Clinical trial NCT02014740
Conditions: Type 2 Diabetes Overweight Obesity
Keywords: Epicardial fat Type 2 diabetes Obesity GLP-1 analogs
Sponsor: University of Miami
Start date: 2014-03-01; Completion date: 2017-03-01
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to learn about the effect of Liraglutide, (Victoza®), on the fat surrounding the heart.Excessive amount of the fat around the heart is common in people with type 2 diabetes and can be associated with poor sugar control. Liraglutide is an injectable prescription medicine that can improve blood sugar control in adults with type 2 diabetes.

Detailed description:

Arms: arm 1: • L-group will be started and dose-escalated to 1.8mg sc once daily according to below schedule: Liraglutide will be administered with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). L-group subjects will need to achieve the final dose of 1.8 mg by at least three weeks from the starting dose. Subjects who would not be able to achieve the dose of 1.8 mg (due to potential side effects) will be advised to lower the dose to 1.2 mg. Metformin regimen will be continued. arm 2: M-group will be treated with Metformin for the duration of the study. Metformin (from 500 mg twice daily to a maximum of 1000 mg twice daily) regimen will be continued to achieve fasting glucose between 80 and 140 mg/dl
Interventions: intervention 1: Liraglutide intervention 2: Metformin
Intervention descriptions: intervention 1: Liraglutide (Victoza) is an acylated analogue of glucagon-like peptide-1 (GLP-1) indicated for the treatment of type 2 diabetes mellitus• L-group will be started and dose-escalated to 1.8mg sc once daily according to below schedule: Liraglutide will be administered with a starting dose of 0.6 mg (after a least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after at least a week on 1.2 mg). L-group subjects will need to achieve the final dose of 1.8 mg by at least three weeks from the starting dose. Subjects who would not be able to achieve the dose of 1.8 mg (due to potential side effects) will be advised to lower the dose to 1.2 mg. Metformin regimen will be continued. . intervention 2: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
1 
 
FINAL REPORT 
 
 
EFFECT OF LIRAGLUTIDE ON EPICARDIAL FAT  
IN SUBJECTS WITH TYPE 2 DIABETES 
 
INVESTIGATOR-INITIATED STUDY 
NCT 2014740 
University of Miami Clinical Trial # 20120811 
 
 
Gianluca Iacobellis MD, PhD 
 
Professor of Clinical Medicine 
Director of University of Miami Hospital Diabetes Service 
 
Division of  Endocrinology, Diabetes and Metabolism, Department of Medicine, 
University of Miami, Miller School of Medicine, Miami, FL, USA 
giacobellis@med.miami.edu 
 
 
 
 
 


2 
 
SUMMARY 
Background Epicardial adipose tissue (EAT) is a peculiar visceral fat depot with anatomical and 
functional contiguity to the myocardium and coronary arteries. EAT is a highly inflammatory 
tissue enriched with genes involved in endothelial function, coagulation, immune signalling, lipid 
metabolism, potassium transport and apoptosis. EAT is associated with coronary artery disease, 
diabetes and obesity.  EAT is easily measurable and an emerging therapeutic target that responds 
and modifies to medications targeting the adipose tissue Liraglutide, an analogue of glucagon-like 
peptide-1 (GLP-1), is indicated for the treatment of type 2 diabetes mellitus. Liraglutide has 
recently shown to reduce cardiovascular risk.  Nevertheless, whether liraglutide could reduce EAT 
is unknown.  
Aim The primary objective of this interventional study was to evaluate whether liraglutide can 
cause a significant and rapid reduction of EAT, organ-specific visceral fat and cardiovascular risk 
factor itself, in overweight/obese type 2 diabetic patients.  
 
Methods To test this hypothesis we performed a 6-month randomized, open-label, controlled 
study in 100 type 2 diabetic subjects with body mass index (BMI) ≥ 27 kg/m2 and HemoglobinA1c 
(HbA1c) ≤ 8% on metformin monotherapy. Individuals were randomized in 2 groups to receive 
additional liraglutide up to 1.8 mg sc once daily (n=55) or to remain on metformin up to 1000 mg 
twice daily (n=45). Ultrasound-measured EAT thickness was measured at baseline, 3 and 6-month 
follow ups.  
 
