Impact of OCT1 on Metformin Tolerance

Study Overview
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Brief Summary
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Metformin is the first-line treatment for medical management of Type 2 Diabetes. Up to 25% of patients experience significant gastrointestinal symptoms and in approximate 5%, side-effects result in the discontinuation of metformin. It would be of great clinical significance if the underlying cause of this intolerance was identified. Recent data has highlighted a metformin transporter in the gut - Organic Cation Transporter 1(OCT1) - as a potential culprit for the variability in metformin tolerance. Across a diabetic population, up to one in four people were shown to have a single reduced function allele for OCT1, with approximately 8% having two reduced function alleles. This may increase the risk of the individual experiencing metformin-associated side-effects, potentially due to accumulation within the cells lining the intestine. The investigators aim to show that loss of function of OCT1, either due to genetic variation or drug inhibition of OCT1, may lead to an increase in the symptoms associated with metformin intolerance. The study is being undertaken at the Clinical Research Centre in Ninewells Hospital, Dundee. The investigators will recruit participants from the GoDARTS study (Genetics of Diabetes and Audit Research Tayside Study). The participants will be healthy controls, i.e. non-diabetic, and recruited according to their genotype of OCT1 (information from GoDARTS). The volunteers will then enter a matched cross-over study with two treatment periods. Metformin is taken during both treatment periods alongside either Omeprazole (a proton pump inhibitor used to prevent excess stomach acid, known to interact with OCT1) or placebo. The metformin dose is increased gradually during each period, to a maximum tolerated dose. The investigators expect to see a lower maximum tolerated dose in individuals with loss of function genotype, or in those taking concurrent omeprazole compared to placebo. The study will last approximately 9 weeks. Volunteers have 3 visits to the CRC, and weekly phone call interviews.

Official Title
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Impact of OCT1 Genotype and OCT1 Inhibiting Drugs on an Individual's Tolerance of Metformin

Conditions
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Tolerance

Intervention / Treatment
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* Drug: Metformin
* Drug: Omeprazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 - 80 White European (to limit genetic variation as much as possible) Non-diabetic No previous treatment with metformin No known gastrointestinal pathology e.g. inflammatory bowel disease, IBS, coeliac No daily treatment with PPI, anti-spasmodic, or anti-motility drugs No daily OCT1 inhibiting drugs Able to complete the symptom severity score and Bristol stool chart independently i.e. no cognitive impairment or visual impairment Normal renal function - eGFR>60 Known OCT1 genotype - either normal (wild type) or two reduced function alleles. Exclusion Criteria: Does not meet inclusion criteria Heterozygous OCT1 genotype i.e. only one reduced function allele Recent involvement (<30 days) in a CTIMP Pregnancy or planning to conceive Inability/unwillingness to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: OCT1 -/-<br>Cohort of patients with two loss of function alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort. | Drug: Metformin<br>* Metformin is given alongside omeprazole / placebo. Started at low dose and titrated gradually over four weeks according to the individual's tolerance of metformin. We anticipate that their tolerance of metformin will be reduced by loss of function variants in OCT1, and by concurrent use of OCT1 inhibiting drugs (in our study this is omeprazole).<br>Drug: Omeprazole<br>* Given as concurrent treatment in one of the two treatment periods. Omeprazole treatment dose is fixed at 20mg twice daily for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.<br>Drug: Placebo<br>* Given as concurrent treatment in one of the two treatment periods. Placebo treatment dose is fixed at one tablet twice daily (to match the dosing pattern of omeprazole) for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.<br>|
| Other: OCT wt/wt<br>Cohort of patients with two normal or wild type alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort. | Drug: Metformin<br>* Metformin is given alongside omeprazole / placebo. Started at low dose and titrated gradually over four weeks according to the individual's tolerance of metformin. We anticipate that their tolerance of metformin will be reduced by loss of function variants in OCT1, and by concurrent use of OCT1 inhibiting drugs (in our study this is omeprazole).<br>Drug: Omeprazole<br>* Given as concurrent treatment in one of the two treatment periods. Omeprazole treatment dose is fixed at 20mg twice daily for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.<br>Drug: Placebo<br>* Given as concurrent treatment in one of the two treatment periods. Placebo treatment dose is fixed at one tablet twice daily (to match the dosing pattern of omeprazole) for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of metformin | Each treatment period consists of four weeks. Metformin dose titrated gradually in presence of omeprazole or placebo. | At the completion of the study, after approximately 1.5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, OCT1