Topics

Probiotics in Metformin Intolerant Patients With Type 2 Diabetes

2019-09-17 02:47:13 | BioPortfolio

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 SCFA-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 investigestors 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 insulin-resistant index - HOMA-IR).

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 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, BMI measurements, WHR (waist-hip ratio).

Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, C-reactive protein (CRP), HbA1c, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells), PLT (platelets), creatinine, lipogram, ALT (alanine aminotransferase) activity and oxidative stress parameters (antioxidant enzymes: SOD - superoxide dismutase, GPx - glutathione peroxidase; CAT - catalase; GR - glutathione reductase, radical damage indicators of free of lipids and proteins: TOC - total oxidation capacity; LHP concentration of lipid hydroperoxides; LPS - concentration of lipofuscin - serum and lysate of erythrocytes; PSH - concentration of sulphydryl protein; MDA - malondialdehyde concentration - serum and erythrocyte lysate; GSH - concentration of reduced glutathione; non-enzymatic antioxidant system: TAS (TAC) total antioxidant capacity of plasma (total antioxidant status)) .

Stool collection for microbial analysis, short chain fatty acids (SCFAs), 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 3A - 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 4A - 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 (waist-hip ratio).

Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, C-reactive protein (CRP), HbA1c, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells), PLT (platelets), creatinine, lipogram, ALT (alanine aminotransferase) activity and oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

Stool collection for microbial analysis, short chain fatty acids (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 (waist-hip ratio).

Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, C-reactive protein (CRP), HbA1c, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells), PLT (platelets), creatinine, lipogram, alanine aminotransferaze activity and oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

Stool collection for microbial analysis, short chain fatty acids (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 7A - 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 8A - 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 (waist-hip ratio).

Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, C-reactive protein (CRP), HbA1c, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells), PLT (platelets), creatinine, lipogram, ALT (alanine aminotransferase) activity and oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).).

Stool collection for microbial analysis, short chain fatty acids (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 (waist-hip ratio).

Blood collection for zonulin and immunoglobulins against zonulin, calprotectin, C-reactive protein (CRP), HbA1c, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells), PLT (platelets), creatinine, lipogram, ALT (alanine aminotransferase) activity and oxidative stress parameters (SOD, GPx,CAT, GR, TOC, LPS, PSH, MDA, GSH, TAS (TAC).) .

Stool collection for microbial analysis, short chain fatty acids (SCFAs), zonulin and calprotectin concentration.

Gastrointestinal symptoms questionnaire administration. The patient will finish participation in the study.

Study Design

Conditions

Diabetes Mellitus, Type 2

Intervention

Sanprobi Barrier-multispecies probiotic, Placebo Comparator

Location

Department of Internal Diseases, Diabetology and Nephrology
Zabrze
Poland
41-800

Status

Recruiting

Source

Medical University of Silesia

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-09-17T02:47:13-0400

Clinical Trials [5476 Associated Clinical Trials listed on BioPortfolio]

The Effect of a Multispecies Probiotic on Hypersensitivity in Irritable Bowel Syndrome (IBS) Patients

The purpose of this study is to determine whether a specifically designed multispecies probiotic decreases visceral hypersensitivity in IBS-patient (defined by an increased pain tolerance ...

The Effect of a Multispecies Probiotic on Reducing the Incidence of Antibiotic-associated Diarrhoea in Children.

In this trial, the investigators aim to assess the effectiveness of a multispecies probiotic consisting of 2 strains of Bifidobacterium (B. bifidum W23, B. lactis W51) and 6 strains of Lac...

Probiotics in Diabesity: A Pilot Study

Obesity and type 2 diabetes are a pandemic disease leading to a high morbidity and mortality. Probiotic modulation of gut flora is a possible therapeutic mechanism. The aim of this study ...

Sulfonylurea Add-on Study in Patients With Type 2 Diabetes Mellitus

The purpose of this clinical study is to determine the safety and efficacy of an investigational drug in patients with Type 2 diabetes mellitus.

Sitagliptin vs Glipizide in Patients With Type 2 Diabetes Mellitus and Chronic Renal Insufficiency

The purpose of the study is to compare how sitagliptin and glipizide lower blood glucose levels in patients with moderate and severe renal insufficiency.

PubMed Articles [6579 Associated PubMed Articles listed on BioPortfolio]

Efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: A randomized, double-blind, phase 3 trial.

To assess the efficacy and safety of once-daily 50-mg ipragliflozin versus placebo in Japanese patients with type 1 diabetes mellitus (T1DM) inadequately controlled with insulin.

Ameliorative Effects of Probiotic Lactobacillus paracasei NL41 on Insulin Sensitivity, Oxidative Stress and Beta-Cell Function in a Type 2 Diabetes Mellitus Rat Model.

The present study aims to assess the antidiabetic effect of Lactobacillus paracasei strain NL41 and its potential mechanisms in rats with type 2 diabetes mellitus (T2DM) induced by a high-fat diet and...

Efficacy and safety of Cinnamon in Type 2 Diabetes Mellitus and Pre-diabetes patients: A Meta-analysis and Meta-regression.

Cinnamon has been used as a dietary component and in the management of diabetes mellitus. This study systematically reviewed and synthesized evidence on the efficacy of cinnamon for the treatment of t...

Risk of Mortality and Hospitalization After Post-Pancreatitis Diabetes Mellitus vs Type 2 Diabetes Mellitus: A Population-Based Matched Cohort Study.

To investigate the risk of mortality and hospitalization in individuals with post-pancreatitis diabetes mellitus (PPDM) compared with those with type 2 diabetes mellitus (T2DM).

The influence of ICAM1 rs5498 on diabetes mellitus risk: evidence from a meta-analysis.

Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are classified as forms of diabetes mellitus (DM) and commonly considered inflammatory process. Intercellular adhesion molecule-1 (ICAM-1) is invol...

Medical and Biotech [MESH] Definitions

A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY.

Diabetes mellitus induced experimentally by administration of various diabetogenic agents or by PANCREATECTOMY.

Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes (DIABETES MELLITUS; DIABETES INSIPIDUS).

A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence.

A strain of Rattus norvegicus which is a model for spontaneous insulin-dependent diabetes mellitus (DIABETES MELLITUS, INSULIN-DEPENDENT).

More From BioPortfolio on "Probiotics in Metformin Intolerant Patients With Type 2 Diabetes"

Quick Search

Relevant Topics

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Anesthesiology
An anesthesiologist (US English) or anaesthetist (British English) is a physician trained in anesthesia and perioperative medicine. Anesthesiologists are physicians who provide medical care to patients in a wide variety of (usually acute) situations. ...


Searches Linking to this Trial