Results In the liraglutide group EAT decreased from 9.6±2 to 6.8±1.5 and 6.2±1.5 mm (p< 0.001), 
accounting for a -29% and -36% of reduction at 3 and 6 months, respectively, whereas there was 
no EAT reduction in the metformin group; BMI and HbA1c improved only in the liraglutide group 
after 6 months.  
 
Conclusions. For the first time, we found that liraglutide added to metformin caused an 
unprecedented, close to 40%, reduction of EAT. EAT reduction was not only quantitatively 
important, but also very rapid, as the earliest reduction, of almost 30%, occurred within 3 months.  
We suggest that the recently reported (LEADER study) beneficial cardiovascular effects 
associated with liraglutide treatment may be EAT-mediated.  
 
 
 


3 
 
PROTOCOL 
STUDY RATIONALE 
This study was designed to reflect a real-life and common clinical scenario of type 2 diabetic 
patients presenting with fairly good glucose control, but at mild-moderate cardiovascular risk. We 
intentionally chose HbA1c ≤ 8% to rule out the confounding effect of a poor diabetes control on 
study outcomes. Also, as prior treatment with metformin was a criteria for entry into the study, we 
could evaluate the independent effect of liraglutide on EAT. Epicardial fat has recently shown to 
be a modifiable and measureable cardiovascular risk factor, and therefore it could well serve as 
primary outcome of the study. In addition, EAT is known to be higher in subjects with diabetes, 
due to its strong correlation with visceral adiposity and insulin resistance.  
METHODS 
Study design 
This was a randomized, open-label controlled 6-month study in 100 overweight/obese (body mass 
index (BMI) ≥27 kg/m2) type 2 diabetic subjects on metformin monotherapy.  Patients were 
screened among those routinely referred to the Division of Endocrinology, Diabetes and 
Metabolism out-patient clinic at the University of Miami. Approximately 500 patients were 
screened between January 2014 and January 2016.  All the patients provided written informed 
consent before participation. The study was approved by the University of Miami Institutional 
Review Board (# 20120811) and conducted in accordance with the Declaration of Helsinki and 
Good Clinical Practice guidelines. 
 
Study Criteria and Treatment Arms 
Patients were enrolled on the basis of the following inclusion criteria:  type 2 diabetes, HbA1c ≤ 
8 % measured at least 1 month prior to the study, BMI ≥27 kg/m2, prior treatment with metformin 
only, age ≥ 18 and ≤ 65 years old. Exclusion criteria were the following: type 1 diabetes, current 
use of insulin, other GLP-1 receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, 
pramlintide, sulfonylureas, thiazolidinediones, history of diabetic ketoacidosis, history of diabetic 
macro or micro vascular complications, known contra-indications to liraglutide, such as previous 
history of pancreatitis or medullary thyroid carcinoma, personal or family history of multiple 
endocrine neoplasia type 2, renal or liver or heart failure, acute or chronic infective diseases, cancer 
or chemotherapy, current use of systemic corticosteroids or in the 3 months prior this study, known 
or suspected allergy to liraglutide, excipients, or related products, pregnant, breast-feeding or the 
intention of becoming pregnant. Eligible individuals were randomly assigned to receive additional 
liraglutide, or to remain on metformin.  The liraglutide-group was started on liraglutide (Victoza®) 
up to 1.8 mg s.c. once daily. Liraglutide was administered with a starting dose of 0.6 mg (for a 
least one week) and subsequent increments to 1.2 mg (after a least one week) and to 1.8 mg (after 
at least a week on 1.2 mg). Liraglutide-group subjects had to achieve the final dose of 1.8 mg by 
at least three weeks from the starting dose. Subjects who were not able to tolerate the dose of 1.8 
mg, were advised to lower the dose to 1.2 mg. Patients received full training and titration 


