Enhancing the Efficacy and Tolerability of Metformin by add-on Polyherbal Formulation: a Gut Microbiome Study (Metherb)

Study population: Type 2 diabetes patients Design of the study: Randomized, two-arm, placebo-controlled, and prospective crossover cohort study.

Objective: To evaluate the effects of interactions between metformin and traditionally used polyherbal formulations on gut microbiota in a prospective crossover study involving type 2 diabetes mellitus patients.

Sample size: 66 patients. Duration of study: 06/2024 - 12/2026

Study Overview

• Status: Enrolling by invitation
• Conditions: Diabetes Mellitus Type 2
• Intervention / Treatment: Dietary supplement: Polyherbal Formulation (PHF); Drug: Metformin (Standard Treatment for Type 2 Diabetes); Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Latvia
  • Riga, Latvia, LV-1002
    • Pauls Stradins Clinical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for enrollment:

Clinical diagnosis of Type 2 Diabetes Mellitus (T2D) HbA1c level between 6.5% and 8.5% On a stable dose of oral antidiabetic therapy for at least 6 months Age: ≥ 25 years and ≤ 80 years History of metformin intolerance, defined as previously reported gastrointestinal side effects or inability to tolerate full-dose metformin Willing and able to provide written informed consent Willing to comply with study procedures, including stool sample collection and continuous glucose monitoring (CGM)

Exclusion Criteria:

Participants will be excluded if they meet any of the following criteria:

Type 1 Diabetes Mellitus Current or recent (last 6 months) use of polyherbal formulations (PHF) Pregnancy or breastfeeding

Severe diabetic complications, such as:

Diabetic ketoacidosis Proliferative retinopathy Chronic kidney disease Stage IIIb or higher (eGFR <45 mL/min/1.73m²)

Recent cardiovascular events (within the last 6 months), including:

Stroke Myocardial infarction Unstable angina Heart failure

Severe systemic disease that could interfere with participation, such as:

Active cancer Severe autoimmune disease Current antibiotic therapy (within 2 months of study enrollment) Use of probiotics or prebiotics (within 1 month of study enrollment)

Severe gastrointestinal conditions, including:

Inflammatory bowel disease Chronic diarrhea of unknown origin Severe infection requiring antibacterial therapy Participation in another interventional study within the last 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Polyherbal formulation; Participants in this arm will receive an add-on polyherbal formulation (PHF). Treatment Duration: 24 weeks, followed by a crossover to the placebo arm.	Dietary supplement: Polyherbal Formulation (PHF); Description: A polyherbal formulation with known beneficial effects on gut microbiota and metabolic regulation. The formulation contains selected plant extracts studied for their hypoglycemic, antioxidant, and gut microbiota-modulating properties. Administration: Oral, daily dosage as per study protocol. Supplier: Arya Vaidya Pharmacy (AVP), Coimbatore, India (GMP-certified).; Drug: Metformin (Standard Treatment for Type 2 Diabetes); Description: Metformin is an FDA and EMA-approved antihyperglycemic medication that improves glycemic control by reducing hepatic glucose production and enhancing insulin sensitivity. Administration: Oral, per standard dosing guidelines. Availability: Provided to all participants per the national reimbursement scheme for T2D patients in Latvia.
Placebo Comparator: Placebo; Participants in this arm will receive a placebo. Treatment Duration: 24 weeks, followed by a crossover to the PHF arm.	Drug: Metformin (Standard Treatment for Type 2 Diabetes); Description: Metformin is an FDA and EMA-approved antihyperglycemic medication that improves glycemic control by reducing hepatic glucose production and enhancing insulin sensitivity. Administration: Oral, per standard dosing guidelines. Availability: Provided to all participants per the national reimbursement scheme for T2D patients in Latvia.; Other: Placebo; Type: Placebo Comparator Description: A placebo formulation that matches PHF in appearance, texture, and administration schedule. Administration: Oral, daily dosage as per study protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glycemic Control (HbA1c Levels)	Measurement of HbA1c (%) to evaluate the impact of PHF on glycemic control compared to placebo.	Baseline, Week 24, Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Abundance of Key Bacterial Taxa in Gut Microbiota	Description: Measurement of the relative abundance of specific bacterial taxa (Akkermansia muciniphila, Escherichia spp., Intestinibacter) in fecal samples using metagenomic sequencing.	Baseline, Week 2, Week 24, Week 25, Week 48
Gastrointestinal Tolerability of Metformin	Assessment of gastrointestinal side effects, including nausea, bloating, diarrhea, and abdominal discomfort, using a standardized gut microbiota-related symptom questionnaire. Scale Name: Gastrointestinal Symptom Rating Scale (GSRS) Score Range: Minimum = 0, Maximum = 4 Interpretation: Lower scores indicate better gastrointestinal tolerability.	Baseline, Week 2, Week 24, Week 25, Week 48
Fasting and Postprandial Blood Glucose Levels	Measurement of fasting and postprandial glucose levels using standard biochemical assays. Unit of Measure: mmol/L	Baseline, Week 24, Week 48
Time in Range (TIR) Measured by Continuous Glucose Monitoring (CGM)	Time in Range (TIR) Measured by Continuous Glucose Monitoring (CGM) Description: Measurement of the percentage of time that blood glucose levels remain within the target range (70-180 mg/dL) using data from Continuous Glucose Monitoring (CGM).	Week 1
Metabolomic Analysis of Stool Samples (Short-chain fatty acids (SCFAs))	The levels of acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, and caproic acid will be quantified using gas chromatography-mass spectrometry (GC-MS). These concentrations will be reported in micromoles per gram of fecal matter (μmol/g).	Baseline, Week 24, Week 48
Patient-Reported Outcomes on Quality of Life	Description: Evaluation using a validated diabetes-related quality of life questionnaire. Diabetes Quality of Life (DQOL) Questionnaire. Scoring: Items are scored on a 5-point Likert scale, with higher scores typically indicating more negative impacts or dissatisfaction.	Baseline, Week 24, Week 48
Metabolomic Analysis of Stool Samples (Amino acids)	The following amino acids will be analyzed using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS): acetylcarnitine, arginine, butyrylcarnitine, carnitine, citrulline, creatinine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serotonin, taurine, tryptophan, tyrosine, and valine. Results will be expressed in nanomoles per gram of fecal matter (nmol/g).	Baseline, Week 24, Week 48
Metabolomic Analysis of Stool Samples (Bile acids)	The bile acids to be measured include cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid, along with their conjugated forms: glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, glycolithocholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, taurolithocholic acid, and ursodeoxycholic acid. These will be quantified using liquid chromatography-mass spectrometry (LC-MS), with concentrations reported in micromoles per gram of fecal matter (μmol/g).	Baseline, Week 24, Week 48

Collaborators and Investigators

• Sponsor: Pauls Stradins Clinical University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: February 7, 2025
• First Submitted That Met QC Criteria: February 20, 2025
• First Posted (Actual): February 25, 2025

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: diabetes; metformin; microbiome; polyherbal formulation
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: lzp-2023/1-0422 (Other Grant/Funding Number: Latvian Council of Science)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No