Impact of Liraglutide 3.0 on Body Fat Distribution

Study Overview
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Brief Summary
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This study is a clinical study to investigate the efficacy of liraglutide compared to placebo in reducing visceral adiposity measured by MRI in overweight or obese subjects at high risk for cardiovascular disease after 40 weeks on-treatment.

Detailed Description
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Obesity has long been recognized as a risk factor for all-cause mortality and morbidity, including the development of cardiovascular and metabolic diseases such as coronary artery disease, hypertension, insulin resistance, diabetes, and dyslipidemia. Obesity has recently been formally defined as a chronic disease characterized by pathophysiological processes that result in increased adipose tissue mass and can result in increased morbidity and mortality. Although the health risks associated with obesity are clear, there is an emerging appreciation that obesity per se, as defined by simple anthropometric measures such as waist circumference or body mass index (BMI), is neither necessary nor sufficient to promote cardiometabolic disease and atherosclerotic cardiovascular disease (ASCVD) risk. As a result, BMI alone is an insufficient marker of risk and may not accurately identify individuals at elevated risk for ASCVD. There is a pressing need to more accurately phenotype obesity to identify individuals at elevated risk for ASCVD that may benefit from more intensive preventive and therapeutic strategies

Official Title
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Impact of Liraglutide 3.0 on Body Fat Distribution, Visceral Adiposity, and Cardiometabolic Risk Markers In Overweight and Obese Adults at High Risk for Cardiovascular Disease

Conditions
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Obesity, Visceral, Cardiovascular Diseases, Fat Disorder

