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.
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
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
56
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.
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.
Time frame: 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.
Time frame: 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
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.
Time frame: 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).
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Time frame: 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).
Time frame: BMI will be measured at the following time points: before treatment, and at weeks 4, 8, 12, 16, 20, 24, and 28 after treatment