Clinical trial NCT01919489
Conditions: Type 2 Diabetes
Keywords: Incretins Liraglutide Glargine Randomized controlled trial basal insulin hospital discharge inpatient diabetes
Sponsor: Emory University
Start date: 2014-03-01; Completion date: 2020-08-30
Enrollment: 273 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
High blood glucose levels in hospitalized patients with diabetes are associated with increased risk of medical complications and death. Improved glucose control with insulin injections may improve clinical outcome and prevent some of the hospital complications. Increasing evidence indicates that incretin-based agents are safe and effective for the hospital management of patients with type 2 diabetes (T2D).

Liraglutide is a once-daily human glucagon-like peptide (GLP-1) analogue approved for the treatment of T2D. Liraglutide has been shown to lower blood glucose, stimulate endogenous insulin secretion, decrease plasma glucagon levels, inhibit gastric emptying, reduce food intake and body weight and improve ß-cell function when administered subcutaneously. Liraglutide increases insulin secretion in a glucose-dependent manner (i.e., only when plasma glucose levels are elevated), resulting in low-risk of hypoglycemia when used as monotherapy. When compared to insulin glargine therapy, the use of GLP-1 has resulted in comparable reduction in HbA1c level, lower rates of hypoglycemia and less weight gain. No prospective studies; however, have compared the efficacy and safety of liraglutide in the hospital setting or after hospital discharge.

The primary objective is to compare the safety and efficacy of liraglutide (Victoza®) versus glargine insulin in combination to oral anti-diabetic agents (OADs: metformin, sulfonylureas, nateglinide, repaglinide or pioglitazone) on glycemic control after 26 weeks of treatment in medicine patients with T2D after hospital discharge.

Detailed description:
Specific Aim: To determine whether treatment with liraglutide (Victoza®) will result in similar glycemic control (HbA1c at 26 weeks) and a lower rate of hypoglycemic events compared to treatment with glargine (Lantus®) in patients with T2D after hospital discharge. Patients with poorly controlled (HbA1c \>7%-10%) T2D treated with diet or oral antidiabetic agents or low dose insulin naïve (0.4u/kg/day) prior to admission will be randomized to liraglutide or glargine in combination to OADs at hospital discharge.

Arms: arm 1: Liraglutide once daily in combination to oral anti-diabetic agents (OADs) arm 2: Glargine once daily in combination to oral anti-diabetic agents (OADs)
Interventions: intervention 1: Liraglutide + OADs intervention 2: Glargine + OADs
Intervention descriptions: intervention 1: Liraglutide subcutaneously daily intervention 2: Glargine once daily subcutaneously

Protocol documents:
Prot_SAP_000.pdf: 
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A Randomized Controlled Trial Comparing the Safety and Efficacy of Liraglutide versus 
Glargine insulin for the Management of Patients with Type 2 Diabetes After Hospital 
Discharge 
 
NCT# NCT01919489 
 
Date: October 28, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Title: 
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Liraglutide Hospital Discharge Trial: A Randomized Controlled Trial Comparing the Safety 
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and Efficacy of Liraglutide versus Glargine insulin for the Management of Patients with Type 2 
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Diabetes After Hospital Discharge  
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INVESTIGATOR-INITIATED STUDY PROPOSAL 
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UNIVERSAL TRIAL NUMBER (UTN) 
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U1111-1139-2991 
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Principal Investigator: 
 
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Guillermo E. Umpierrez, M.D. 
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Professor of Medicine 
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Department of Medicine/Endocrinology 
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Emory University School of Medicine 
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49 Jesse Hill Jr Dr. 
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Atlanta, GA 30303 
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Phone:
 
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Cell Phone: 
 
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Fax: 
 