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 35 years Able to provide informed consent BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with metabolic syndrome Metabolic syndrome is defined as at least three of the following:3 waist circumference > 102 cm (40 in) in men and 88 cm (35 in) in women triglycerides > 150 mg/dL or on treatment for hypertriglyceridemia HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women blood pressure > 130/85 mmHg or on treatment for hypertension fasting glucose > 100 mg/dL Exclusion Criteria: Treatment with Glucagon-like peptide-1 (GLP-1) receptor agonists (including liraglutide, exenatide or others as they become available), dipeptidyl peptidase 4 (DPP-4) inhibitors or insulin within the last 3 months. Receipt of any anti-obesity drug or supplement within 1 month prior to screening for this trial. Self-reported or clinically documented history of significant fluctuations (>5% change) in weight within 3 months prior to screening for this trial. History of diabetes mellitus (type 1 or 2) or on treatment with anti-diabetes medication. History of chronic pancreatitis or idiopathic acute pancreatitis (current or prior history). History of gallbladder disease (cholelithiasis or cholecystitis). Chronic kidney disease stage III or greater (eGFR<60 mL/min). Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome). Current or history of treatment with medications that may cause significant weight gain, within 1 month prior to screening for this trial, including systemic corticosteroids (except for a short course of treatment, i.e., 7- 10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g., imipramine, amitryptiline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium). Diet attempts using herbal supplements or over-the-counter medications within 1 month prior to screening for this trial. Current participation in an organized weight reduction program or within the last 1 month prior to screening for this trial. Participation in a clinical trial within the last 3 months prior to screening for this trial. Familial or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. Personal history of non-familial medullary thyroid carcinoma. History of Major Depressive Disorder within the last 2 years. History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder. Any lifetime history of a suicide attempt. A history of any suicidal behavior in the last month prior to randomization. Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of the Investigator. Known or suspected hypersensitivity to trial product(s) or related product(s). Known or suspected abuse of alcohol or narcotics. Language barrier, mental incapacity, unwillingness or inability to understand. Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods. These include abstinence and the following methods: diaphragm with spermicide, condom with spermicide (by male partner), intrauterine device, sponge, spermicide, Norplant®, Depo-Provera® or oral contraceptives.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide 3.0 mg<br>Drug: Liraglutide Active Drug Other Names: Saxenda Escalate the liraglutide (active) dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day through subcutaneous injection. | Drug: Liraglutide<br>* Liraglutide is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the liraglutide dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.<br>* Other names: Saxenda;|
| Placebo Comparator: Placebo<br>Drug: Placebo (for Liraglutide at a concentration of 6.0 mg/mL) Placebo tablet manufactured to mimic Liraglutide at a concentration of 6.0 mg/mL Other Names: Placebo Saline injection Escalate the Placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day through subcutaneous injection. | Drug: Placebo<br>* Placebo is administered once daily by subcutaneous injections with the pen-injector, either in the abdomen, thigh or upper arm. Injections can be done at any time of day irrespective of meals. Subjects will be instructed to escalate the placebo dose to 3.0 mg/day over a 4 week period following an initial dose of 0.6 mg/day and weekly dose escalation steps of 0.6 mg/day.<br>* Other names: Saline injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Percent Reduction in Visceral Adipose Tissue Mass Measured by MRI | The effect on relative percent reduction from baseline in visceral adipose tissue mass measured by MRI after 40 weeks on treatment. Positive numbers reflect the reduction in the value from baseline to study endpoint as a percent of the baseline. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Reduction in Visceral Adipose Tissue Volume | The effect on absolute reduction from baseline in visceral adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Reduction in Body Weight | The effect on relative percent reduction from baseline in body weight after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Absolute Reduction in Body Weight | The effect on absolute reduction from baseline in body weight after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Reduction in Waist Circumference | The effect on relative percent reduction from baseline in waist circumference after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Absolute Reduction in Waist Circumference | The effect on absolute reduction from baseline in waist circumference after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Reduction in Total Body Adipose Tissue | The effect on relative percent reduction from baseline in total body adipose tissue (fat) mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Absolute Reduction in Total Body Adipose Tissue | The effect on absolute reduction from baseline in total body adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Reduction in Abdominal Subcutaneous Adipose Tissue | The effect on relative percent reduction from baseline in abdominal subcutaneous adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Absolute Reduction in Abdominal Subcutaneous Adipose Tissue | The effect on absolute reduction from baseline in abdominal subcutaneous adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Relative Percent Reduction in Lower Body Subcutaneous Adipose Tissue | The effect on relative percent reduction from baseline in lower body subcutaneous adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Absolute Reduction in Lower Body Subcutaneous Adipose Tissue | The effect on absolute reduction from baseline in lower body subcutaneous adipose tissue mass measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Relative Percent Reduction in Liver Fat Percent | The effect on relative percent reduction from baseline in liver (hepatic) fat percentage measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Negative values reflect an increase in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Absolute Reduction in Liver Fat Percent | The effect on absolute reduction from baseline in liver (hepatic) fat percentage measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Negative values reflect an increase in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Reduction in Total Body Lean Volume | The effect on relative percent reduction from baseline in total body lean volume (fat-free mass) measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Absolute Reduction in Total Body Lean Volume | The effect on absolute reduction from baseline in total body lean volume (fat-free mass) measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Relative Percent Reduction in Total Thigh Muscle Volume | The effect on relative percent reduction from baseline in total thigh muscle volume measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Absolute Reduction in Total Thigh Muscle Volume | The effect on absolute reduction from baseline in total thigh muscle volume measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. | Baseline, 40 weeks | 
