Semaglutide's Weight Loss Effects in Obesity

Official title

Clinical Assessment of Semaglutide-Induced Weight Reduction in Obese Populations

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• Body weight [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 [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]

Secondary outcome measures (3)

• Blood biochemical indicators [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 [Time frame: concentration of semaglutide will be measured at weeks 24 after treatment]
• BMI [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]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06825793 · 2025-Semaglutide-obesity

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