Impact of OCT1 on Metformin Tolerance
Condition: Tolerance
Study type: Interventional
Phase: Phase 4

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.
    


Intervention name(s): Metformin; Omeprazole; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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).; 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.; 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.
Intervention MeSH terms: Metformin; Omeprazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Metformin; OCT1