-5. 
8. 
Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM, et al. Hyperglycaemia is 
associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic 
obstructive pulmonary disease. Thorax. 2006;61(4):284-9. 
9. 
Furnary AP, Gao G, Grunkemeier GL, Wu Y, Zerr KJ, Bookin SO, et al. Continuous insulin infusion 
reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac 
Cardiovasc Surg. 2003;125(5):1007-21. 
10. 
Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive 
insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-61. 
11. 
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive 
insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-67. 
12. 
Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American 
Association of Clinical Endocrinologists and American Diabetes Association consensus statement on 
inpatient glycemic control. Diabetes Care. 2009;32(6):1119-31. 
13. 
Schnipper JL, Magee M, Larsen K, Inzucchi SE, Maynard G. Society of Hospital Medicine Glycemic 
Control Task Force summary: practical recommendations for assessing the impact of glycemic 
control efforts. J Hosp Med. 2008;3(5 Suppl):66-75. 
14. 
Seley JJ, D’Hondt N, Longo R, Manchester C, McKnight K, Olson L, et al. Position Statement: 
Inpatient Glycemic Control. Diabetes Educator 2009;35(Suppl 3):65-9. 
15. 
Queale WS, Seidler AJ, Brancati FL. Glycemic control and sliding scale insulin use in medical 
inpatients with diabetes mellitus. Arch Intern Med. 1997;157(5):545-52. 
16. 
Umpierrez GE, Palacio A, Smiley D. Sliding scale insulin use: myth or insanity? Am J Med. 
2007;120(7):563-7. 
17. 
Korytkowski MT, Salata RJ, Koerbel GL, Selzer F, Karslioglu E, Idriss AM, et al. Insulin therapy 
and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a 
randomized controlled clinical trial. Diabetes Care. 2009;32(4):594-6. 
 
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18. 
Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, et al. Comparison of inpatient 
insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical 
patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(2):564-9. 
19. 
Umpierrez GE, Smiley D, Jacobs S, Peng L, Temponi A, Mulligan P, et al. RAndomized Study of 
Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes 
Undergoing General Surgery (RABBIT Surgery). Diabetes Care. 2011;34(2):256-61. 
20. 
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of 
stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32(10):2426-32. 
21. 
Braithwaite SS, Buie MM, Thompson CL, Baldwin DF, Oertel MD, Robertson BA, et al. Hospital 
hypoglycemia: not only treatment but also prevention. Endocr Pract. 2004;10 Suppl 2:89-99. 
22. 
Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous 
population of critically ill patients. Mayo Clin Proc. 2003;78(12):1471-8. 
23. 
Inzucchi SE. Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med. 
2006;355(18):1903-11. 
24. 
Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is blood glucose an independent 
predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol. 
2002;40(10):1748-54. 
25. 
Norhammar AM, Ryden L, Malmberg K. Admission plasma glucose. Independent risk factor for 
long-term prognosis after myocardial infarction even in nondiabetic patients. Diabetes Care. 
1999;22(11):1827-31. 
26. 
Montori VM, Bistrian BR, McMahon MM. Hyperglycemia in acutely ill patients. Jama. 
2002;288(17):2167-9. 
27. 
Stranders I, Diamant M, van Gelder RE, Spruijt HJ, Twisk JW, Heine RJ, et al. Admission blood 
glucose level as risk indicator of death after myocardial infarction in patients with and without 
diabetes mellitus. Arch Intern Med. 2004;164(9):982-8. 
28. 
Umpierrez GE, A.E. K. ICU Care for Patients with Diabetes. Current Opinions Endocrinol. 
2004;11:75-81. 
29. 
Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. 
Chest. 2006;129(3):644-50. 
30. 
Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the 
incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann 
Thorac Surg. 1999;67(2):352-60; discussion 60-2. 
31. 
Estrada CA, Young JA, Nifong LW, Chitwood WR, Jr. Outcomes and perioperative hyperglycemia 
in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann Thorac 
Surg. 2003;75(5):1392-9. 
32. 
Standards of medical care in diabetes--2006. Diabetes Care. 2006;29 Suppl 1:S4-42. 
33. 
McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 
2001;17(1):107-24. 
34. 
Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, et al. Randomized study of 
basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 
trial). Diabetes Care. 2007;30(9):2181-6. 
35. 
Umpierrez GE, Jones S, Smiley D, Mulligan P, Keyler T, Temponi A, et al. Insulin analogs versus 
human insulin in the treatment of patients with diabetic ketoacidosis: a randomized controlled trial. 
Diabetes Care. 2009;32(7):1164-9. 
36. 
Graefe-Mody U, Retlich S, Friedrich C. Clinical pharmacokinetics and pharmacodynamics of 
linagliptin. Clin Pharmacokinet. 2012;51(7):411-27. 
37. 
Sonne DP, Engstrom T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-
36) amide against ischemia-reperfusion injury in rat heart. Regul Pept. 2008;146(1-3):243-9. 
 
