Semaglutide's Weight Loss Effects in Obesity

Clinical Assessment of Semaglutide-Induced Weight Reduction in Obese Populations

This is a non-randomized, concurrent, parallel-controlled clinical trial. The objective of this trial is to determine the relationship between weight loss responsiveness to semaglutide in obese patients and their gut microbiota.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity
• Intervention / Treatment: Drug: Semaglutide Subcutaneous Injection

Detailed Description

Obesity has gradually emerged as a major public health concern. Although the GLP-1 receptor agonist semaglutide is used for chronic weight management in obese patients, significant individual variability exists in its weight-loss efficacy, and the underlying mechanisms remain unclear. Our preliminary studies have revealed that the low-response group to semaglutide exhibits significantly reduced plasma drug concentrations accompanied by a marked increase in the abundance of Prevotella copri (P. copri). Colonization with P. copri was found to attenuate semaglutide's weight-reducing effects in obese mice while decreasing its plasma concentration. In vitro experiments demonstrated an 85% degradation rate of semaglutide after 24-hour co-cultivation with P. copri. Based on these findings, we hypothesize that intestinal P. copri may produce specific enzymes that metabolize semaglutide, thereby influencing its therapeutic efficacy. This project aims to investigate the individual variability in semaglutide response through multi-omics approaches including fecal metagenomic sequencing. Utilizing in vitro bacterial screening platforms combined with gut microbiota gene knockout/heterologous expression systems, protein isolation-activity tracking, and structural characterization, we will elucidate the mechanisms underlying gut microbiota-mediated semaglutide resistance from microbial, animal, and clinical perspectives. The outcomes may identify novel therapeutic targets to overcome semaglutide resistance in weight management.

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jia Liu; Phone Number: 010-85231710; Email: liujia0116@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-60 years
• BMI ≥ 30 kg/m²
• At least one self-reported unsuccessful attempt at lifestyle weight loss

Exclusion Criteria:

• Weight change (self-reported) > 5% in the past 3 months prior to screening
• Use of any medication for obesity indication in the past 3 months prior to screening.
• Use of antidiabetic medications in the past 3 months, or HbA1c ≥ 6.5%, or a history of Type 1 or Type 2 diabetes.
• Use of immunosuppressants, corticosteroids, antidiarrheal drugs, antibiotics, probiotics, lipid-lowering medications, and/or other gastrointestinal motility drugs in the past 3 months prior to screening.
• A history of endocrine-related overweight or obesity diagnoses, such as Cushing's syndrome.
• Triglycerides ≥ 500 mg/dL (5.65 mmol/L) at screening.
• Known clinically significant gastric emptying abnormalities (e.g., severe diabetic gastroparesis or gastric outlet obstruction), gastrointestinal diseases, or surgical history.
• Thyroid dysfunction.
• History of mental illness.
• History or family history of multiple endocrine neoplasia or medullary thyroid cancer, or calcitonin ≥ 6 pg/mL.
• Abnormal liver function at screening, defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3*ULN.
• Abnormal kidney function at screening, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.75m².
• History of cardiovascular disease.
• History of malignancy.
• Pregnancy or breastfeeding.
• Any other physiological, psychological, or other conditions deemed by the investigator as unsuitable for participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: SLR group; Patients with a weight loss of less than 5% at the end of treatment are defined as semaglutide low responders (SLR).	Drug: Semaglutide Subcutaneous Injection; All subjects received subcutaneous injections of semaglutide over a 28-week treatment period, which included an initial 16-week dose-escalation phase. The escalation protocol began with a starting dose of 0.25 mg administered once weekly. Every 4 weeks, the dose was gradually increased in a stepwise manner to 0.5 mg, 1.0 mg, 1.7 mg, and finally 2.4 mg, each administered once weekly.
Active Comparator: SHR group; Patients who experience a weight reduction of ≥15% at the treatment endpoint are defined as high responders to semaglutide (SHR).	Drug: Semaglutide Subcutaneous Injection; All subjects received subcutaneous injections of semaglutide over a 28-week treatment period, which included an initial 16-week dose-escalation phase. The escalation protocol began with a starting dose of 0.25 mg administered once weekly. Every 4 weeks, the dose was gradually increased in a stepwise manner to 0.5 mg, 1.0 mg, 1.7 mg, and finally 2.4 mg, each administered once weekly.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight	When measuring the subject's body weight, ensure shoes, hats, and heavy clothing or accessories are removed, and record the measurement to the nearest 0.1 kg.	Weight changes will be measured at the following time points: before treatment, and at weeks 4, 8, 12, 16, 20, 24, and 28 after treatment
Gut microbiota	Using metagenomic sequencing to assess changes in the composition and abundance of gut microbiota between two groups of subjects. By analyzing the metagenomic data, we will identify specific microbial taxa and functional genes that show significant variation between the groups. This approach will provide insights into the microbial diversity, stability, and metabolic capabilities of the gut microbiome.	Gut microtioba will be measured at the following time points: before treatment, and at weeks 4, 8, 12, 16, 20, 24, and 28 after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood biochemical indicators	The study subjects were all in a fasting state. A professional nurse collected 1 tube of blood from the antecubital vein, and the blood sample was sent to the hospital's laboratory for testing on the same morning. The tests included complete blood count, fasting blood glucose, fasting insulin, glycated hemoglobin, serum triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase (ALT), uric acid, creatinine, electrolytes, and other measurements. All tests were conducted using an automatic biochemical analyzer. Post-test blood was used to measure serum DPP4 concentration and GLP-1 activity, among others.	Blood biochemical indicators will be measured at the following time points: before treatment, and at weeks 16 and 28 after treatment
The blood concentration of semaglutide	At 24 weeks, all study subjects had one tube of blood collected from the antecubital vein in a fasting state by a professional nurse. After centrifugation, the plasma was collected and analyzed for semaglutide plasma drug concentration using liquid chromatography-tandem mass spectrometry (LC-MS/MS).	concentration of semaglutide will be measured at weeks 24 after treatment
BMI	Height (measured without shoes, accurate to 0.1 cm), weight (measured without shoes, hat, heavy clothing, and accessories, accurate to 0.1 kg), and Body Mass Index (BMI) are calculated after converting the height unit. BMI = weight / height² (kg/m²).	BMI will be measured at the following time points: before treatment, and at weeks 4, 8, 12, 16, 20, 24, and 28 after treatment

Collaborators and Investigators

• Sponsor: Beijing Chao Yang Hospital
• Investigators: Study Chair: Guang Wang, Beijing Chao Yang Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): February 20, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 8, 2025
• First Submitted That Met QC Criteria: February 8, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 8, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Hypoglycemic Agents; Semaglutide
• Other Study ID Numbers: 2025-Semaglutide-obesity

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No