Probiotics in Metformin Intolerant Patients With Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2; Metformin Adverse Reaction
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Metformin, the first-line drug in the treatment of type 2 diabetes (T2DM), may cause dose
      dependent undesirable side-effects like diarrhea, abdominal pain, nausea or bloating which
      may affect up to 20 % of patients treated with this drug. The mechanism of the
      gastrointestinal intolerance in patients treated with metformin is poorly understood. The
      number of studies on this topic increases and data are mounting that metformin treatment is
      associated with changes in gut bacterial composition. Among other drugs, metformin also leads
      to enrichment of short chain fatty acids (SCFAs) producing microbiota which exert positive
      influence on the human metabolic state.

      It has been shown that the therapeutic effect of metformin depends on the microbiota and
      metformin's main site of action in humans is the intestine. It is also known that patients
      with T2DM, in general, show evidence of gut dysbiosis followed by alterations of an
      intestinal barrier leading to an increase in intestinal permeability and elevated
      inflammatory state.

      Therefore, it has been speculated that metformin's versatile effect mediated through the gut
      microbiota is responsible not only for its therapeutic effect but also for its undesirable
      digestive symptoms.

      Probiotics, defined as "live microorganisms, that when administered in adequate amounts,
      confer a health benefit on the host", may have the potential to modulate the gut bacterial
      composition. This is why the investigators hypothesize that it may also reduce the intensity
      of adverse effects associated with metformin use.

      The investigators have chosen Sanprobi Barrier multi-strain formula probiotic because it is
      identical, in relation to bacterial strains and number, to Ecologic® BARRIER which has been
      proven in in vitro studies to improve the function of epithelial barrier of the intestine. It
      was also shown that 12-week administration of strains included in Ecologic® BARRIER in obese
      postmenopausal women improved intestinal barrier permeability marker (lipopolysaccharide) and
      cardiometabolic risk factors (waist, fat mass, subcutaneous fat, uric acid, total
      cholesterol, triglycerides, low-density lipoprotein cholesterol, glucose, insulin, and
      homeostatic model assessment - insulin resistance (HOMA-IR).
    

Detailed description: 
      The optimal daily dose of metformin is thought to be 2000 mg, however patients with metformin
      intolerance cannot reach this target dose. Participate in this study are metformin
      intolerant. Metformin intolerant patients have been defined as those not able to be treated
      with the metformin daily dose exceeding 1500 mg due to gastrointestinal upset. Patient's
      metformin intolerance assessment will be questionnaire based (questionnaire adapted from
      Laura J. Mc Creight et al.). Patients will fill out questionnaires regarding the
      gastrointestinal symptoms associated with metformin at a dose they did not tolerate and at a
      time of reduced daily dose of metformin they do tolerate (patients are accepted to have
      gastrointestinal symptoms which they accept). Sanprobi Barrier probiotic/placebo will be
      administrated and the gastrointestinal symptoms will be repeatedly assessed with the use of
      above mentioned questionnaire at certain time points during the study. Patients will be
      advice to increase the daily dose of metformin as described below. At certain visits patients
      will undergo the tests measuring the intestinal permeability (blood and stool zonulin
      immunoenzymatic tests). Inflammatory state will be assessed by measurement of blood
      C-reactive protein (CRP) as well as blood and stool calprotectin. Zonulin is an endogenous
      protease, which concentration provides information about the condition of tight junctions
      between intestinal cells and has been used a a marker of intestinal permeability.
      Calprotectin, constitutes up to 60% of soluble cytosolic proteins in human neutrophils. In
      addition, it occurs in monocytes, macrophages and epithelial cells. Therefore, fecal and
      serum calprotectin content may be proportional to the number of neutrophils migrating through
      the gastric and intestinal mucosa and may be associated with inflammatory diseases of the
      gastrointestinal tract. Calprotectin has been widely used in contemporary clinical practice
      to monitor inflammation of the gut mucosa. CRP blood concentration is a marker of
      inflammation. Additionally, fecal samples will be used for microbial analysis (16S ribosomal
      ribonucleic acid (rRNA) sequencing) and blood samples for oxidative stress parameters, HbA1c,
      lipogram and alanine aminotransferase activity will be collected. Oxidative stress being a
      disturbance in oxidative balance, has been associated with type 2 diabetes and linked to
      adverse health effects, including alterations within the intestinal microbiota and vascular
      endothelium. Probiotics have already been shown to modify the intestinal microbiota and their
      usage may exert a beneficial effect on the oxidative stress parameters. This will be a 32 -
      weeks, prospective, single center, randomized, double-blind, cross-over study consisting of
      10 site visits and 4 telephone contacts.

      Visit 1. Written informed consent for participation in the study and medical history
      collection.

      Visit 2 - month 0. Randomization visit. (within 3 ± 1 days of the visit 1) Fasting state.
      Blood pressure, heart rate, body mass index (BMI) measurements, waist-hip ratio (WHR).

      Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, CRP, HbA1c,
      hemoglobin (HGB), red blood cells (RBC), white blood cells (WBC), platelet count (PLT),
      creatinine, lipogram, alanine aminotransferase (ALT) activity and oxidative stress parameters
      (antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GPx); catalase
      (CAT); glutathione reductase (GR), radical damage indicators of free of lipids and proteins:
      total oxidation capacity (TOC); concentration of lipid hydroperoxides (LHP); concentration of
      lipofuscin (LPS) - serum and lysate of erythrocytes; concentration of sulphydryl protein
      (PSH); malondialdehyde (MDA) concentration - serum and erythrocyte lysate; concentration of
      reduced glutathione (GSH); non-enzymatic antioxidant system: total antioxidant capacity (TAC)
      of plasma (total antioxidant status (TAS)) .

      Stool collection for microbial analysis, short chain fatty acids, zonulin and calprotectin
      concentration.

      Gastrointestinal symptoms questionnaire administration. Randomization to probiotic/placebo
      group with the permutation method. Patient will be advised to consume 2 capsules in the
      morning and 2 capsules in the evening. There will be two groups of probiotic/placebo products
      namely "A" and "B". Patients who will be randomized to probiotic/ placebo "B" at visit 2 will
      be switched to probiotic/ placebo "A" at visit 6 and patients who will be randomized to group
      probiotic/ placebo "A" at visit 2 will be switched to probiotic/ placebo "B" at visit 6. The
      patient will receive two probiotic/ placebo packs containing 120 capsules each.

      Visit 3 - month 1 (4 weeks ± 3 days from the visit 2) Gastrointestinal symptoms questionnaire
      administration. Return of the empty packages or unused probiotic/placebo issued at the visit
      2. The patient will receive two probiotic/ placebo packs containing 120 capsules each.

      The current dose of metformin will be increased by 500 mg per day if possible.

      Visit 3 A - telephone contact (1 week ± 3 days from the visit 3) Gastrointestinal symptoms
      will be assessed after increasing the dose of metformin. Decision about the possibility of
      continuing the increased dose of the drug will be made.

      Visit 4 - month 2 (4 weeks ± 3 days from the visit 3) Gastrointestinal symptoms questionnaire
      administration. Return the empty packages or unused probiotic/placebo issued at the visit 3.
      The patient will receive two probiotic/ placebo packs containing 120 capsules each. Depending
      on the patient's clinical symptoms and tolerability of previously increased dose of
      metformin, increasing the dose of metformin (additional 500 mg/day) will be advised in order
      to achieve metformin dose of at least 2000 mg. In the case of side-effects from the
      gastrointestinal system, the dose will be reduced to the dose where there were no symptoms or
      there were symptoms that patients accepts.

      Visit 4 A - Telephone contact (1 week ± 3 days from visit 4) Gastrointestinal symptoms will
      be assessed after increasing the dose of metformin. Decision about the possibility of
      continuing the increased dose of the drug will be made.

      Visit 5 - month 3 (4 weeks ± 3 days from the the visit 4) Fasting state. Blood pressure,
      heart rate, BMI measurements, WHR. Blood collection for zonulin and immunoglobulins against
      zonulin, calprotectin, CRP, HbA1c, HGB, RBC, WBC, PLT, creatinine, lipogram, ALT activity and
      oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

      Stool collection for microbial analysis, SCFAs, zonulin and calprotectin concentration.

      Gastrointestinal symptoms questionnaire administration. Return the empty packages or unused
      probiotic/placebo issued at the visit 4. Probiotic / placebo will be discontinued.

      Visit 6 - month 4. Cross-over visit. (4 weeks ± 3 days from the visit 5).

      Fasting state. Blood pressure, heart rate, BMI measurements, WHR. Blood collection for
      zonulin and immunoglobulins against zonulin, calprotectin, CRP, HbA1c, HGB, RBC, WBC, PLT,
      creatinine, lipogram, ALT activity and oxidative stress parameters (SOD, GPx,CAT, GR, TOC,
      LPS, PSH, MDA, GSH, TAS (TAC).) .