26 

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38. 
Bromage PR, Shibata HR, Willoughby HW. Influence of prolonged epidural blockade on blood sugar 
and cortisol responses to operations upon the upper part of the abdomen and the thorax. Surg Gynecol 
Obstet. 1971;132(6):1051-6. 
39. 
Nathanson D, Ullman B, Lofstrom U, Hedman A, Frick M, Sjoholm A, et al. Effects of intravenous 
exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised 
controlled clinical trial of efficacy and safety. Diabetologia. 2007;55(4):926-35. 
40. 
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial 
combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic 
control in patients with type 2 diabetes. Diabetes Care. 2007;30(8):1979-87. 
41. 
Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily sitagliptin, a 
dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res 
Opin. 2007;23(6):1329-39. 
42. 
Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the 
dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. 
Diabetologia. 2006;49(11):2564-71. 
43. 
Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. 
Hyperglycemic crises in diabetes. Diabetes Care. 2004;27 Suppl 1:S94-102. 
44. 
Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 
1988. Am J Infect Control. 1988;16(3):128-40. 
 
 
 
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Linagliptin Inpatient_07.19.2016 
 
Appendix 1. 
 
Table 1.   
 
BEFORE MEAL, Supplemental Sliding Scale Insulin (number of units) - Add to scheduled insulin 
dose.   
 
BEDTIME.  Give half of Supplemental Sliding Scale Insulin for BG > 220 mg/dl. 
 
 
Blood Glucose 
 
(mg/dL) 
            Insulin Sensitive 
Usual  
Insulin Resistant             
 
______________________________________________________________ 
                            
 
>141-180 
 
 
2 
 
   3 
 
 
4 
181-220 
 
 
3 
 
   4 
 
 
6 
221-260 
 
 
4 
 
   5 
 
 
8 
261-300 
 
 
5 
 
   6 
 
 
10 
301-350 
 
 
6 
 
   8 
 
 
12 
351-400 
 
 
7 
 
   10 
 
 
14 
> 400  
 
 
8 
 
   12 
 
 
16 
______________________________________________________________ 
 
** Check appropriate column below and cross out other columns 
 
The numbers in each column indicate the number of units of lispro/aspart insulin per dose.  Supplemental” 
dose is to be added to the scheduled dose of lispro/aspart insulin.  If a patient is able and expected to eat all 
or most of his/her meals, supplemental insulin will be administered before each meal following the “usual” 
column dose.  Supplemental insulin at bedtime = half of premeal insulin dose at BG > 220 mg/dl.  Example, 
a patient with blood glucose of 240 mg/dl will receive 8 U before a meals or 2-4 U at bedtime of 
supplemental insulin.     
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.  Example, a patient kept NPO with blood glucose of 240 mg/dl will 
receive 4 U of supplemental insulin.     
 