4 
 
instructions by a registered nurse.  Metformin regimen was continued. Metformin-group was 
treated with metformin monotherapy for the duration of the study at the dosage from 500 mg twice 
daily to a maximum of 1000 mg twice daily. Both groups received lifestyle and diabetes education, 
as part of the standard care. Patients in both groups were advised to continue with their usual 
dietary habit and physical activity. Once patient eligibility and written consent were obtained, the 
study participants were scheduled for the baseline clinic visit. Each patient underwent a 
transthoracic echocardiographic study, full physical examination and a fasting blood drawn for 
measurement of blood glucose and haemoglobinA1c (HbA1c) and other parameters. Study 
patients were then scheduled for follow-up visits at 3 and 6 months and the same visit procedures 
were repeated at each follow-up visit. 
Study procedures 
Echocardiographic Epicardial Fat Thickness.   EAT thickness was measured according to the 
method first described and validated by Iacobellis et al. Briefly, EAT was identified as the echo-
free space between the outer wall of the myocardium and the visceral layer of pericardium. EAT 
thickness was measured perpendicularly on the free wall of the right ventricle at end-systole in 
three cardiac cycles. Maximum EAT thickness was measured at the point on the free wall of the 
right ventricle along the midline of the ultrasound beam, perpendicular to the aortic annulus, used 
as the anatomical landmark for this view. The average value of three cardiac cycles was calculated 
and used for analysis. Echocardiograms were done by an experienced operator who was blinded 
to the patients’ data. Intra-observer reproducibility of echocardiographic measurement of EAT was 
assessed by the intra-class correlation coefficient. 
Physical Examination All anthropometric measures were obtained by the study nurse at each 
visit. Height (in cm) and weight (in kg) were measured, and BMI was automatically calculated as 
weight in kilograms divided by the square of height in meters (kg/m2). Blood pressure was 
measured in the seated position, using an automated cuff and digital readout, and entered by the 
study nurse into the electronic database. Resting heart rate was also measured 
Blood Measurements Fasting blood samples for fasting blood glucose (FBG) and HbA1c were 
obtained from all individuals according to the study design timetable. Blood parameters were 
measured according to standard and previously described procedures. Fasting comprehensive 
metabolic panel and lipid profile were also measured at each visit as standard diabetes care. 
Follow up of glucose profile Study patients were advised to monitor their capillary glucose twice 
daily, fasting in the morning and post-prandially. Glucose profile was tracked weekly by the 
research coordinator and/or principal investigator who were in contact with study patients 
throughout MyUHealth e-mail system or by telephone.  
 
 


5 
 
STATISTICAL ANALYSIS  
Primary outcome of the study was EAT changes on liraglutide combined to metformin vs 
metformin monotherapy; secondary outcomes were determinants of HbA1c changes during 
treatment. Assuming a difference of 1±0.5 mm in EAT to be clinically significant and using a 
significance level of p<0.05 and 90% power, the current study sample size was sufficient to detect 
statistical significant differences in EAT between liraglutide and metformin group. Continuous 
variables were considered as age-adjusted and sex-adjusted means with their standard deviations 
(SDs).  Patients were randomized consecutively using a computer generated randomization table. 
Two-sample t test with 95 % CI for difference was performed to evaluate differences between the 
two groups at baseline. Two-way ANOVA was used to calculate changes (∆) in EAT and other 
study variables between baseline, 3 and 6 months in both groups. Relations between study 
variables were calculated using simple linear regression analysis. Two-tailed p < 0.05 indicates 
statistical significance. Statistical analysis was performed using Minitab 17 Software.  
 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
Consent (Permission) to Participate in a Clinical Research Study 
Title of Study:  
EFFECT OF LIRAGLUTIDE ON EPICARDIAL FAT 
IN SUBJECTS WITH TYPE 2 DIABETES 
 
Principal Investigator: Dr Gianluca Iacobellis MD PhD 
Department: Medicine, Division of Endocrinology, Diabetes and Metabolism 
Phone Number:  305 243 3203 
Email Address: giacobellis@med.miami.edu 
 
Study Contact Name: Dr Gianluca Iacobellis MD PhD 
 
Study Contact Telephone Number:  305 243 3203 
 
Study Contact Email:  giacobellis@med.miami.edu 
 
 
READ THE FOLLOWING CAREFULLY  
 
This consent form contains important information, so that you can decide if you wish to take part in this study. 
If you have any questions that remain unanswered, please ask the study doctor or one of his/her research study 
personnel before signing this form. 
 
You are being asked to volunteer to participate in a research study.  Before you give your consent (permission) 
for you to be part of this study, please read the following and ask as many questions as necessary to be sure that 
you understand what your participation will involve.    
 
PURPOSE 
The purpose of this research study is to learn about the effect of Liraglutide, (Victoza®), on the fat of the heart. 
Excessive amount of the fat around the heart is common in people with type 2 diabetes and can be associated 
with a poor sugar control. Victoza® is an injectable prescription medicine that can improve blood sugar control 
in adults with type 2 diabetes. 
 
