Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1

Summary: 
      Metformin is a biguanide that is marketed as an oral anti-diabetic drug. Metformin treatment
      in concert with diet and exercise is the consensus first-line treatment for type 2 diabetes
      mellitus (T2DM), and therefore it will likely be an adjunct therapy for all assets in
      development by GSK for the treatment of T2DM. Metformin has potent effects in lowering
      circulating glucose concentrations, and it is believed to have additional benefits in
      improving macrovascular outcomes, fatty liver disease and polycystic ovarian syndrome. Its
      use in a significant proportion of T2DM subjects is limited by contraindications of heart
      failure and renal insufficiency or gastrointestinal side effects. The mechanisms underlying
      its glucose-lowering effect and adverse event profile of metformin are not well understood.
      Whilst activation of AMP kinase may be important for therapeutic effect, changes in incretin
      secretion and bile acid excretion have been described, but not consistently linked to its
      therapeutic effect or AE profile. The aim of this study is to recruit T2DM patients on
      prescribed metformin monotherapy to further investigate how the glucose effects are related
      to the alterations in bile acid absorption, incretin and lipid profiles by studying these
      parameters on and off the drug. This will be done in combination with frequent capillary
      blood glucose monitoring to ensure patient safety. This study will facilitate the development
      of a pharmacodynamic model that can be used by clinical teams developing non-absorbable NCEs
      such as iBAT inhibitors.
    

Detailed description: 
      As metformin has become first-line therapy for T2DM patients in many countries, it is
      important to ensure early-on in development that novel anti-diabetic NCEs work well as
      add-ons to this drug. Furthermore, the broad spectrum of effects of metformin that may be
      related to its glucose-lowering action offers the opportunity to use this drug as an
      investigative tool to explore the relationship between the various pharmacodynamic endpoints.
      In this situation, reliable PD endpoints are essential because systemic PK measurements are
      not available to track how a NCE target is being activated or inhibited. Therefore, a clearer
      understanding of metformin's mechanism of action as it relates to glycaemic control, lipid
      metabolism, bile acid excretion and gastrointestinal adverse effects will enable the
      EnteroEndocrine (EE) project teams to design more efficient studies for the evaluation of
      non-absorbable NCEs targeted to receptors that are accessible from the gut lumen, including
      the ileal bile acid transport inhibitor.

      Because of the complexity of metformin kinetics within the gut, it is proposed to follow the
      rise and fall of fasting blood glucose during metformin washout and re-introduction,
      respectively, to determine the two appropriate timepoints for more detailed investigation.

      As a result, subjects will be studied on 4 occasions:

        1. Whilst on their usual stable dose of metformin (baseline state),

        2. 7 days after stopping metformin to replicate the washout paradigm frequently used in
           early phase T2DM studies in GSK

        3. When fasting capillary glucose has increased by 25% from the pre-metformin washout level
           or two weeks from the start of the wash-out period.

        4. After metformin is re-introduced, when fasting capillary glucose has returned to the
           pre-metformin washout level (baseline state established at screening )

      This study will entail the withdrawal and re-introduction of metformin under closely
      supervised conditions. The withdrawal of metformin will be for a maximum period up to three
      weeks and the glucose increases projected are not expected to result in significant long-term
      risk for the subjects.

      If subjects do not already test blood glucose at home, a glucometer, instructions on its use,
      and testing strips will be provided to them for capillary blood glucose (CBG) monitoring
      during withdrawal and reinstatement of metformin. They will be instructed to test their blood
      glucose twice a day, fasting before breakfast and before dinner, and at any time they are
      concerned that blood glucose may have risen excessively. A written diary card will be kept by
      each subject for recording CBG values, beginning approximately 7 days before discontinuation
      of metformin after baseline assessments are completed during visit 1.

      Fasting CBG values >15mM or < 3.5mM must be reported to the site at once. If fasting CBG are
      >15mM or < 3.5 mM on any two consecutive days during the wash-out period, the subject will be
      discontinued and the usual dose of metformin will be reinstated, if appropriate

      Subjects are required to call the study centre while not in the unit or to alert site staff
      while in the clinical unit:

        1. When they have CBG values that are >15mM

        2. When they have CBG values that are <3.5mM

        3. When they have any concerns relating to their CBG levels

        4. When they have rapid, unexplained changes in their blood glucose levels

      Study staff will attempt to contact the subjects daily to check on the CBG values and to
      record any adverse events whilst the subject is at home.

      Subjects will be encouraged to keep their usual lifestyle in term of diet and exercise for
      all duration of the study.

      The Entero-Test device is simple, safe device for the collection of duodenal bile. It is well
      tolerated, although some subjects may feel slight nausea on removal. Some blood may be seen
      on the string when removed. This occurs if the string "nicks" the oesophagus on removal, this
      is very minor trauma that heals rapidly and is not a cause for concern.

      Primary enpoints-During metformin wash out and when treatment reinstated, pharmacodynamic
      endpoints will include the following as data permit:

        -  24h profiles of blood glucose and insulin

        -  Faecal and serum bile acid profiles

        -  Enteroendocrine peptide profiling including but not limited to tGLP-1, tGIP, and tPYY

        -  Serum lipid analysis including but not limited to fasting HDL and LDL cholesterol,
           fasting and prandial TGs, ApoA1, ApoB and ApoE

      Secondary Endpoints- • Relative bile acid composition as determined by EnteroTest bile string
      sampling of duodenal bile.

      • Sparse metformin PK profiles will be determined from plasma samples
    

Intervention name(s): Metformin
Intervention type(s): Other
Intervention description(s): withdrawral
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment