Impact of OCT1 on Metformin Tolerance

Summary

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.

Conditions

• Tolerance

Interventions

DRUG

Metformin

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).

DRUG

Omeprazole

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.

DRUG

Placebo

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.

Sponsors & Collaborators

• University of Dundee

  collaborator OTHER

• NHS Tayside

  lead OTHER_GOV

Principal Investigators

• Ewan R Pearson, MBBCh, PhD · University of Dundee / NHS Tayside

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2016-03-31

Primary Completion

2018-04-09

Completion

2018-04-09

Countries

• United Kingdom

Study Locations