 
 
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 1 OF 6 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
NUMBER OF STUDY PARTICIPANTS 
 
If you decide to be in this study, you will be one of approximately 100 people in this research study. 
 
DURATION OF STUDY 
 
The study consists of three visits. Each visit will take around 1 to 1 and 1/2 hours. Your total involvement in the 
study will be about 6 months.  
 
PROCEDURES 
During the first visit you will be assigned, by chance, to one of two study groups (Victoza + Metformin or 
Metformin only). In each visit (Visits 1-3) you will undergo the same research procedures: basic body 
measurements as your weight, height, waist and hip circumference; have approximately one tsp of 5 ml blood 
drawn; and an ultrasound of the heart.   
 
The heart ultrasound (called echocardiogram) is a simple test that measures the morphology of the heart and 
that can identify the amount of the cardiac fat (called epicardial fat). The procedure is performed by placing a 
probe on the outside of the chest wall with a gel-like substance to transmit harmless waves into the body. The 
gel allows the ultrasound beams to “see” your heart. You will be asked to remove your clothing from the waist 
up and women will be given a gown to wear during the procedure. If you need help, the investigator will assist 
you in getting onto the exam table, where you will be asked to lie on your left side. The test may take 15 to 30 
minutes. 
 
We will also collect information from your medical records for research purposes.  
 
RISKS AND DISCOMFORTS 
 
Medication: Victoza and Metformin may cause mild and usually well-tolerable gastro-intestinal side effects. 
Victoza may increase the risk of thyroid C-cell tumor, a rare form of thyroid tumor, in mice. No evidences of 
increased risk of cancer in humans have been reported.  
Blood Draw The risks of blood drawing include: fainting, the occurrence of temporary discomfort and/or bruise 
at the site of puncture; rarely, infection or the formation of a small clot or swelling to the vein and surrounding 
area may occur. 
 
 
Echocardiogram  
An echocardiogram is painless and safe. It does not use radiation and so carries none of the associated risks.  
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 2 OF 6 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
 There is a low chance for slight discomfort—like pulling off a Band-Aid—when the electrodes are removed 
from 
your 
skin. 
 
 
Breach of Confidentiality (Data Collection) 
 
There is a risk of breach of confidentiality with your medical record information; however every precaution will 
be taken to protect the records. 
 
BENEFITS 
 
This research may improve your diabetes control and may also benefit society by gaining new knowledge on 
the drugs available to treat diabetes.  
 
ALTERNATIVES 
 
You have the alternative not to participate in this study. You can decide to stop participating in this study at any 
time. Not participating in this study will not affect your medical care. You will receive standard care such as 
diabetes education, life style and dietary counseling, assessment and monitoring of glucose control, screening 
and prevention of diabetes complications, regardless of your participation in this study 
 
COSTS 
 
There is no cost for you in participating in this research study. You are not responsible for costs of the 
ultrasounds, physical examination, blood draws performed.  You will be not responsible for the cost of the 
drugs that will be given (neither Metformin or Victoza or both). 
 
INCENTIVES/PAYMENTS TO PARTICIPANTS 
 
You will not be paid for taking part in this study.   
 
COMPENSATION FOR STUDY-RELATED INJURY  
 
You may be exposed to risk of injury from participation in this study. If injury occurs, treatment will in most 
cases be available. If you have insurance, your insurance company may or may not pay for these costs. If you 
do not have insurance, or if your insurance company refuses to pay, you will be expected to pay. Funds to 
compensate for pain, expenses, lost wages and other damages caused by injury are not available. 
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 3 OF 6 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL FROM STUDY    
 
You participation in this study is voluntary. You may refuse to participate, or withdraw from the study at any 
time, without penalty or loss of benefits to which you are otherwise entitled.  This will not affect the medical 
care you receive from the study doctor or UM/Jackson Memorial Hospital. You must tell the study doctor if you 
wish to stop taking part in the study.  Your  participation in this study may be discontinued, without your 
consent, at any time by the study doctor, if he/she believes that participation in the study is no longer in your 
best interest.  The Institutional Review Board (IRB), regulatory authorities, or the sponsor may also discontinue 
your participation in the study.  
Dr Gianluca Iacobellis 
Division of Endocrinology, Diabetes and Metabolism  
1400 NW 10th Ave 
Miami, Fl, 33136 
 
If you cancel your permission after you have started in the study, the study staff and the Study doctor will stop 
collecting your health information.  Although they will stop collecting new information about you they may 
need to use the information they have already collected to evaluate the study results.  If you start the study and 
then you cancel your permission, you will not be able to continue to participate in the study.  
 
