Last updated: 11/07/2018 07:44:18
Effect of Metformin on gut peptides , bile acids and lipid profiles in Type 2 Diabetics
Clinicaltrials.gov ID
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: Effect of Metformin on gut peptides , bile acids and lipid profiles in Type 2 Diabetics
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Randomized
Primary outcomes:
To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations
Timeframe: 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
To investigate the relationship between the glucose lowering action of metformin and enteroendocrine peptide profiles including, but not limited to, incretins and PYY
Timeframe: 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
To investigate the relationship between the glucose lowering action of metformin and lipid metabolism including, but not limited to, fasting lipids and prandial TGs
Timeframe: 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
Secondary outcomes:
• To provide a relative estimate of the composition of bile acids in bile sampled using the EnteroTest string
Timeframe: 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
To measure sparse metformin profiles on the days when the PD endpoints are measured
Timeframe: 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
Interventions:
Enrollment:
8
Primary completion date:
Not applicable
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Antonella Napolitano,Sam R Miller, Aaron Spivak, Andrew W. Nicholls, David Baker, Deepak K. Rajpal, James R. Brown, Derek J. Nunez. Novel gut-based pharmacology of metformin in patients with Type 2 Diabetes Mellitus.PLoS ONE.2014;Jul2; 9(7):e100778
Medical condition
Diabetes Mellitus, Type 2
Product
Not applicable
Collaborators
Not applicable
Study date(s)
October 2010 to July 2011
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18 - 70 years
Accepts healthy volunteers
No
- 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
- 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.
Inclusion and exclusion 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
Trial location(s)
Location
GSK Investigational Site
Cambridge, Cambridgeshire, United Kingdom, CB2 2GG
Status
Study Complete
Study documents
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Refer to study documents
Recruitment status
Study complete
Actual primary completion date
Not applicable
Actual study completion date
2011-07-07
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
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Additional information
Results for study 114453 can be found on the GSK Clinical Study Register.
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