Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I

October 27, 2020 updated by: Alexis McKee, MD, St. Louis University

Metformin is associated with a high degree of gastrointestinal intolerance, which limits the effective use of the medication. It is proposed to be an inhibitor of liver mitochondrial glycerophosphate dehydrogenase which results in partial blockade of mitochondrial complex 1 and inhibition of metabolism of lactate to pyruvate. There is also evidence that it is accumulated in gastrointestinal cells, and that there are certain genotypes associated with inclusion or lack of exclusion of the metformin from these cells. To validate this hypothesis investigators propose to give metformin after a standard meal test to see if there is the accumulation of lactic acid in those with gastrointestinal intolerance to metformin, compared to those without intolerance, and to determine if these elevations of lactic acid and GI symptoms are associated with genetic predispositions.

Aims:

  1. To determine if the GI intolerance to metformin is associated with post meal elevations of lactic acid.

    a. The test will measure the inhibition of mitochondrial complex 1 levels of lactate to pyruvate compared with non- intolerant subjects.

  2. To determine if individuals with gastrointestinal symptoms and elevated lactate/pyruvate ratios have genetic variation in the organic cation transporters.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Metformin is the primary drug of choice for management of type 2 diabetes mellitus. Most recent evidence suggest that the drug is a noncompetitive inhibitor of mitochondrial glycerophosphate dehydrogenase which modifies mitochondrial complex 1 in the liver, reducing the generation of NADH, increasing the ratio of lactate to pyruvate, and reducing gluconeogenesis. Metformin which is a guanidine/ biguanide analog is not metabolized in vivo and is cleared by the kidney. It has a limited degree of mitochondrial inhibition, and only becomes toxic when serum levels accumulate in renal failure. Other guanidine analogs, such as fenformin or galegine, however may be associated with irreversible complete mitochondrial blockade and lactic acidosis.

The incidence of gastrointestinal intolerance to the drug can range between 10% and 30%. It is postulated that the gastrointestinal enterocyte may accumulate the metformin. It is postulated that metformin uptake and accumulation may be exacerbated in those with genetic predispositions for certain organic transporters which are involved in the uptake and removal of metformin in cells. Metformin appears to be taken up from the intestine by plasma monoamine transporter (PMAT; SLC29A4), organic cation transporter 1 (OCT1; SCLC22A1) and organic cation transporter 3 (OCT3; SLC22A3) and actively removed from target tissues by multi-antimicrobial extrusion protein 1 (MATE1; SLC47A1) and eliminated by the urinary multi-antimicrobial extrusion protein 2 (MATE2; SCL47A2). Although certain genotypes are associated with a high incidence of intolerance, the gene low gene frequency does not explain the high degree of intolerance in the population.

ii) Innovation: The plan is to develop a test to evaluate whether there is accumulation of lactic acid after a therapeutic dose of metformin and whether the levels of lactic acid are higher in subjects with GI intolerance than those not intolerant. The hypothesis is that there is increased generation of lactic acid in those intolerant individuals, independent of glucose lowering effect on liver metabolism. Investigators propose to measure the generation of lactate/pyruvate (L/P, mitochondrial complex 1), in those with and without clinically known metformin gastrointestinal symptoms. Investigators will correlate gastrointestinal symptoms with L/P ratios. Investigators will also evaluate for genomic susceptibility for the origin transporters with comparison to the metformin tolerance test generation of lactic acid.

iii) Approach: Investigators wish to develop a pilot project of 24 subjects who will complete the protocol. Subject will be seen in the Endocrinology clinic of St. Louis University, and investigators will recruit 12 subjects who have clinical symptoms of gastrointestinal symptoms (diarrhea or bloating) and 12 subjects who are tolerant. Subjects will be randomized to receive a fasting standard dose of 1000 mg brand metformin (Glucophage) or comparable placebo on day one and then the alternate medicine on a second day. The study drug will be given with Diabetasourse meal (standard meal) which will provide carbohydrates to challenge the mitochondrial system [2]. Bloods for glucose, L/P, will be obtained at 0, 30 60 90 and 120 minutes. Symptoms of gastrointestinal effects will be documented by a Likert type questionnaire. Outcomes will be 1) the effect of metformin vs. placebo on the meal tolerance glucose levels 2) the effect of metformin on post meal challenge levels of L/P, in intolerant vs. tolerant individual and 3) the correlation of gastrointestinal symptoms with changes in L/P. From animal data, metformin causes a 2 fold increase in lactic acid at 60 minutes. In our laboratory with a normal reference lactic acid of 1.0 mmol/L and a SD=0.725. Twelve pairs would be sufficient for a pilot study to determine a difference at an alpha of 0.05 and beta of 0.80.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Saint Louis University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Diabetes mellitus
  2. Tolerance to meformin
  3. Intolerance to metformin

Exclusion Criteria:

  1. Exclusion: Pregnant or nursing mothers
  2. Those not competent to provide informed consent
  3. Known systemic allergy (not intolerance) to metformin
  4. Congestive heart failure NYHA class III-IV
  5. Renal impairment,EGFRr<45ml/min
  6. Liver cirrhosis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin intolerant & metformin
Metformin 1000mg once
Drug: Metformin
Metformin 1000mg once
Other Names:
  • Glucophage
Placebo Comparator: Metformin intolerant & placebo
Placebo 1000mg once
Drug: Placebo
Sugar pill manufactured to mimic metformin 1000mg
Active Comparator: Metformin tolerant & metformin
Metformin 1000mg once
Drug: Metformin
Metformin 1000mg once
Other Names:
  • Glucophage
Placebo Comparator: Metformin tolerant and placebo
Placebo 1000mg once
Drug: Placebo
Sugar pill manufactured to mimic metformin 1000mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lactate to pyruvate ratio
Time Frame: 2 weeks
Meal tolerance test. Absolute levels and ratios of L/P will be compared pre and post metformin and between group by analysis of variance for repeated measures where the covariance is group (tolerant or intolerant) and drug (metformin vs placebo).
2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Genomic testing
Time Frame: 2 weeks
The subjects will have genomic testing for variations in cellular transporters
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Louis University

Collaborators

Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 15, 2018

Primary Completion (Actual)

October 27, 2020

Study Completion (Actual)

October 27, 2020

Study Registration Dates

First Submitted

February 19, 2018

First Submitted That Met QC Criteria

February 19, 2018

First Posted (Actual)

February 26, 2018

Study Record Updates

Last Update Posted (Actual)

October 28, 2020

Last Update Submitted That Met QC Criteria

October 27, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 25319

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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