Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01357876
First received: November 4, 2010
Last updated: August 14, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Other: Metformin
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations [ Time Frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies ] [ Designated as safety issue: No ]
  • To investigate the relationship between the glucose lowering action of metformin and enteroendocrine peptide profiles including, but not limited to, incretins and PYY [ Time Frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies ] [ Designated as safety issue: No ]
  • To investigate the relationship between the glucose lowering action of metformin and lipid metabolism including, but not limited to, fasting lipids and prandial TGs [ Time Frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • • To provide a relative estimate of the composition of bile acids in bile sampled using the EnteroTest string [ Time Frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies ] [ Designated as safety issue: No ]
  • To measure sparse metformin profiles on the days when the PD endpoints are measured [ Time Frame: We will track this measure over a 5 week period. This may change as a patient's response to withdrawl and resumption of metformin varies ] [ Designated as safety issue: No ]

Enrollment: 8
Study Start Date: October 2010
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Type two diabetics
Type two diabetics
Other: Metformin
withdrawral

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. T2DM men and women between 18 -70 years of age on stable dose of metformin
  2. Subjects taking stable regimens of aspirin, ACE inhibitors, beta-blockers, calcium channel blockers, thyroid replacement hormone, and HMG-CoA reductase inhibitors (statins) will be allowed if their dose regimen(s) remain constant throughout the study period
  3. HBA1C >6.5% <8.5%
  4. BMI from 22.5 up to 37.5 kg/m2, inclusive
  5. AST, ALT, alkaline phosphatase and bilirubin less than or equal to 3xULN
  6. Has a normal ECG as determined by unit physician.
  7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  1. medically unable or unwilling to discontinue current metformin therapy for as required by the protocol and remain off medication until the completion of Visit 3
  2. past or present disease (other than T2DM) as judged by the Investigator, which may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease and endocrine disease.
  3. subject is currently on bile acid sequestrant therapy.
  4. Gastrointestinal surgery or disease that would compromise the use of the EnteroTest
  5. fasting triglycerides >450mg/dL (>5.1 mmol/L)
  6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  7. A positive pre-study drug/alcohol screen.
  8. History of regular alcohol consumption within 6 months of the study defined as:

    -An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

  9. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  10. Pregnant females as determined by positive (serum or urine) hCG test at screening or prior to dosing.
  11. Lactating females.
  12. Unwillingness or inability to follow the procedures outlined in the protocol.

12.Subject is mentally or legally incapacitated or unable to provide informed consent

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01357876

Locations
United Kingdom
GSK Investigational Site
Cambridge, Cambridgeshire, United Kingdom, CB2 2GG
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01357876     History of Changes
Other Study ID Numbers: 114453
Study First Received: November 4, 2010
Last Updated: August 14, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Bile Acids and Salts
Metformin
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 14, 2014