The Interaction Between Metformin and Microbiota - the MEMO Study. (MEMO)

The Interaction Between Metformin and Microbiota - the Reason for Gastrointestinal Side Effects?

Metformin has been used in Sweden since 1957, and it is recommended as first line therapy for type 2-diabetes (T2D) in national and international guidelines. However, adverse effects involving diarrhea, constipation, bloating, and abdominal pain are common which leads to discontinuation of medication or not being able to reach therapeutic doses. Here the investigators will perform a prospective study to investigate whether i) participants with T2D who experience adverse events following metformin treatment have an altered microbiota at baseline compared to participants without adverse events and ii) if the microbiota is altered in participants during onset of adverse events. The investigators hypothesis is that adverse effects associated with metformin are caused by an altered gut microbiota, either at base line or following metformin treatment. The study design is a nested case-cohort study. The investigators will recruit 600 patients and expect 200 individuals to have side effects and 400 without during a 24-month study period. Fecal samples will be collected at baseline, 2 months, and 4 months or when gastrointestinal symptoms occur. All fecal samples will be sequenced by 16s rRNA (ribosomal ribonucleic acid) sequencing to obtain a baseline microbiota profile; a subpopulation consisting of homogenous groups of participants will be in depth-analyzed using shotgun sequencing. If the hypothesis is confirmed this project may lead to bacterial therapies that will allow more patients tolerate metformin.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Metformin

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

• Study Contact: Name: Olov Rolandsson, Professor; Phone Number: +46 90 786 50 00; Email: olov.rolandsson@umu.se

Study Locations

• Sweden
  • Umeå, Sweden
    • Recruiting
    • Region Västerbotten
    • Contact: Kenny Kalin, MD; Phone Number: 070-7991186; Email: kenny.kalin@umu.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

newly diagnosed patients with type 2 diabetes without previous treatment with metformin.

Description

Inclusion criteria:

• Type 2 diabetes (diagnosis set within the last 12 months)
• planned metformin treatment
• Age: 40 - 80 years
• Have provided written informed consent.

Exclusion criteria:

• already started treatment with Metformin
• intestinal disease incl. irritable bowel syndrome
• treatment with antibiotics in the last 3 months
• Inflammatory disorder t.ex. rheumatoid arthritis
• anemia, haemoglobinopathy
• alcohol or drug abuse
• cancer disease under treatment

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
prospective cohort; All participants receive Metformin in accordance to the ordinary therapy practice. They will be part of one subject group/cohort. After onset of metformin treatment the subjects who develop gastrointestinal side effects will be compared with cases without gastrointestinal side effects.	Drug: Metformin; Receiving Metformin is no study intervention. The investigators have no influence on the Metformin treatment. All participants receive Metformin provided by the health care system. The individual case determine dose and frequency of the treatment as part of the usual therapy guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change from baseline in the fecal microbiota composition by detecting bacteria families with help of relative abundance (%) and diversity metrics	Faeces samples will be collected at baseline, after 2 months and after 4 months of Metformin treatment and analysed using 16S rRNA sequencing, whole genome shotgun sequencing and metagenomic analyses	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
genetic correlation between Microbiota and gastrointestinal side effects	The microbiota genome and the relation to the appearance of gastrointestinal side effects will be analysed.	4 months
number of patients with gastrointestinal side effects	A questionnaire will be answered at baseline, after 2 and 4 months and refers to a period of 2 weeks before study visit. Six different side effects will be monitored: loss of appetite, nausea, vomiting, diarrhea, meteorism, stomach ache.	4 months
rate of gastrointestinal side effects	Changes in the rate of side effects using questionnaire at baseline, after 2 and 4 months.The answer possibilities are: never, one or a few times, daily, multiple times a day.	4 months
time to first appearance of gastrointestinal side effects	How many months till the onset of side effects during metformin treatment: depending on the time of assessment, 2 or 4 months	4 months
time to first appearance of side effects which requires dose changes in the Metformin treatment	Analysing changes in metformin treatment and relation to appearance of side effects	4 months
time to first appearance of side effects which requires termination of the Metformin treatment	Analysing length of metformin treatment and relation to appearance of side effects	4 months
correlation between microbiota and beneficial glucose lowering response	Plasma glucose will be analysed at baseline, after 2 and 4 months of Metformin treatment and correlated to the changes in the composition of microbiota.	4 months

Collaborators and Investigators

• Sponsor: Umeå University
• Collaborators: Karolinska Institutet; Göteborg University; Linkoeping University; Örebro University, Sweden
• Investigators: Principal Investigator: Olov Rolandsson, Professor, Umea University

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 20, 2019
• Primary Completion (ANTICIPATED): December 1, 2021
• Study Completion (ANTICIPATED): March 1, 2022

Study Registration Dates

• First Submitted: May 4, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (ACTUAL): October 24, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Microbiota; Metformin; Gastrointestinal side effects
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MEMO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No