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Administrative Assistant: Anita Hendricks 
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BACKGROUND and SIGNIFICANCE: 
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The association between hyperglycemia and poor clinical outcomes in patients with and without 
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diabetes is well established (2-6). Extensive data from observational and prospective randomized 
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controlled trials in hospitalized patients have reported a strong association between 
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hyperglycemia and poor clinical outcome, such as mortality, morbidity, length of stay (LOS), 
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infections and overall complications (2, 5, 7-9).  Most clinical trials in critically ill and general 
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medicine and surgery patients have reported that improvement of glycemic control reduces LOS, 
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risk of multiorgan failure and systemic infections (10-12), as well as short- and long-term 
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mortality (7, 12) in patients with hyperglycemia and diabetes.   
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Clinical guidelines from professional organizations (13-15) recommend the use of subcutaneous 
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(SQ) insulin as the preferred therapy for glycemic control in general medical and surgical 
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patients with T2D.  The two most common SQ insulin regimens for inpatient glycemic 
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management are sliding scale regular insulin (SSRI) and basal bolus insulin therapy in 
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combination with correction insulin scale (16, 17).  The use of basal bolus regimen results in 
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better glycemic control and lower rate of hospital complications compared to sliding scale 
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regular insulin (SSRI) (17-20).  The basal bolus regimen, however, requires multiple insulin 
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daily injections and is associated with a significant risk of hypoglycemia, which has been 
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reported in up to 32% of non-ICU patients with T2D (17, 19, 20).   
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Increasing evidence indicates that incretin-based agents are safe and effective for the hospital 
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management of patients with T2D.  We recently completed a randomized open label trial 
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comparing differences in glycemic control between treatment with sitagliptin (Januvia) alone 
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or in combination with glargine compared to a standard basal bolus regimen in general medicine 
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and surgery patients with T2D (see preliminary result section). We found no differences in mean 
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daily BG, frequency of hypoglycemia, length of hospital stay and complications.  Similarly, the 
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use of GLP-1 and its analogues have also been shown to improve glycemic control and to have a 
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beneficial cardiovascular profile improving functional status and endothelial function (21), 
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increasing left ventricular function in patients with heart failure (22) and in surgery patients 
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undergoing CABG (22, 23), and to reducing infarct size and preserving left ventricular 
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myocardial performance in ischemic models (24).   
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Liraglutide is a once-daily human GLP-1 analogue approved for the treatment of T2D. 
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Liraglutide has been shown to lower blood glucose, stimulate endogenous insulin secretion, 
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decrease plasma glucagon levels, inhibit gastric emptying, reduce food intake and body weight 
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and improve ß-cell function when administered subcutaneously (25). Liraglutide increases 
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insulin secretion in a glucose-dependent manner (i.e., only when plasma glucose levels are 
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elevated), resulting in low-risk of hypoglycemia when used as monotherapy. When compared to 
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insulin glargine therapy, the use of GLP1 has resulted in comparable reduction in HbA1c level, 
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lower rates of hypoglycemia and less weight gain (26).  No prospective studies; however, have 
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compared the efficacy and safety of liraglutide in the hospital setting or after hospital discharge. 
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SPECIFIC OBJECTIVES: 
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Primary objective is to compare the safety and efficacy of liraglutide (Victoza®) versus glargine 
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insulin on glycemic control after 26 weeks of treatment in medicine and surgical patients with 
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T2D after hospital discharge. 
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RESEARCH DESIGN AND METHODS 
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Study Hypothesis (hypotheses): 
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We hypothesize that treatment with liraglutide (Victoza®) will result in a similar improvement in 
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HbA1c levels and in lower rate of hypoglycemic events compared to treatment with glargine 
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(Lantus) in patients with T2D after hospital discharge.  
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Specific Aim 1: To determine whether treatment with liraglutide (Victoza®) will result in 
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similar glycemic control (HbA1c at 26 weeks) and a lower rate of hypoglycemic events 
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compared to treatment with glargine (Lantus) in patients with T2D after hospital 
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discharge. Patients with poorly controlled (HbA1c ≥7%-10%) T2D treated with diet or oral 
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antidiabetic agents, or on low-dose insulin therapy (TDD ≤0.4 unit/kg/day) will be randomized 
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to liraglutide or glargine with or without oral agents at hospital discharge.  
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Endpoints: 
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Study Outcomes: 
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The primary outcome of the study is to determine differences in HbA1c concentration at 26 
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weeks from discharge between liraglutide and glargine insulin therapy.    
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The secondary outcome is to compare differences between treatment groups in any of the 
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following measures during the 26 weeks following hospital discharge in patients with T2D: 
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• Self-measured blood glucose (SMBG) 7-point profiles 
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• Fasting and postprandial BG concentration 
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• Incidence rate and number of hypoglycemic events (<70 mg/dl) and severe hypoglycemic 
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events (<40 mg/dl). 
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• Percent of patients with 26 week HbA1c <7.0% and no hypoglycemia 
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• Percent of patients with 26 week HbA1c <7.0% and no weight gain  
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• Percent of patients with 12 week HbA1c <7.0% and no hypoglycemia 
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• Change in body weight and BMI 
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• Cardiovascular risk factors including changes in blood pressure, heart rate, and lipid 
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profile. 
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• Total daily dose of insulin 
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• Number of emergency room visits and hospital readmissions 
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• Acute renal failure during the 26-week follow-up defined as a clinical diagnosis of acute 
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renal failure with documented new-onset abnormal renal function (increment in 
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creatinine ≥ 0.5 mg/dL from baseline) 
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Study type: 
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The trial is a 26-week, randomized, open label-controlled two-armed, multi-center, multi-
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national trial investigating the efficacy and safety of liraglutide versus glargine insulin in 
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medicine and surgical patients with T2D after hospital discharge.   
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We will recruit a total of 330 poorly controlled (HbA1c ≥7%-10%) patients with T2D treated 
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with diet or oral antidiabetic agents (OAD) or on low-dose insulin therapy (TDD ≤0.4 
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unit/kg/day) prior to admission. Patients will be treated with a standard basal bolus insulin 
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regimen during the hospital stay.  Prior to hospital discharge, patients will be randomized to 
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liraglutide or glargine with or without oral antidiabetic drugs. After discharge, a member of the 
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diabetes research team will contact patients via telephone call every 2 weeks to assess response 
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to therapy. In addition, patients will be asked to attend an outpatient clinic visit at 2 (optional), 4, 
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12 and 26 weeks after hospital discharge.  Recommendation on insulin dose adjustment will be 
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provided to patients at each telephone contact and clinic visits.  
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Recommendation for liraglutide dose escalation will be done every one or two weeks until the 
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maintenance dose of 1.8 mg is reached. Dose escalation can be extended over 2 weeks at the 
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discretion of the investigator in case of gastrointestinal adverse events.  Liraglutide and insulin 
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will be add-on to the subject’s pre-admission OAD regimen. Dose of OAD should remain 
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unchanged throughout the trial, however dose reduction of insulin and sulfonylurea is allowed 
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due to hypoglycemia. 
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Study Groups: 
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We plan to analyze a total of 280 patients (who receive study medication) with T2D at the time 
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of hospital discharge. 
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• Group 1.  Liraglutide once daily in combination to OADs (n=140). 
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▪ Group 2.  Glargine once daily in combination to OADs (n=140). 
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Study population: 
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This will analyze 380 general medicine and surgical patients with a known history of T2D, age 
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18-80, treated with diet alone and/or oral antidiabetic agents including sulfonylureas, repaglinide, 
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nateglinide, DPP4s, SGLT2, or metformin as monotherapy or in combination therapy or on low-
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dose insulin therapy (TDD ≤0.4 unit/kg/day) prior to admission. Subjects will be recruited from 5 
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medical centers in the United States.  A total of 300 patients will be recruited at Grady Memorial 
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Hospital, Emory University Hospital and Emory Midtown hospital.  
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Study Sites: This study will be performed at Grady Memorial Hospital, Emory University 
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Hospital, Emory University Hospital at Midtown, and 3 institutions in the United States: 
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1. MetroHealth Medical Center, Cleveland (PI: Jorge Calles-Escandon, MD.) 
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2. State University of NY at Buffalo (PI: Ajay Chaudhuri, MD.) 
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3. University of Miami, Florida (PI: Gianluca Iacobellis, MD.) 
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4. Sanatorio Guemes, Buenos Aires -Argentina (PI: Javier Farias) 
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Inclusion Criteria 
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1. Males or females between the ages of 18 and 80 years discharged after hospital admission 
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from non- ICU general medicine and surgical services ( excluding gastrointestinal and 
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cardiac surgeries).   
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2. Admission HbA1c between 7% and 10%   
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3. Patients with T2D treated with diet alone or with oral antidiabetic agents as monotherapy or in 
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combination therapy (excluding GLP1 receptor agonists) or on low-dose insulin therapy 
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(TDD ≤0.4 unit/kg/day) prior to admission.  
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4. Subjects with a hospital admission BG < 400 mg/dL without laboratory evidence of diabetic 
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ketoacidosis (serum bicarbonate < 18 mEq/L or positive serum or urinary ketones). 
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5. BMI > 25 Kg/m2 and ≤ 45 Kg/m2 
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Exclusion Criteria 
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1. Age < 18 or > 80 years.  
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2. Subjects with stress hyperglycemia (BG > 140 mg/dL and HbA1c < 6.5%) 
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3. Subjects with a history of type 1 diabetes (1).  
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4. Treatment with GLP1 analogs during the past 3 months prior to admission. 
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5. Recurrent severe hypoglycemia or hypoglycemic unawareness. 
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6. Subjects with gastrointestinal obstruction, gastroparesis or those expected to require 
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gastrointestinal suction. 
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7. History of medullary thyroid cancer or multiple endocrine neoplasias 
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8. Patients with acute or chronic pancreatitis, pancreatic cancer or gallbladder disease. 
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9. Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver 
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disease, portal hypertension) and elevated ALT and AST > 3 times upper limit of normal, or 
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significantly impaired renal function (GFR < 30 ml/min). 
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10. Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone 
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5mg/day), parenteral nutrition and immunosuppressive treatment. 
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11. Mental condition rendering the subject unable to understand the nature, scope, and possible 
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consequences of the study. 
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12. Female subjects who are pregnant or breast-feeding at time of enrollment into the study. 
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13. Females of childbearing potential who are not using adequate contraceptive methods (as 
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required by local law or practice). 
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Investigational drugs. 
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• Liraglutide 6.0 mg/mL solution for subcutaneous (s.c.) injection. The solution will be 
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provided in 3 mL prefilled pen.  
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• Liraglutide will be provided to patients  
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• Glargine will be provided  
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Withdrawal Criteria 
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1. The subject may withdraw at will at any time. 
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2. The subject may be withdrawn from the trial at the discretion of the investigator due to a 
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safety concern or if judged non-compliant with trial procedures or included in contravention 
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to the inclusion and/or exclusion criteria. 
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3. Subject diagnosed with acute pancreatitis by clinical and/or radiographic criteria. 
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4. If the fasting BG and average daily BG on 3 consecutive days exceeds > 15.0 mmol/L (240 
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mg/dL).  If this occurs, the subject will be called for an unscheduled visit as soon as possible. 
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A confirmatory FPG should be obtained and analyzed by the hospital laboratory. If this FPG 
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exceeds 15.0 mmol/L (240 mg/dL), and no treatable intercurrent cause for the hyperglycemia 
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has been identified, the subject must be withdrawn.  
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5. Pregnancy or intention to become pregnant. 
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Subject Replacement 
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There will be no replacement of subjects in this trial. 
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Rationale for Study Population 
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We will recruit patients with poorly controlled T2D (HbA1c ≥7%-10%) treated with diet and/or 
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oral antidiabetic agents or on low-dose insulin therapy (TDD≤0.4unit/kg/day)prior to admission. 
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Patients will be treated with a basal bolus insulin regimen during the hospital stay (standard of 
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care).  Prior to hospital discharge, patients will be randomized to receive liraglutide or glargine 
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as monotherapy in treatment of patients treated with low-dose insulin therapy (TDD ≤0.4 
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unit/kg/day) (or as add-on therapy to the subject’s pre-admission OAD regimen.  
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We plan to analyze a total of 280 patients (who receive study medication) with T2D at the time 
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of hospital discharge [liraglutide once daily in combination to OADs (n=140) or glargine once 
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daily in combination to OADs (n=140)]. 
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GROUP 1.  Liraglutide Treatment Group.  
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▪ Patients receiving no Therapy prior to admission: 
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• Discharge on liraglutide once daily.  
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• Start metformin if A1C≥8% and no contraindications. 
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▪ Patients receiving OAD prior to admission: 
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• If no contraindication, restart pre-admission OADs according to standard of care and 
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investigator’s medical discretion (metformin, sulfonylureas, nateglinide, repaglinide, 
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pioglitazone) in combination to liraglutide.  
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• The total daily dose of insulin secretagogues (sulfonylureas, nateglinides and 
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repaglinide) will be reduced to 50% of pre-admission dose to avoid risk of 
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hypoglycemia.    
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• DPP4-inhibitors will not be used in combination with liraglutide during the study 
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period. 
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Liraglutide Titration: 
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Liraglutide will be administered once daily in accordance with a 3-4 week dose escalation 
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regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg is reached.  
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Liraglutide will be administered once daily by s.c. injections, either in the abdomen, thigh or 
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upper arm. Injections can be done at any time of the day and irrespective of meals. It is 
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recommended that the time of injection is consistent throughout the trial. Subjects will be 
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instructed to perform an air shot before the first use of a new prefilled pen.  
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GROUP 2.  Glargine Group 
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V.e. 
Treatment recommendations at discharge: 
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▪ Patients receiving no Therapy prior to admission: 
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•  Discharge on glargine once daily at 50% of total hospital dose 
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• Add metformin if A1C≥8% and no contraindications. 
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▪ Patients receiving OAD prior to admission: 
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• If no contraindication, restart pre-admission OADs according to standard of care and 
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investigator’s medical discretion (metformin, sulfonylureas, repaglinide, nateglinide, 
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pioglitazone) in combination to glargine at 50% of hospital dose.  
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• The total daily dose of insulin secretagogues (sulfonylureas, nateglinides and 
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repaglinide) will be reduced to 50% of pre-admission dose to avoid risk of 
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hypoglycemia.    
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• DPP4-inhibitors will not be used in combination with liraglutide during the study 
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period 
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Algorithm for outpatient glargine insulin dose adjustment: 
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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% 
 
