Gut Microbiome Changes Following Liraglutide Treatment in Obese Subjects or Overweight Subjects With Co-morbidities

Study Overview
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Brief Summary
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We performed a multicenter, randomized, double-blind, placebo-controlled 28-week trial. 300 non-diabetic obese subjects or overweight subjects with co-morbidities were randomly assigned. Eligible participants were randomized 2:1 to once-daily subcutaneous injections of either liraglutide or placebo. The primary outcome is to investigate the composition of the gut microbiota from baseline to end of treatment.

Detailed Description
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We performed a multicenter, randomized, double-blind, placebo-controlled 28-week trial. 300 individuals (18-75 years of age, body-mass index ≥30 kg/m2 or BMI 27-30kg/m2 accompanied by at least one weight-related complication (treated or untreated hypertension, dyslipidemia, pre-diabetes)) were randomly assigned. All the patients provided written informed consent before participation. Key exclusion criteria were type 1 or 2 diabetes, the use of medications that cause clinically significant weight gain or loss, previous bariatric surgery, a history of pancreatitis, a history of major depressive or other severe psychiatric disorders, and a family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. Eligible participants were randomized 2:1 to once-daily subcutaneous injections of either liraglutide or placebo using a computer-generated, centrally administered procedure. Patients, investigators, and the sponsor were unaware of the study-group assignments. The primary outcome is to investigate the composition of the gut microbiota from baseline to end of treatment.

Official Title
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Changes of Gut Microbiome Following Liraglutide Treatment in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: A Randomised, Double-blind, Placebo Controlled, Parallel Group, Multi-centre, 28-week Trial

Conditions
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Obesity

Intervention / Treatment
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* Drug: Liraglutide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activity takes place Obesity (BMI ≥30.0 kg/m2); or overweight (BMI ≥27.0 kg/m2) with treated or untreated co-morbid dyslipidemia (Low-density lipoprotein ≥3.38mmol/l (130 mg/dl), or triglycerides ≥1.7mmol/l (150 mg/dl), or high-density lipoprotein <1.04mmol/l (40 mg/dl) for males and <1.30mmol/l (50 mg/dl) for females) and/or hypertension (Systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) Age ≥18 years, ≤75 years Exclusion Criteria: Diagnosis of type 1 or type 2 diabetes per the judgment of the investigator HbA1c ≥6.5% or fasting plasma glucose ≥7.0 mmol/l or 2-hour post-challenge plasma glucose ≥11.1 mmol/liter (at screening) less than 5 kg self-reported change during the previous 3 months Previous treatment with GLP-1 receptor agonists (including liraglutide or exenatide) within the last 3 months Known or suspected hypersensitivity to trial product, related products or other GLP-1 receptor agonist Diet attempts using herbal supplements or over-the-counter medications within 1 months before screening, or use prescription drugs for weight loss within 3 months before screening (for example: orlistat, fenfluramine, maindole ) Or lipid dissolving injection (for example: lipolysis needle) treatment Current or history of treatment with medications that may cause significant weight gain, within 3 months prior to screening, including systemic corticosteroids (more than 1 week),tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g. imipramine, amitriptiline, mirtazapin, paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, lanzapine, valproic acid and its derivatives, and lithium) A history of malignant tumors within 5 years before screening (except for fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical resection, and ductal carcinoma in situ after radical operation) A history of severe heart disease is defined as: decompensated heart insufficiency (NYHA III-IV), and/or a history of unstable angina within 6 months before screening, and a history of myocardial infarction within 12 months Obesity induced by other endocrinologic disorders (e.g. Cushing's Syndrome) Suffer from gastrointestinal motility disorders or obstruction diseases, such as gastroparesis, gastroesophageal reflux disease Any lifetime history of a suicidal attempt or A history of any suicidal behavior in the last month prior to randomization A patient health questionnaire (PHQ-9) score of ≥15 Montreal Cognitive Assessment Scale (MoCA) score <26 at screening; Any suicidal ideation of type 4 or 5 on the Columbian Suicidality Severity Rating Scale (C-SSRS) in the last month prior to randomization Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as thyroid-stimulating hormone >6 mIU/liter or <0.4 mIU/liter Screening calcitonin ≥50 ng/liter Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC) or Personal history of non-familial medullary thyroid carcinoma History of chronic pancreatitis or idiopathic acute pancreatitis or amylase ≥ 3 times the upper limit of normal value during screening ALT or AST or TBiL>3 times the upper limit of normal value during screening Impaired renal function, defined as serum creatinine level ≥1.5mg/dL (132µmol/L) in men or ≥1.4mg/dL (123µmol/L) in women at screening Untreated or uncontrolled severe dyslipidemia, defined as blood LDL-C≥190mg/dl (4.94mmol/L) and/or TG≥500mg/dl (5.65mmol/L) at screening Uncontrolled treated/untreated hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥100 mm Hg) Previous surgical treatment for obesity (excluding liposuction if performed >1 year before trial entry) According to the investigator's judgment, those who have a surgical plan during the trial period (except for minor operations) Participated in any weight loss clinical trials within 3 months before screening, and took any experimental drugs within 1 month (Re-screening is allowed once within the limit of the recruitment period) Known or suspected abuse of alcohol or narcotics within 6 months Poor compliance with restrictions on diet and behavior during screening Females of child-bearing potential who are pregnant, breast-feeding Participants intend to become pregnant or are not using adequate contraceptive methods or subjects who use hormonal contraceptives The investigator considers that it is not suitable for participants (for example, the investigator judges that severe obstructive sleep apnea will cause gastroesophageal reflux).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide<br>Subject receiving liraglutide 3.0 mg subcutaneous (under the skin) injection once daily for 28 weeks. | Drug: Liraglutide<br>* Randomization was performed with the use of a computer-generated system provided by the sponsor. Eligible patients were randomly assigned, in a 2:1 ratio, to receive once-daily subcutaneous injections of liraglutide, starting at a dose of 0.6 mg with weekly 0.6-mg increments to 3.0 mg, or placebo; both groups received counseling on lifestyle modification<br>* Other names: S20200402;|
| Placebo Comparator: placebo<br>Subject receiving placebo 3.0 mg subcutaneous (under the skin) injection once daily for 28 weeks. | Drug: placebo<br>* Randomization was performed with the use of a computer-generated system provided by the sponsor. Eligible patients were randomly assigned, in a 2:1 ratio, to receive once-daily subcutaneous injections of liraglutide, starting at a dose of 0.6 mg with weekly 0.6-mg increments to 3.0 mg, or placebo; both groups received counseling on lifestyle modification<br>* Other names: S20200301;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The composition of the gut microbiota from baseline to end of treatment. | The composition of the gut microbiota from baseline to end of treatment compared to placebo. | week 28 |