| Relative Percent Reduction in Mean Anterior Thigh Muscle Fat Infiltration Percent | The effect on relative percent reduction from baseline in mean anterior thigh muscle fat infiltration percent measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Negative values reflect an increase in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower risk for metabolic disease. | Baseline,40 weeks | 
| Absolute Reduction in Mean Anterior Thigh Muscle Fat Infiltration Percent | The effect on absolute reduction from baseline in mean anterior thigh muscle fat infiltration percent measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. Negative values reflect an increase in the value from baseline to study endpoint. Reduction in this variable is believed to be associated with lower risk for metabolic disease | Baseline,40 weeks | 
| Change From Baseline in VAT/SAT Ratio | The effect on absolute reduction from baseline in Visceral adipose tissue/subcutaneous adipose tissue (VAT/SAT) ratio measured by MRI after 40 weeks on treatment versus placebo. Positive numbers reflect the reduction in the value from baseline to study endpoint. This is the ratio of visceral adipose tissue to subcutaneous adipose tissue and it is thought that lower values (relatively less visceral adipose tissue) are better. | Baseline, 40 weeks | 
| Change From Baseline in Total Fat/Fat-free Mass Ratio | The effect on absolute change from baseline in total fat/fat-free mass ratio measured by MRI after 40 weeks on treatment versus placebo. This is a ratio of fat to lean mass and it is believed that lower values (less fat relative to lean mass) is better. | Baseline, 40 weeks | 
| Relative Percent Change in Fasting Blood Glucose | The relative percent change in fasting blood glucose from baseline to study end point as a percent of baseline by treatment group. Negative values reflect a reduction. This is a blood based biomarker for diabetes in which normal levels are desirable (70-100 mg/dL). | Baseline, 40 weeks | 
| Relative Percent Change in Insulin | The relative percent change in insulin from baseline to study end point as a percent of baseline by treatment group. Positive values reflect an increase. Collection was impacted by coronavirus disease 2019 (COVID-19) and limitations to in person study visits, limiting complete collection of data for this measure. This is a blood based biomarker in which lower fasting levels are desirable. | Baseline, 40 weeks | 
| Relative Percent Change in HOMA-IR | The relative percent change in HOMA-IR from baseline to study end point as a percent of baseline by treatment group. Positive values reflect an increase. Collection was impacted by coronavirus disease 2019 (COVID-19) and limitations to in person study visits, limiting complete collection of data for this measure. The relative percent change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) from baseline to study end point by treatment group measures insulin resistance. Levels above 1.9 signal early insulin resistance, while levels above 2.9 signal significant insulin resistance. There will be optimal insulin sensitivity if HOMA-IR is less than 1. | Baseline, 40 weeks | 
| Relative Percent Change in C-reactive Protein | The relative percent change in biomarker of inflammation: C-reactive protein (CRP) from baseline to study end point as a percent of baseline by treatment group. Negative values reflect a decrease. Collection was impacted by coronavirus disease 2019 (COVID-19) and limitations to in person study visits, limiting complete collection of data for this measure. This is a blood based test for which lower values are associated with less inflammation and lower risk for cardiovascular events. | Baseline, 40 weeks | 
| Relative Percent Change in Triglyceride/HDL-C Ratio | The relative percent change in triglyceride/HDL-C ratio from baseline to study end point as a percent of baseline by treatment group. Negative values reflect a decrease. Collection was impacted by coronavirus disease 2019 (COVID-19) and limitations to in person study visits, limiting complete collection of data for this measure. Lower ratio of triglycerides to HDL-cholesterol is associated with less insulin resistance and lower cardiovascular risk. | Baseline, 40 weeks | 
| Relative Percent Change in Nt-proBNP | The relative percent change in N-terminal Pro Brain Natriuretic Peptides (Nt-proBNP) from baseline to study end point as a percent of baseline by treatment group. Negative values reflect a decrease. Collection was impacted by coronavirus disease 2019 (COVID-19) and limitations to in person study visits, limiting complete collection of data for this measure. NT-proBNP is a blood based biomarker. Lower levels are associated with lower risk for heart failure and cardiovascular events. | Baseline, 40 weeks | 
| Absolute Change in Fasting Blood Glucose | The change in fasting blood glucose from baseline to study end point by treatment group. | Baseline,40 weeks | 
| Absolute Change in Insulin | The absolute change in insulin from baseline to study end point by treatment group. Collection was impacted by COVID-19 and changes to study visits. | Baseline, 40 weeks | 
| Absolute Change in HOMA-IR | The absolute change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) from baseline to study end point by treatment group measures insulin resistance. Levels above 1.9 signal early insulin resistance, while levels above 2.9 signal significant insulin resistance. There will be optimal insulin sensitivity if HOMA-IR is less than 1. Collection was impacted by COVID-19 and changes to study visits. | Baseline, 40 weeks | 
| Absolute Change in CRP | The change in Markers of inflammation: C-reactive protein (CRP) from baseline to study end point by treatment group. Collection was impacted by COVID-19 and changes to study visits. This is a blood based test for which lower values are associated with less inflammation and lower risk for cardiovascular events. | Baseline, 40 weeks | 
| Absolute Change in Triglyceride/HDL-C Ratio | The change in triglyceride/HDL-C ratio from baseline to study end point by treatment group. Collection was impacted by COVID-19 and changes to study visits. Lower ratio of triglycerides to HDL-cholesterol is associated with less insulin resistance and lower cardiovascular risk. | Baseline, 40 weeks | 
| Absolute Change in Nt-proBNP | The change in N-terminal Pro Brain Natriuretic Peptides (Nt-proBNP) from baseline to study end point by treatment group. Collection was impacted by COVID-19 and changes to study visits. NT-proBNP is a blood based biomarker. Lower levels are associated with lower risk for heart failure and cardiovascular events. | Baseline, 40 weeks | 
| Change From Baseline in Heart Rate | The change in heart rate/pulse from baseline to study endpoint visit by treatment group. | Baseline, 40 weeks | 
| Change From Baseline in Blood Pressure | The change in systolic blood pressure from baseline to study endpoint visit by treatment group. | Baseline, 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Visceral, Cardiovascular Disease, Fat