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In hospital Diabetes Education.  Prior to discharge, participants will be trained on: 
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1. Diabetes education if not received within 1 year of admission.   
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2. ADA targets for fasting and premeal BG between 70 to 130 mg/dL. 
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3. Use of glucose meters for home glucose self-monitoring (meters may vary at different 
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institutions).   
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4. Keeping BG records, and will receive a log-book to record glucose tests results. 
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5. Hypoglycemia recognition and management (see VI.B.) 
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6. Insulin administration (if needed). 
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Follow-up Care: 
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• If baseline visit was not fully completed at the time of discharge, patients will be 
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scheduled to return for a short in-person visit to complete (body measurements) study 
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procedures within 7 days of discharge. Research team will call to verify correct 
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administration of study medication and availability of medications and glycemic control 
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monitoring supplies.  
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• 
After discharge, a member of the diabetes research team will contact patients via 
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telephone call every 2 weeks for a total of 26 weeks.   
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• Patients will be asked to attend the next outpatient clinic visit at 4 weeks of hospital 
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discharge.  During this visit, patients will receive 8 weeks drug supply of liraglutide and 
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will be asked to return to clinic at 12 weeks for the next outpatient visit.  During this visit, 
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patients will receive 12 weeks (3 months) drug supply of liraglutide and will be asked to 
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return to a fourth and final visit at 26 weeks of hospital discharge.  
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• Recommendations on insulin adjustment will be provided to patients at each telephone 
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and clinic visits by a licensed physician (fellow or study physician) (see section Vf).     
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During follow up we will collect the following information:   
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1. Glycemic control: 
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a. Mean daily fasting and premeal blood glucose levels.  
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b. HbA1c at 3 and 6 months of discharge 
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c. Number of hypoglycemic events  
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- Symptomatic hypoglycemia is defined as an event with typical symptoms (i.e., 
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sweating, palpitation, and feeling of hunger) with or without confirmation by 
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plasma glucose <70 mg/dl (3.9 mmol/L).   
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- Severe hypoglycemia is defined as episodes necessitating assistance and 
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associated with measured plasma glucose < 40 mg/dl (2.2 mmol/L) or with 
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prompt recovery after administration of carbohydrates, glucagon, or other 
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resuscitative actions. These episodes may be associated with sufficient 
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neuroglycopenia to induce seizure or coma. Blood glucose measurements may 
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not be available during such an event, but neurological recovery attributable to 
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the restoration of BG to normal is considered sufficient evidence that the event 
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was induced by low plasma glucose. 
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2. Diabetes treatment: 
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a. Number of patients receiving insulin therapy, dosage and compliance. 
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b. Use of liraglutide and other oral agents, dosage and compliance. 
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c. Protocol adherence by PCP (diabetes clinic versus PCP) 
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3. Clinical Outcome: 
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a. Hospital readmissions 
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b. Emergency room visits 
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7-point self-measured blood glucose profile: 
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Subjects will be instructed to perform a 7-point SMBG profile three times during the trial within 
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one week prior to site visit on a day where the subject do not anticipate unusual strenuous 
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exercise. 
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Time-points for 7-point profile:  
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The blood glucose levels should be measured and recorded in the diary (including date, actual 
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clock time and blood glucose value) at the following time points, always starting with 
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measurement before breakfast. 
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• Before breakfast 
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• 90 min after the start of breakfast 
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• Before lunch 
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• 90 min after the start of lunch 
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• Before dinner 
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• 90 min after the start of dinner 
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• At bedtime 
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Body measurements 
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Body measurements consist of the parameters: Body weight, height, waist circumference, hip 
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circumference and BMI 
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Body weight: Body weight should be measured in kilogram or pound, without shoes and only 
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wearing light clothing. 
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Height: Height (without shoes) should be measured in centimeters or inches and recorded 
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without decimals. 
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Waist and hip circumference: The waist circumference is defined as the minimal abdominal 
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circumference located midway between the lower rib margin and the iliac crest. The hip 
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circumference is defined as the widest circumference around the buttocks.  Three consecutive 
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measurements of waist and hip circumference should be taken and recorded.  Mean values will 
366 
be used for result analysis. The waist and hip circumferences will be measured to the nearest 0.5 
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cm (0.2 inches) using a non-stretchable measuring tape. 
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The subject should be measured in a standing position with an empty bladder and wearing light 
369 
clothing with accessible waist and hip. The tape should touch skin, but not compress soft tissue 
370 
and twist in tape should be avoided. The subject should be asked to breathe normally and the 
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measurement should be taken when the subject is breathing out gently.  
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Body Mass Index (BMI): BMI will be calculated by the formula Body weight (Kg)/m2. 
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Assessment for Safety 
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379 
Potential Risks to the Subjects: 
380 
 