      Stool collection for microbial analysis, SCFAs, zonulin and calprotectin concentration.

      Gastrointestinal symptoms questionnaire administration. Patient will be cross-over to the
      different group of probiotic/placebo ("A" or "B" as described on the visit 2) and will be
      advised to consume 2 capsules in the morning and 2 capsules in the evening.

      The patient will receive two probiotic/ placebo packs containing 120 capsules each.

      Visit 7 - month 5 (4 weeks ± 3 days from the visit 6) Gastrointestinal symptoms questionnaire
      administration. Return the empty packages or unused probiotic/placebo issued at the visit 6.
      The patient will receive two probiotic/ placebo packs containing 120 capsules each.

      Depending on the patient's clinical symptoms and tolerability of previously increased dose of
      metformin, increasing the dose of metformin (additional 500 mg/day) will be advised in order
      to achieve the metformin dose of at least 2000 mg. In the case of side-effects from the
      gastrointestinal system, the dose will be reduced to the dose where there were no symptoms or
      there were symptoms that patients accepts.

      Visit 7 A - telephone contact (1 week ± 3 days form the visit 7) Gastrointestinal symptoms
      will be assessed after increasing the dose of metformin. Decision about the possibility of
      continuing the increased dose of the drug will be made.

      Visit 8 - month 6 (4 weeks ± 3 days from the visit 7) Gastrointestinal symptoms questionnaire
      administration. Return the empty packages or unused probiotic/placebo issued at the visit 7.
      The patient will receive two probiotic/ placebo packs containing 120 capsules each.

      Depending on the patient's clinical symptoms and tolerability of previously increased dose of
      metformin, increasing the dose of metformin (additional 500 mg/day) will be advised in order
      to achieve the metformin dose of at least 2000 mg. In the case of side-effects from the
      gastrointestinal system, the dose will be reduced to the dose where there were no symptoms or
      there were symptoms that patients accepts.

      Visit 8 A - telephone contact (1 week ± 3 days form the visit 7) Gastrointestinal symptoms
      will be assessed after increasing the dose of metformin. Decision about the possibility of
      continuing the increased dose of the drug will be made.

      Visit 9 - month 7 (4 weeks ± 3 days from the visit 8) Fasting state. Blood pressure, heart
      rate, BMI measurements, WHR. Blood collection for zonulin and immunoglobulins against
      zonulin, calprotectin, CRP, HbA1c, HGB, RBC, WBC, PLT, creatinine, lipogram, ALT activity and
      oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

      Stool collection for microbial analysis, SCFAs, zonulin and calprotectin concentration.

      Gastrointestinal symptoms questionnaire administration. Return the empty packages or unused
      probiotic/placebo issued at the visit 8 Probiotic / placebo will be discontinued.

      Visit 10 - month 8 (4 weeks ± 3 days from the visit 9) Fasting state. Blood pressure, heart
      rate, BMI measurements, WHR. Blood collection for zonulin and immunoglobulins against
      zonulin, calprotectin, CRP, HbA1c, HGB, RBC, WBC, PLT, creatinine, lipogram, ALT activity and
      oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

      Stool collection for microbial analysis, SCFAs, zonulin and calprotectin concentration.

      Gastrointestinal symptoms questionnaire administration. The patient will finish participation
      in the study.
    

Intervention name(s): Sanprobi Barrier-multispecies probiotic; Placebo Comparator
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Multi-strain probiotic Sanprobi Barrier (Bifidobacterium lactis W52, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus lactis W19, Lactobacillus lactis W58, Lactobacillus acidophilus W37, Bifidobacterium bifidum W23, Lactobacillus salivarius W24) or placebo. Patients will be randomized to one of the two products ("A" or "B") each containing probiotic/placebo and administered for 12 weeks. After 12 weeks of supplementation, the probiotic/placebo product "A" or "B" will be discontinued and reintroduced again after next 4 weeks - patients will be switched to the other "A or B" group of probiotic/placebo arm. Patients will be administered with 4 capsules per day for 24 weeks (12 weeks for group A probiotic/placebo and 12 weeks for group B probiotic/placebo allowing 4 weeks washout between the group assignment).; Carrier material of Sanprobi Barrier-multispecies probiotic product, not containing bacterial strains,similar appearance as the probiotic
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: prospective, single center , interventional
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: diabetes type 2; probiotics; metformin intolerance