CONFIDENTIALITY 
 
By signing this consent, you authorize the Investigator(s) and his/her/their staff to access your medical records 
and associated information as may be necessary for purposes of this study. Your records and results will not be 
identified as pertaining to you in any publication without your expressed permission. The Investigator and 
his/her collaborators, staff will consider your records confidential to the extent permitted by law. The Food and 
Drug Administration (FDA) and Department of Health and Human Services (DHHS) may review these research 
records. Your health care providers, including authorized University or Hospital staff not involved in the study.  
Your records may also be reviewed for audit purposes by authorized University of Miami employees or other 
agents who will be bound by the same provisions of confidentiality. 
 
INCLUSION OF CERTAIN STUDY TEST AND PROCEDURE RESULTS IN YOUR MEDICAL 
RECORD 
 
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 4 OF 6 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
If you are or have been a patient at a University of Miami facility, then you will have a University of Miami 
medical record.  The University of Miami has implemented an electronic medical record system known as 
UChart, which will improve access to information important to your medical care.   
 
Since this study is related to your medical care, the University of Miami electronic system will show that you 
are a research participant and the consent form you sign will be included in your electronic medical record.  In 
order to provide as complete a record as possible, some of your study-related research information may also be 
placed in your University of Miami medical record.  This information will be available to University of Miami 
health-care providers and other authorized University of Miami staff who may not be engaged in the research 
study but who are involved in the provision of your medical care.  The confidentiality of the results and other 
documents in the University of Miami medical record will be governed by laws, such as HIPAA, that concern 
medical records.   
 
It is suggested that you tell any non University of Miami provider that you are participating in University of 
Miami research and that this information may be made available at your request.  
 
The patients that opt to take part in the study will have their name recorded on the consent form. All data for 
participants will be identified only by a number that will correspond to a list of participants. The list of 
participants that the identification numbers correspond to will be stored in locked filing cabinets. The list will 
only be accessed by the principal investigator to confirm the correct identification number is reported by the 
patient in all visits. 
 
The study site personnel may use your information to notify you of appointments, send you appointment 
reminders, or schedule additional appointments.   
 
WHOM TO CONTACT  
 
If at any time you have any questions about the study, you may contact Dr Gianluca Iacobellis 305- 243-3203 
 
In case of study-related injury, please contact Dr Gianluca Iacobellis 305- 243-3203 
 
If you have any questions relating to your rights as a research subject, please contact the University of Miami’s 
HUMAN SUBJECTS RESEARCH OFFICE (HSRO), at 305-243-3195. 
 
AGREEMENT OF DECISION TO PARTICIPATE 
 
You will receive a copy of this signed informed consent form. 
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 5 OF 6 
 


eProst ID: «IRBNo» 
«Approved» 
 
 
Approval Date: «ApproveDate» 
 Exp. Date: «ExpireDate» 
«ApproveAt» 
University of Miami - Medical Informed Consent Form 
EPROST # 20120811 
 
 
I have read this consent, which is printed in English (a language which I read and understand).  This study has 
been explained to my satisfaction and all of my questions relating to the study procedures, risks and 
discomforts, and side effects have been answered.  If I have any further questions regarding this study, or in the 
event of a study-related injury, I should contact the appropriate person named above.  Based on this 
information, I voluntarily agree to give permission (consent) for me to take part in this study. 
 
________________  
__________________ 
Signature of Participant 
 
 
 
Date 
 
________________ 
Printed Name of Participant 
 
 
 
 
_______________ 
 
 
____________ 
Signature of Person Obtaining Consent 
 
 
Date 
 
________________ 
Printed Name of Person Obtaining Consent 
Revised 12/10/2010              
 
 
NAME: 
_________________________________ 
 
MRN: 
__________________________________ 
 
AGE: ___________ DOB: 
_____/_____/______ 
 
PAGE 6 OF 6