381 
Hypoglycemia.    It is possible that following the proposed protocol, patients receiving basal 
382 
insulin or liraglutide may develop hypoglycemia. For the purpose of this analysis we 
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symptomatic hypoglycemia is defined as an event with typical symptoms (i.e., sweating, 
384 
palpitation, and feeling of hunger) with or without confirmation by plasma glucose <70 mg/dl 
385 
(3.9 mmol/L).  We expect that approximately 20% to 40% of subjects treated with basal insulin 
386 
alone or in combination to OADs will experience one or more episodes of hypoglycemia during 
387 
follow-up. We anticipate that less than 10% of patients taking liraglutide alone or in combination 
388 
to OADs will experience hypoglycemic events.   
389 
Severe hypoglycemia is defined as episodes necessitating assistance and associated with 
390 
measured plasma glucose < 40 mg/dl (2.2 mmol/L) or with prompt recovery after administration 
391 
of carbohydrates, glucagon, or other resuscitative actions. These episodes may be associated with 
392 
sufficient neuroglycopenia to induce seizure or coma. Blood glucose measurements may not be 
393 
available during such an event, but neurological recovery attributable to the restoration of BG to 
394 
normal is considered sufficient evidence that the event was induced by low plasma glucose.  We 
395 
anticipate that less than 5% of patients on insulin or liraglutide alone or in combination to OADs 
396 
will experience severe hypoglycemic events.   
397 
 
398 
Gastrointestinal side effects including nausea and vomiting are more common in patients 
399 
treated with liraglutide compared to placebo.  The frequency of nausea and vomiting is reported 
400 
in up to 14% of patients receiving higher doses of liraglutide 1.8 mg in combination to 
401 
metformin and sulfonylurea therapy compared to 3.5% in patients receiving placebo plus OADs 
402 
(Victoza package insert).  The number of adverse events will be collected at each telephone 
403 
contact or clinic visit.  There have been few reported events of acute pancreatitis. Subjects 
404 
should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe 
405 
abdominal pain. If pancreatitis is suspected, liraglutide and other potentially suspect medicinal 
406 
products should be discontinued. If the investigator suspects acute pancreatitis, all suspected 
407 
drugs should be discontinued until confirmatory test have been conducted and appropriate 
408 
treatment should be initiated. Subjects diagnosed with acute pancreatitis (as a minimum 2 of 3: 
409 
characteristic abdominal pain, amylase and/or lipase >3xUNR or characteristic findings on CT 
410 
scan/ MRI should be withdrawn from the study. 
411 
 
