Probiotic Intervention for Digestive Health in Obese Patients Initiating GLP-RA Treatment

Official title

Evaluation of the Efficacy of Probiotics on Digestive Quality of Life in Patients Initiating GLP-1 Receptor Agonists for the Treatment of Obesity. A Randomized, Double-blind Trial

Overview

Obesity is a prevalent chronic disease affecting 17% of the French population. Treatment involves multiple factors, with pharmacotherapy playing an increasingly important role. GLP-1 receptor agonists (GLP1 RAs) are considered revolutionary in obesity treatment, with three approved molecules available in France: liraglutide, semaglutide, and tirzepatide. These treatments, combined with a healthy lifestyle, induce significant weight loss: 9% with liraglutide, 15% with semaglutide, and 20% with tirzepatide. The most common adverse events (AEs) associated with GLP-1 RAs are gastrointestinal (GI) disorders, including nausea, vomiting, diarrhea, and abdominal pain. These AEs are dose-dependent and often decline over time. In phase 3 trials, semaglutide 2.4 mg showed higher rates of GI AEs compared to placebo, but most were mild to moderate and transient. GI AEs led to dose reduction or temporary treatment interruption in 12.5% of participants, with few permanent discontinuations. Probiotics, are live microorganisms that benefit the host by improving gut microflora. Probiotics has been clinically proven to benefit gastrointestinal health. Probiotics may reduces symptoms of irritable bowel syndrome (IBS), improves gut barrier function, reduces inflammation, and decreases the incidence of C. difficile infection (CDI) in patients taking antibiotics. Probiotics is therefore theorized to potentially reduce GI side effects associated with GLP-1 RA treatment for obesity. Hypothesis Probiotics will prevent and limit the digestive disorders induced by GLP-1 R agonists, particularly during the dose escalation period. This would allow better digestive tolerance of the treatments, limiting the number of definitive treatment interruptions, facilitating compliance and dose escalation with a larger number of subjects at full dose and therefore with better systemic exposure to the compounds, a key factor in their effects on weight loss.

Detailed description

Obesity is a prevalent chronic disease affecting 17% of the French population. Treatment involves multiple factors, with pharmacotherapy playing an increasingly important role. GLP-1 receptor agonists (GLP1 RAs) are considered revolutionary in obesity treatment, with three approved molecules available in France: liraglutide, semaglutide, and tirzepatide. These treatments, combined with a healthy lifestyle, induce significant weight loss: 9% with liraglutide, 15% with semaglutide, and 20% with tirzepatide.

The most common adverse events (AEs) associated with GLP-1 RAs are gastrointestinal (GI) disorders, including nausea, vomiting, diarrhea, and abdominal pain. These AEs are dose-dependent and often decline over time. In phase 3 trials, semaglutide 2.4 mg showed higher rates of GI AEs compared to placebo, but most were mild to moderate and transient. GI AEs led to dose reduction or temporary treatment interruption in 12.5% of participants, with few permanent discontinuations.

Probiotics, are live microorganisms that benefit the host by improving gut microflora. Probiotics has been clinically proven to benefit gastrointestinal health. Probiotics may reduces symptoms of irritable bowel syndrome (IBS), improves gut barrier function, reduces inflammation, and decreases the incidence of C. difficile infection (CDI) in patients taking antibiotics.

Probiotics is therefore theorized to potentially reduce GI side effects associated with GLP-1 RA treatment for obesity.

Hypothesis Probiotics will prevent and limit the digestive disorders induced by GLP-1 R agonists, particularly during the dose escalation period. This would allow better digestive tolerance of the treatments, limiting the number of definitive treatment interruptions, facilitating compliance and dose escalation with a larger number of subjects at full dose and therefore with better systemic exposure to the compounds, a key factor in their effects on weight loss.

Interventions

• Dietary supplement Probiotics (Natural product)
  Participants will be instructed to daily take, during 26 weeks (that will begin 2 weeks before the initiation of semaglutide or tirzepatide treatment) one capsule of a probiotic with water at room temperature with the first meal. Dosage levels: 1 capsule Digestive Quality of life during the study will be assessed.
• Other Placebo
  Participants will be instructed to daily take, during 26 weeks (that will begin 2 weeks before the initiation of semaglutide or tirzepatide treatment) one capsule of PLACEBO with water at room temperature with the first meal. Digestive Quality of life during the study will be assessed.

Primary outcome measures

• Assessment of the Limitation of the impairment in digestive quality of life during the dose escalation of GLP1-RA (semaglutide or tirzepatide) [Time frame: Every 5 weeks]

Secondary outcome measures (12)

• Digestive quality of life [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• Nausea [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• Dyspepsia [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• Diarrhea [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• Constipation [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• Abdominal pain [Time frame: From baseline to 4, 8, 12, 16, 20 and 24 weeks of treatment]
• GLP-1 receptor agonist dosage [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]
• GLP1-RA dose escalation [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]
• GLP1-RA dose discontinuation/maintenance [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]
• Weight loss [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]
• Weight loss [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]
• Weight loss [Time frame: 4, 8, 12, 16, 20 and 24 weeks of intervention]

Eligibility criteria

Inclusion criteria

• Patient who is going to start a GLP-1 RA (semaglutide or tirzepatide) for weight management
• Men or Women
• BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 associated with one or more co-morbidities (arterial hypertension, sleep apnea, dyslipidemia, arthritis)
• Between 18 and 75 years old
• In the opinion of the investigator, the patient must have adequate support to comply with the entire study requirements as described in the protocol (e.g. transportation to and from trial site, ability to understand and fill the self-rating scales, drug compliance, availability to attend to the scheduled visits, etc…).
• Patient who agrees to be included in the study and who signs the informed consent form
• Female participants of childbearing potential must agree to use effective contraception
• Patient affiliated to a healthcare insurance plan

Exclusion criteria

Criteria relating to the study population:

• Patients under 18 years old
• Patient with contraindication to semaglutide or tirzepatide according to the Summary of Product Characteristics (SPC).
• Patients scheduled for bariatric surgery during the study period
• Patients who have had bariatric surgery in the last 12 months
• Patient with a current diagnosis of diabetes.
• Patients with a current diagnosis of liver cirrhosis, short bowel syndrome or inflammatory bowel disease (IBD).
• Patients with severely weakened immune system.
• Clinically unstable medical disease, including cardiovascular, hepatic, renal, gastrointestinal, pulmonary, metabolic, endocrine, or other systemic disease.

Product criteria:

Patient with known allergy to the product of the study

Prohibited treatments :

Current associated treatments or used in the last 30 days: GLP-1 RA, Anti-obesity drugs (AOD), Corticosteroids, Atypical neuroleptics, Antibiotics, Probiotics, Prebiotics

Regulatory criteria :

• Persons deprived of their liberty by a judicial or administrative decision
• Persons under psychiatric care
• Persons admitted to a health or social institution for purposes other than research
• Adults subject to a legal protection measure (guardianship, curatorship)
• Persons not affiliated to a social security scheme or beneficiaries of a similar scheme
• Subjects participating in other interventional research with an exclusion period still in progress at pre-inclusion

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Prevention

Study locations

France · 1 center

• Hôpital Lyon Sud — Pierre-Bénite

Identifiers

NCT: NCT07213323 · 69HCL25_0321 · 2025-A01248-41

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