 
 
28 

Linagliptin Inpatient_07.19.2016 
 
Appendix 2. 
Following preferred terms are considered as Adverse Event of Special Interest 
Hepatic events 
Acute graft versus host disease in liver 
Acute hepatic failure 
Alanine aminotransferase abnormal 
Alanine aminotransferase increased 
Ammonia abnormal 
Ammonia increased 
Ascites 
Ascites 
Aspartate aminotransferase abnormal 
Aspartate aminotransferase increased 
Asterixis 
Autoimmune hepatitis 
Bacterascites 
Bacterascites 
Bile output abnormal 
Bile output decreased 
Biliary cirrhosis 
Biliary cirrhosis primary 
Biliary fibrosis 
Bilirubin conjugated abnormal 
Bilirubin conjugated increased 
Bilirubin excretion disorder 
Biopsy liver abnormal 
Blood bilirubin abnormal 
Blood bilirubin increased 
Blood bilirubin unconjugated increased 
Caput medusae 
Child-Pugh-Turcotte score increased 
Cholaemia 
Cholestasis 
Cholestatic liver injury 
Cholestatic liver injury 
Cholestatic pruritus 
Chronic hepatic failure 
Chronic hepatitis 
Coma hepatic 
Cryptogenic cirrhosis 
Cytolytic hepatitis 
Duodenal varices 
Foetor hepaticus 
Galactose elimination capacity test abnormal 
Galactose elimination capacity test decreased 
Gamma-glutamyltransferase abnormal 
Gamma-glutamyltransferase increased 
Gastric varices 
Gastric varices haemorrhage 
 
29 

Linagliptin Inpatient_07.19.2016 
 
Guanase increased 
Hepaplastin abnormal 
Hepaplastin decreased 
Hepatectomy 
Hepatic artery flow decreased 
Hepatic atrophy 
Hepatic calcification 
Hepatic cirrhosis 
Hepatic congestion 
Hepatic encephalopathy 
Hepatic encephalopathy prophylaxis 
Hepatic enzyme abnormal 
Hepatic enzyme decreased 
Hepatic enzyme increased 
Hepatic failure 
Hepatic fibrosis 
Hepatic function abnormal 
Hepatic hydrothorax 
Hepatic hydrothorax 
Hepatic infiltration eosinophilic 
Hepatic lesion 
Hepatic mass 
Hepatic necrosis 
Hepatic pain 
Hepatic sequestration 
Hepatic steatosis 
Hepatic vascular resistance increased 
Hepatitis 
Hepatitis acute 
Hepatitis cholestatic 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis fulminant 
Hepatitis toxic 
Hepatobiliary disease 
Hepatobiliary scan abnormal 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatomegaly 
Hepatopulmonary syndrome 
Hepatorenal failure 
Hepatorenal syndrome 
Hepatosplenomegaly 
Hepatotoxicity 
Hyperammonaemia 
Hyperbilirubinaemia 
Hyperbilirubinaemia 
 
30 

Linagliptin Inpatient_07.19.2016 
 
Hypercholia 
Hypertransaminasaemia 
Icterus index increased 
Ischaemic hepatitis 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Kayser-Fleischer ring 
Liver and small intestine transplant 
Liver disorder 
Liver function test abnormal 
Liver induration 
Liver injury 
Liver operation 
Liver palpable subcostal 
Liver scan abnormal 
Liver tenderness 
Liver transplant 
Lupoid hepatic cirrhosis 
Lupus hepatitis 
Mitochondrial aspartate aminotransferase increased 
Mixed liver injury 
Mixed liver injury 
Molar ratio of total branched-chain amino acid to tyrosine 
Nodular regenerative hyperplasia 
Ocular icterus 
Oedema due to hepatic disease 
Oedema due to hepatic disease 
Oesophageal varices haemorrhage 
Perihepatic discomfort 
Portal hypertension 
Portal hypertensive enteropathy 
Portal hypertensive gastropathy 
Portal triaditis 
Portopulmonary hypertension 
Radiation hepatitis 
Renal and liver transplant 
Retrograde portal vein flow 
Retrograde portal vein flow 
Reye's syndrome 
Subacute hepatic failure 
Total bile acids increased 
Transaminases abnormal 
Transaminases increased 
Ultrasound liver abnormal 
Urine bilirubin increased 
Urobilin urine present 
Varices oesophageal 
X-ray hepatobiliary abnormal 
 