412 
Protection against Risks: 
 
413 
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor 
414 
response to medical treatment every 2 weeks by telephone contact and every 3 months during 
415 
clinic visits, b) women of reproductive age who are sexually active will undergo a urine 
416 
pregnancy tests prior to participation in the study, c) female subjects whom are pregnant, 
417 
breast-feeding, or not willing to use appropriate contraception at time of enrollment will not be 
418 
included in the study, d) patients with significant comorbidities such as chronic kidney disease 
419 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
13
greater than stage III, liver cirrhosis, gastroparesis, and pancreatic disorders will be excluded 
420 
from the study.  
421 
 
422 
Hypoglycemia: Patients will receive diabetes education prior to discharge and will be instructed 
423 
on hypoglycemia sign/symptoms and treatment.  Patients will be asked to call the diabetes center 
424 
and/or PCP in the event of hypoglycemia. If a patient develops hypoglycemia, the dose of OAD 
425 
will be reduced or discontinued and the daily dose of basal insulin will be reduced by 10% to 
426 
30% (see treatment algorithm).     
427 
Gastrointestinal side effects including nausea and vomiting may be expected, more commonly in 
428 
patients treated with liraglutide. In subjects with suspected acute pancreatitis liraglutide and 
429 
other potentially suspect medicinal products should be discontinued until confirmatory tests have 
430 
been conducted and appropriate treatment initiated.  
431 
 
432 
 
433 
STATISTICAL CONSIDERATIONS: 
434 
This study is randomized multicenter, open-label controlled trial. The overall hypothesis is that 
435 
patients with T2D discharged on liraglutide and glargine will experience similar improvement in 
436 
glycemic control (HbA1c level at 26 weeks post-discharge).  In addition, we anticipate that 
437 
compared to patients treated with insulin glargine, patients on liraglutide will experience lower 
438 
number of hypoglycemic events and less weight gain during follow-up.  
439 
 
440 
Sample Size and Power Calculations: The primary endpoint in this study is glycemic control 
441 
measured by HbA1c at 26 weeks after discharge between treatment groups. To show the non-
442 
inferiority of liraglutide to basal glargine insulin in terms of glycemic control, we set the 
443 
equivalence margin as 0.5%, from a view that an HbA1c difference < 0.5% is usually not 
444 
considered as clinically significant.  
445 
Based on preliminary discharge data, we assume the standard deviation of 26 week A1c is 
446 
bounded about 1.5%.  We set the margin of equivalence as 0.5% and assume the true difference 
447 
between mean A1c is 0. A sample size of 124 for each treatment group would achieve 80% 
448 
power to reject the hypothesis that the mean HbA1c in patients treated with liraglutide is < 0.5% 
449 
more than that in patients treated with glargine based on a two-sample one-sided t test, with 
450 
alpha=0.05. Accounting for 10% attrition rate, we would need 140 patients per treatment group. 
451 
This leads to a final total sample size estimate of 280 patients that receive study medication. 
452 
 
453 
The secondary outcome of major interest in this study is the difference in hypoglycemia (BG <70 
454 
mg/dl). Based on our preliminary discharge data, 30-40% of patients treated with basal insulin 
455 
will have at least one hypoglycemia episode. Assuming a hypoglycemia rate of 20-35% in the 
456 
insulin group in this study, given the sample size of 140 subjects per treatment group, based on a 
457 
two sided Fisher’s exact test with alpha=0.05, we would have 80% power to detect an odds ratio 
458 
in hypoglycemia rate of 0.42 in liraglutide group (versus glargine group). In the following table, 
459 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
14
we give the estimated power under different assumed group differences in hypoglycemia rate, 
460 
represented by four hypothesized odds ratios. 
461 
Table: Estimated power with 140 subjects per group (before 10% attrition) and the anticipated 
462 
hypoglycemia rate of 35% in the insulin group based on two-sided Fisher’s exact test with 
463 
alpha=0.05. 
464 
 
465 
Odds Ratio 0.2  
0.3  
0.4  
0.5  
Power 
>0.99 0.97  0.85 0.64  
   
466 
The above calculations show that we will have a good chance to achieve over 80% power for the 
467 
secondary outcome of hypoglycemia rate. 
468 
 
469 
 
470 
 
471 
Analysis of Primary Endpoint: 
472 
The primary endpoint in this study is glycemic control measured by HbA1c concentration at 26 
473 
weeks post-discharge. We will first compare the primary outcome using two-sample t-tests (or 
474 
Wilcoxon tests) or one-way ANOVA, followed by multivariate linear regression to estimate and 
475 
test the difference between the two treatment groups while simultaneously accounting for other 
476 
potential confounders . Particularly, we will investigate center effect for the HbA1c outcome by 
477 
stratified univariate analysis or multivariate linear regression. Transformations will be applied if 
478 
normality violation is detected. Stepwise, backward, or forward model selection strategy will be 
479 
adopted to determine the variables to be included in the final model. Standard diagnostic and 
480 
model checking procedures will be applied to examine the fit of the developed models. 
481 
 
482 
Analysis of Secondary Endpoints: 
483 
Secondary endpoints in this study include rate of hypoglycemia, number of hypoglycemia 
484 
events, change in body weight in kilograms, number of episodes of severe hyperglycemia, 
485 
complications and Emergency Room or hospital readmissions. For hypoglycemia outcomes, we 
486 
will first conduct nonparametric comparisons of the rate of hypoglycemia based on a two-sided 
487 
Chi-square test (or Fisher’s exact test in the presence of low incidence rates), followed by the 
488 
Cochran-Mantel-Haenszel test which adjusts for the potential center effect. Univariate Poisson 
489 
regression (or Negative Binomial regression) will be performed to assess whether there is any 
490 
difference in the number of hypoglycemia events between the two treatment groups. We will 
491 
further conduct multivariate Logistic regression, Poisson regression (or negative binomial 
492 
regression) to estimate the difference in the rate and frequency of hypoglycemia while adjusting 
493 
for relevant covariates.  Stepwise, backward, or forward model selection strategy will be adopted 
494 
to determine the variables to be included in the final model. Standard diagnostic and model 
495 
checking procedures, such as deviance residual plot and Hosmer-Lemeshow test, will be applied 
496 
to examine the fit of the developed models. Similar analyses will be conducted for severe 
497 
hyperglycemia outcomes. For single measurement continuous outcomes, such as length of 
498 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
15
hospital stay, we will use two-sample t-tests or nonparametric Wilcoxon tests to compare them 
499 
between groups. Transformations will be applied if normality violation is detected.  Multivariate 
500 
linear regression will be further conducted to assess the difference in continuous secondary 
501 
outcomes between the two groups with other relevant covariates. We will use standard model 
502 
selection and model checking procedures for linear regression to decide the final models and 
503 
assess their fits to the data. For repeated measurement continuous outcomes, such as fasting BG 
504 
values, we will first conduct cross-section analysis following the same strategy for the single 
505 
measurement continuous outcome. Then we plan to fit repeated measures ANOVA or linear 
506 
models which can simultaneously account for multiple time points during the discharge follow-
507 
up. Model selection and model checking will follow the standard procedures.  
508 
 
