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

NCT01357876 | Completed Phase 1

• 1 other identifier: 114453
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (3)

• To investigate the relationship between the glucose lowering action of metformin and Faecal and serum bile acid concentrations

  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

  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

  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 (2)

• • To provide a relative estimate of the composition of bile acids in bile sampled using the EnteroTest string

  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

  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

Study Arms (1)

Type two diabetics

OTHER

Type two diabetics

Other: Metformin

Interventions

Metformin OTHER

withdrawral

Type two diabetics

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T2DM men and women between 18 -70 years of age on stable dose of metformin
• 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
• HBA1C \>6.5% \<8.5%
• BMI from 22.5 up to 37.5 kg/m2, inclusive
• AST, ALT, alkaline phosphatase and bilirubin less than or equal to 3xULN
• Has a normal ECG as determined by unit physician.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

You may not qualify if:

• 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
• 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.
• subject is currently on bile acid sequestrant therapy.
• Gastrointestinal surgery or disease that would compromise the use of the EnteroTest
• fasting triglycerides \>450mg/dL (\>5.1 mmol/L)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• A positive pre-study drug/alcohol screen.
• 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.
• 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.
• Pregnant females as determined by positive (serum or urine) hCG test at screening or prior to dosing.
• Lactating females.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated or unable to provide informed consent

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 2GG, United Kingdom

Location

Related Publications (1)

• Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR, Nunez DJ. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014 Jul 2;9(7):e100778. doi: 10.1371/journal.pone.0100778. eCollection 2014.

  PMID: 24988476 DERIVED

Related Links

• Results for study 114453 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2010
• First Posted: May 23, 2011
• Study Start: October 1, 2010
• Primary Completion: July 7, 2011
• Study Completion: July 7, 2011
• Last Updated: June 22, 2017

Record last verified: 2017-06

Locations

GB (1)