31 

Linagliptin Inpatient_07.19.2016 
 
 
 
 
Following preferred terms are considered as 
Adverse Event of Special Interest 
Hypersensitivity reactions 
Allergic bronchitis 
Allergic cough 
Allergic oedema 
Allergic respiratory disease 
Allergic respiratory symptom 
Alveolitis allergic 
Anaphylactic reaction 
Anaphylactic shock 
Anaphylactic transfusion reaction 
Anaphylactoid reaction 
Anaphylactoid shock 
Angioedema 
Bronchial hyperreactivity 
Bronchospasm 
Circulatory collapse 
Circumoral oedema 
Conjunctival oedema 
Corneal oedema 
Cough 
Drug eruption 
Drug hypersensitivity 
Epiglottic oedema 
Erythema 
Eye oedema 
Eye swelling 
Eyelid oedema 
Face oedema 
First use syndrome 
Gingival oedema 
Gingival swelling 
Gleich's syndrome 
Hereditary angioedema 
Hypersensitivity 
Idiopathic urticaria 
Kounis syndrome 
Laryngeal oedema 
Laryngotracheal oedema 
Lip oedema 
Lip swelling 
Oculorespiratory syndrome 
Oedema mouth 
Oropharyngeal swelling 
Palatal oedema 
 
32 

Linagliptin Inpatient_07.19.2016 
 
Periorbital oedema 
Pharyngeal oedema 
Pruritus 
Pruritus allergic 
Pruritus generalized 
Rash 
Rash erythematous 
Rash generalized 
Rash pruritic 
Scleral oedema 
Shock 
Small bowel angioedema 
Swelling face 
Swollen tongue 
Tongue oedema 
Toxic skin eruption 
Tracheal oedema 
Type I hypersensitivity 
Type I hypersensitivity 
Urticaria 
Urticaria 
Urticaria cholinergic 
Urticaria chronic 
Urticaria papular 
Urticaria papular 
Wheezing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following preferred terms are considered as 
Adverse Event of Special Interest 
Pancreatitis 
Cullen's sign 
Hereditary pancreatitis 
Ischaemic pancreatitis 
 
33 

Linagliptin Inpatient_07.19.2016 
 
Oedematous pancreatitis 
Pancreatic abscess 
Pancreatic necrosis 
Pancreatic phlegmon 
Pancreatic pseudocyst 
Pancreatic pseudocyst drainage 
Pancreatitis 
Pancreatitis acute 
Pancreatitis chronic 
Pancreatic haemorrhage 
Pancreatitis haemorrhagic 
Pancreatitis necrotizing 
Pancreatitis relapsing 
Pancreatorenal syndrome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following preferred terms are considered as 
Adverse Event of Special Interest 
Renal events 
 
Acute phosphate nephropathy 
Acute prerenal failure 
Anuria 
Azotaemia 
Continuous haemodiafiltration 
Dialysis 
Haemodialysis 
Neonatal anuria 
Nephropathy toxic 
Oliguria 
Peritoneal dialysis 
Renal failure 
Renal failure acute 
Renal failure neonatal 
 
34 

Linagliptin Inpatient_07.19.2016 
 
Renal impairment 
Renal impairment neonatal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following preferred terms are considered as 
Adverse Event of Special Interest 
Skin lesions 
Acute generalized exanthematous pustulosis 
Cutaneous vasculitis 
Dermatitis bullous 
Dermatitis exfoliative 
Dermatitis exfoliative generalized 
Drug eruption 
Epidermal necrosis 
Erythema multiforme 
Exfoliative rash 
Lip exfoliation 
Mucocutaneous ulceration 
Mucosal exfoliation 
Oral mucosal exfoliation 
Penile exfoliation 
Skin erosion 
Skin exfoliation 
Skin necrosis 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
Toxic skin eruption 
Vaginal exfoliation 
 
35 

Linagliptin Inpatient_07.19.2016 
 
Vaginal ulceration 
Vulvar ulceration 
Vulvovaginal ulceration 
 
 
 
 
 
36 

Linagliptin Inpatient_07.19.2016 
 
  
 
 
37