509 
DATA HANDLING AND RECORD KEEPING: 
510 
Data collection records with personal identifiers will be stored in locked file cabinets.  
511 
Presentation of the study results at regional or scientific meetings or in publications will not 
512 
identify subjects.  Access to research and confidential records will be limited to clinical 
513 
investigators, research coordinators, and the IRB at Emory University.  
514 
All data will be entered electronically in Redcap by participating sites. Sponsor site expects data 
515 
to be entered in Redcap within 10 days of phone call or outpatient visit. 
516 
 
517 
 
518 
 
519 
 
520 
ETHICS: 
521 
Informed Consent.  
522 
After identification of eligible patients these individuals will be provided basic information 
523 
regarding the study and, if interested, a member of the research staff using inclusion/exclusion 
524 
criteria delineated elsewhere in the protocol will enroll patients.  Informed consent will be 
525 
obtained before any trial related procedures including screening procedures. The consent form, 
526 
potential risks and benefits, and the rights of research participants will be explained to the 
527 
participant by the investigators or research coordinator.  Individuals will be asked if they have 
528 
questions, and a member of the research staff will answer questions.  The principal investigator 
529 
will also be available at all times to answer questions that participants may have during the 
530 
consent procedure or during the time a participant is enrolled in the study.  The consent form will 
531 
be completed in accordance with the IRB guidelines of Emory University.  A signed copy of the 
532 
consent form will be provided to the participant and a copy will be placed in the file that is 
533 
maintained for each participant in the study office.   
534 
 
535 
Informed consent will follow the procedure of Emory University Institutional Review Board.   
536 
Every potential participant will be informed in writing and verbally with the important and key 
537 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
16
points of the study.   One of the investigators or research coordinators will obtain a witnessed 
538 
informed consent prior to inclusion of a patient into the study.   
539 
 
540 
The study will be conducted in accordance with the Declaration of Helsinki and will be 
541 
conducted in accordance with the ICH GCP guidelines. The sponsor-investigator will comply 
542 
with all applicable regulatory and legal requirements, ICH GCP guidelines and the Declaration 
543 
of Helsinki in obtaining and documenting the informed consent. 
544 
 
545 
STUDY SCHEDULE: 
546 
FIRST PATIENT IN 
2014 FEBRUARY 
SCREENING 
~2000 
RANDOMIZED 
280 
LAST PATIENT RECRUITED 
2020 MAY 
LAST PATIENT IN (COMPLETED) 
2020 DECEMBER 
DATA ANALYSIS 
DECEMBER 2020-JANUARY 2021 
SUBMISSION TO CONGRESS OR 
JOURNAL 
ADA 2021 MAJOR MEDICINE JOURNAL AND/OR 
DIABETES CARE 
547 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
17
Flow Chart 
548 
Visit Type 
Baseline 
Visit 
Hosp-
prior to 
D/C 
TC  
Clinic 
visit 
TC 
TC 
TC 
Clinic 
visit 
TC 
TC 
TC 
TC 
TC 
TC 
Clinic 
visit 
Time-wks.1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
Inf. consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Incl/excl 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Random 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Withdrawal 
criteria 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Drug 
Compliance 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dose 
adjustment 
 
x 
x 
x 
x 
 
x 
 
 
x 
 
x 
 
x 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Phys Exam 
X 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Body wgt 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Body 
measurements 
X2 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
BMI 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
HbA1c 
X3 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Fasting BG 
X3 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Collect 7-
point profile 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Chemistry 
(BMP or CMP) 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adv events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hypoglyc. 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Trial 
material 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug dispense x 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
Drug account 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
Remind 7-
point profile 
prior  
next visit 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
. 
549 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
18
1 TELEPHONE CALLS AND OUTPATIEN VISITS CAN BE COMPLETED ±7 DAYS. 
550 
2 TO BE COMPLETED WITHIN 7 DAYS AFTER D/C (IF NOT COMPLETED AT TIME OF DISCHARGE) 
551 
3 OBTAINED FROM MEDICAL RECORDS (HBA1C≤3MONTHS) 
552 
553 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
19
STUDY DRUGS AND MATERIALS: 
554 
Clinical trial materials will be labeled and should be handled and stored according to the 
555 
respective hospital’s regulatory requirements.  After discharge, patients will be re-started on their 
556 
pre-admission OADs (except for DPP4-inhibitors and selected drugs in the presence of 
557 
contraindication, i.e., metformin and renal failure).  Liraglutide or glargine will be provided 
558 
during the study.  
559 
 
560 
Study medication(s) / devices(s) 
561 
Liraglutide 6.0 mg/mL solution for s.c. injection, provided in 3 mL prefilled pen.   
562 
 
563 
Storage and Drug Accountability of Study Medication(s) 
564 
Liraglutide will be stored and dispensed by the research pharmacy at each institution. The 
565 
liraglutide prefilled pen and glargine will be stored in a refrigerator at a temperature between 
566 
+2°C and +8°C (+36°F and +46°F). 
567 
Once dispensed and in use (after first opening), the liraglutide prefilled pen can be stored for one 
568 
month at room temperature (+15°C to +30°C)/(59°F to 86°F) or in a refrigerator (+2°C to 
569 
+8°C)/(+36°F to +46°F).  The liraglutide prefilled pen must be protected from all sources of light 
570 
and the pen cap should be kept on when the pen is not in use. 
571 
 
572 
 
573 
Drug accountability:  The trial product will be dispensed to each subject as required according 
574 
to treatment group. The research/clinical staff will perform drug accountability by asking 
575 
patients to return all unused, partly used and unused cartridges and vials of liraglutide and 
576 
glargine insulin at each visit.   
577 
 
578 
Randomization and Blinding 
579 
This is an open label randomized controlled trial.  Patients will be randomized consecutively 
580 
using a computer generated randomization table provided by Dr. Limin Peng at the Emory 
581 
School of Public Health. Patient will be randomized (block randomization) based on glucose 
582 
levels (BG>200 or BG<200). The randomization table will be mailed to each institution where a 
583 
member of the research team will be in charge of the randomization process and group 
584 
assignment.  
585 
 
586 
CONCOMITANT ILLNESSES AND MEDICATIONS: 
587 
Background medications: 
588 
 
589 
Metformin.   Metformin is considered background medication (non-investigational medicinal 
590 
product) and will not be provided during the trial.  The total daily dose of metformin prior to 
591 
admission will be restarted at hospital discharge (unless contraindicated = i.e., renal failure or 
592 
eGFR < 45 ml/min) with no dose adjustments occurring during the trial. 
593 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
20
 
594 
Sulfonylurea and Insulin secretagogues.  Sulfonylurea treatment is considered background 
595 
medication (non-investigational medicinal product) and will not be provided during the trial.  
596 
The total daily dose of sulfonylurea prior to admission will be decreased at hospital discharge.  
597 
During the study, no up-titration of sulfonylurea dosage will be allowed.  Dose reduction of SU 
598 
due to hypoglycemia may be allowed at the investigators discretion.  In the event of 
599 
hypoglycemia, the dose of sulfonylurea can be reduced or the drug can be stopped at the 
600 
investigator’s discretion.    
601 
 
602 
Pioglitazone.  Pioglitazone is considered background medication (non-investigational medicinal 
603 
product) and will not be provided during the trial. The total daily dose of pioglitazone prior to 
604 
admission will be restarted at hospital discharge.  No dose adjustment or up-titration will occur 
605 
during the trial; however, in the event of peripheral edema or signs of volume overload, the dose 
606 
of pioglitazone can be reduced or stopped at the investigator’s discretion.    
607 
 
608 
ADVERSE EVENTS: 
609 
Definition:  An AE is any untoward medical occurrence in a subject administered a product, and 
610 
which does not necessarily have a causal relationship with this treatment. An AE is an 
611 
unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease 
612 
temporally associated with the use of a product, whether or not considered related to the product. 
613 
This includes events from the first trial related activity after the subject has signed the informed 
614 
consent and until post treatment follow-up period as defined in the protocol. 
615 
AEs include a clinically significant worsening of a concomitant illness and clinical laboratory 
616 
adverse event (CLAE).  An AE is either a serious AE (SAE) or a non-serious AE. 
617 
 
618 
In this trial, an SAE is an experience that at any dose results in any of the following: 
619 
-Death 
620 
-A life-threatening experience 
621 
-Inpatient hospitalization  
622 
-Persistent or significant disability or incapacity 
623 
-Important medical events that may not result in death, be life threatening or require 
624 
hospitalization 
625 
-Episodes of severe hypoglycemia will be captured as serious AEs. 
626 
 
627 
Severity Assessment Definitions: 
628 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
629 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
630 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
631 
 
632 
Relationship to Trial Product Assessment Definitions: 
633 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
634 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
21
• Possible: A causal relationship is conceivable and cannot be dismissed 
635 
• Unlikely: The event is most likely related to an aetiology other than the trial product 
636 
 
637 
Adverse events will be actively collected from the signing of the informed consent and in all 
638 
following contacts throughout the project. This includes events from all trial related activity after 
639 
the subject has signed the informed consent, and until the post treatment follow-up period, as 
640 
defined in the protocol.  
641 
 
642 
Outcome Categories and Definitions: 
643 
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to 
644 
the level observed at the first trial related activity after the subject signed the informed consent 
645 
• Recovering: The condition is improving and the subject is expected to recover from the event. 
646 
This term should only be used when the subject has completed the trial 
647 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and significant 
648 
disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with sequelae 
649 
should be rated as an SAE 
650 
• Not recovered 
651 
• Fatal 
652 
• Unknown 
653 
 
654 
Reporting of adverse events:  All events meeting the definition of an AE must be collected and 
655 
reported. The events must be recorded in the AE form in a timely manner.  During each contact 
656 
with the trial site staff (site visits and telephone contacts), the subject will be asked about AEs. 
657 
After the ICF is signed, all adverse events related to protocol procedures are to be reported.  
658 
 
659 
The presence of SAE will be reported to the Emory IRB and Novo Nordisk within 24 hours by 
660 
fax or e-mail. A SAE is any adverse event from this study that results in one of the following 
661 
outcomes: death, initial or prolonged inpatient hospitalization, a life-threatening experience (that 
662 
is, immediate risk of dying), persistent or significant disability/incapacity, and events considered 
663 
significant by the investigator for any other reason. 
664 
  
665 
Reporting of pregnancies:  Female subjects who are pregnant or breast-feeding will not be 
666 
recruited in the study.  Female subjects will be instructed to notify the investigator immediately 
667 
if they become pregnant during the trial. The investigator must report any pregnancy in subjects 
668 
who received liraglutide to the Emory IRB and Novo Nordisk. The pregnant subject will be 
669 
asked to provide information about her pregnancy, delivery and the health of her infant until age 
670 
one month. If the infant has a congenital anomaly/birth defect this must be reported and followed 
671 
up as a serious adverse event. 
672 
 
673 
 
674 
 
675 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
22
Medical Events of Special Interest (MESI) 
676 
 Medical Events of Special Interest are those events thought to be [potentially] associated with 
677 
the investigational compound or disease under study. The investigators will collect information 
678 
on medical events of special interest including acute pancreatitis, cardiovascular events (heart 
679 
failure, acute myocardial infarction, and atrial fibrillation), malignancies, and medication errors 
680 
(e.g., incorrect dose of liraglutide or insulin).  
681 
 
682 
LIABILITY AND SUBJECT INSURANCE: 
683 
Financial Obligation. 
 
684 
No additional cost to patients or to the institution will be incurred for research purposes. Patients 
685 
will not be billed for the laboratory work or any test that is being done only for study purposes.  
686 
Novo Nordisk will provide liraglutideat no cost to participants.  Patients will be responsible for 
687 
the cost of their usual ongoing medical care, including procedures and/or non-study medications 
688 
that your doctor requires as part of your usual medical care. 
689 
Research Injuries. 
 
690 
If a patient is injured because of taking part in this study, Dr. Umpierrez and investigators at each 
691 
institution, along with the medical facilities will make medical care available to the patient at the 
692 
patient’s own cost. The only exception is if it is proved that the injury or illness is directly caused 
693 
by the negligence of an Emory or sponsor employee.  “Negligence” is the failure to follow a 
694 
standard duty of care. Financial compensation for such things as lost wages, disability or 
695 
discomfort due to an injury related to the study is not available.   
696 
 
697 
Publication Plan: 
698 
We anticipate completion of the study in October or November 2020.  Data will be analysed in 
699 
December 2020.  One abstract will be submitted to the 2021 American Diabetes Association 
700 
meeting and manuscript(s) will be submitted during the first six months of 2021. 
701 
 
702 
 
 
703 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
23
REFERENCES: 
704 
 
705 
1. 
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in diabetes. 
706 
Diabetes Care. 2004;27 Suppl 1:S94-102. 
707 
2. 
Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. 
708 
Hyperglycemia: an independent marker of in-hospital mortality in patients with 
709 
undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978-82. 
710 
3. 
Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill 
711 
patients. Jama. 2003;290(15):2041-7. 
712 
4. 
Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin 
713 
therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 
714 
2003;31(2):359-66. 
715 
5. 
Pomposelli JJ, Baxter JK, 3rd, Babineau TJ, et al. Early postoperative glucose control 
716 
predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr. 
717 
1998;22(2):77-81. 
718 
6. 
Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion 
719 
followed by subcutaneous insulin treatment in diabetic patients with acute myocardial 
720 
infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 
721 
1995;26(1):57-65. 
722 
7. 
Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and 
723 
hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-97. 
724 
8. 
McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J, Marrie TJ. The relation 
725 
between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with 
726 
community-acquired pneumonia. Diabetes Care. 2005;28(4):810-5. 
727 
9. 
Baker EH, Janaway CH, Philips BJ, et al. Hyperglycaemia is associated with poor 
728 
outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive 
729 
pulmonary disease. Thorax. 2006;61(4):284-9. 
730 
10. 
Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces 
731 
mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac 
732 
Cardiovasc Surg. 2003;125(5):1007-21. 
733 
11. 
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the 
734 
medical ICU. N Engl J Med. 2006;354(5):449-61. 
735 
12. 
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the 
736 
critically ill patients. N Engl J Med. 2001;345(19):1359-67. 
737 
13. 
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical 
738 
Endocrinologists and American Diabetes Association consensus statement on inpatient 
739 
glycemic control. Diabetes Care. 2009;32(6):1119-31. 
740 
14. 
Schnipper JL, Magee M, Larsen K, Inzucchi SE, Maynard G. Society of Hospital 
741 
Medicine Glycemic Control Task Force summary: practical recommendations for 
742 
assessing the impact of glycemic control efforts. J Hosp Med. 2008;3(5 Suppl):66-75. 
743 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
24
15. 
Seley JJ, D’Hondt N, Longo R, et al. Position Statement: Inpatient Glycemic Control. 
744 
Diabetes Educator 2009;35(Suppl 3):65-69. 
745 
16. 
Queale WS, Seidler AJ, Brancati FL. Glycemic control and sliding scale insulin use in 
746 
medical inpatients with diabetes mellitus. Arch Intern Med. 1997;157(5):545-52. 
747 
17. 
Umpierrez GE, Palacio A, Smiley D. Sliding scale insulin use: myth or insanity? Am J 
748 
Med. 2007;120(7):563-7. 
749 
18. 
Korytkowski MT, Salata RJ, Koerbel GL, et al. Insulin therapy and glycemic control 
750 
in hospitalized patients with diabetes during enteral nutrition therapy: a randomized 
751 
controlled clinical trial. Diabetes Care. 2009;32(4):594-6. 
752 
19. 
Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with 
753 
detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients 
754 
with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(2):564-9. 
755 
20. 
Umpierrez GE, Simley D, Jacobs S, et al. RAndomized Study of Basal Bolus Insulin 
756 
Therapy in the Inpatient Management of Patients with Type 2 Diabetes Undergoing 
757 
General Surgery (RABBIT Surgery). Diabetes Care. 2011;34(2):256-61. 
758 
21. 
Nystrom T, Gutniak MK, Zhang Q, et al. Effects of glucagon-like peptide-1 on 
759 
endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J 
760 
Physiol Endocrinol Metab. 2004;287(6):E1209-15. 
761 
22. 
Sokos GG, Bolukoglu H, German J, et al. Effect of glucagon-like peptide-1 (GLP-1) 
762 
on glycemic control and left ventricular function in patients undergoing coronary artery 
763 
bypass grafting. Am J Cardiol. 2007;100(5):824-9. 
764 
23. 
Nathanson D, Ullman B, Lofstrom U, et al. Effects of intravenous exenatide in type 2 
765 
diabetic patients with congestive heart failure: a double-blind, randomised controlled 
766 
clinical trial of efficacy and safety. Diabetologia. 2007;55(4):926-35. 
767 
24. 
Sonne DP, Engstrom T, Treiman M. Protective effects of GLP-1 analogues exendin-4 
768 
and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart. Regul Pept. 
769 
2008;146(1-3):243-9. 
770 
25. 
Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, 
771 
added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and 
772 
weight control compared with adding rosiglitazone or placebo in subjects with Type 2 
773 
diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-78. 
774 
26. 
Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-
775 
treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 
776 
2011;154(2):103-12. 
777 
27. 
McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care 
778 
Clin. 2001;17(1):107-24. 
779 
28. 
Montori VM, Bistrian BR, McMahon MM. Hyperglycemia in acutely ill patients. 
780 
Jama. 2002;288(17):2167-9. 
781 
29. 
Umpierrez GE, Jones S, Smiley D, et al. Insulin analogs versus human insulin in the 
782 
treatment of patients with diabetic ketoacidosis: a randomized controlled trial. Diabetes 
783 
Care. 2009;32(7):1164-9. 
784 


U1111-1139-2991                  OCTOBER 28, 2019 VERS 17 
 
 
 
 
 
 
 
25
30. 
Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo 
785 
in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus 
786 
(LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-55. 
787 
31. 
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect 
788 
of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and 
789 
metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 
790 
2007;30(8):1979-87. 
791 
32. 
Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily 
792 
sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 
793 
diabetes. Curr Med Res Opin. 2007;23(6):1329-39. 
794 
33. 
Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and 
795 
safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with 
796 
type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564-71. 
797 
 
798 
 
799 
  
800 
 
801 
 
802 
 
803