Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR MGH)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by Massachusetts General Hospital
Sponsor:
Collaborators:
Brigham and Women's Hospital
Joslin Diabetes Center
Broad Institute of Harvard and Massachusetts Institute of Technology
Information provided by (Responsible Party):
Jose C. Florez, MD, PhD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01762046
First received: December 28, 2012
Last updated: January 4, 2013
Last verified: January 2013
  Purpose

The SUGARMGH investigators are studying the influence of inherited gene variants on the response to two commonly prescribed type 2 diabetes medications, metformin and glipizide. They hypothesize that variants in genes that are associated with type 2 diabetes or related traits may impact the effect of anti-diabetic medications. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Drug: Glipizide
Drug: Metformin
Other: Oral Glucose Tolerance Test
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Glipizide response [ Time Frame: Between 0-240 minutes, Visit 1 ] [ Designated as safety issue: No ]
    Investigators will measure insulin and glucose levels for 240 minutes after Glipizide administration on Visit 1, and compare them by genotype at selected loci.

  • Metformin response [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Investigators will measure the change in glycemic measures between Visit 1 and Visit 2 as an index of Metformin response, and compare them by genotype at selected loci.


Secondary Outcome Measures:
  • Incretin levels [ Time Frame: 120 minutes, Visit 2 ] [ Designated as safety issue: No ]
    Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.

  • Proinsulin, glucagon [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.

  • Metabolomics [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Investigators will perform metabolomic profiling of plasma samples at regular intervals in Visits 1 and 2, by using initially a targeted approach on an existing platform that measures ~400 metabolites (both polar and non-polar); they will compare their relative concentrations by genotype at selected loci before and after the interventions.

  • Vitamin D [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.


Estimated Enrollment: 1000
Study Start Date: January 2008
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Glipizide and Metformin
On day 1, subjects will receive a single oral dose of glipizide 5 mg, and will have blood drawn at various time points for up to 240 minutes. During study days 2-7, the participants will fill out a dietary intake food record, including 3 weekdays and one weekend day. During days 6-8, the subject will receive a short-course metformin treatment of four 500-mg doses. On the morning of study day 8, 60 minutes after taking the fourth metformin dose, the subject will do a 75g Oral Glucose Tolerance Test. Blood draws will again be taken at time points for 120 minutes.
Drug: Glipizide Drug: Metformin Other: Oral Glucose Tolerance Test

Detailed Description:

Several common genetic variants have been reliably associated with type 2 diabetes and related glycemic traits. Study investigators hypothesize that variants in genes that are reproducibly associated with type 2 diabetes or related glycemic traits may impact the effect of anti-diabetic medications. In particular, sulfonylureas may have differential effects on individuals depending on the allelic variant they carry at KCNJ11 E23K; conversely, because TCF7L2 is postulated to influence insulin secretion by regulating the action of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a different step in the insulin secretion pathway, the effect of sulfonylureas on insulin secretion could be independent of genetic variation at TCF7L2. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.

Despite the convincing associations of several genetic variants with type 2 diabetes and their involvement in physiological pathways involved in drug response, their impact on pharmacological interventions has not been systematically examined. The completion of the Human Genome Project and the high-density characterization of common human variation in four different ethnic groups highlight the promise of genomic medicine. The elucidation of the genetic architecture of complex phenotypes may help clinicians understand disease heterogeneity, uncover new pathophysiological mechanisms, open the opportunity for novel therapeutic interventions, provide predictive diagnostic and prognostic information, and allow for individually tailored therapy that takes into account both the probability of response and the incidence of drug-induced complications.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or non-pregnant female > 18 years of age
  • Investigators will target preferentially people at risk of diabetes or requiring diabetes meds
  • The first tier of risk will be illustrated by one of the following variables (e.g. established type 2 diabetes on diet therapy alone, elevated random glucose in electronic medical record, PCOS, metabolic syndrome, obesity, history of gestational diabetes, etc.)
  • The second tier of risk will be illustrated by other features that correlate with diabetes risk, such as a history of hypertension or dyslipidemia
  • Otherwise healthy subjects may also be candidates for the study.
  • Able and willing to give consent relevant to genetic investigation

Exclusion Criteria:

  • Pregnant, nursing or at risk of becoming pregnant
  • Currently taking any medications for the treatment of diabetes
  • Currently on metformin for any other indication (e.g. PCOS)
  • Onset of diabetes in a family member before age 25, with autosomal transmission of diabetes across three generations
  • History of liver or kidney disease
  • Known severe allergic reactions to sulfonamides
  • History of porphyria
  • Documented estimated glomerular filtration rate (GFR) < 60 ml/min/1.73 m2, based on the most recent serum creatinine measurement available in the electronic medical record, and calculated by the Modification of Diet in Renal Disease equation (49) available at http://www.nephron.com/cgi-bin/MDRD_GFR.cgi
  • Currently taking medications known to affect glycemic parameters, such as glucocorticoids, growth hormone or fluoroquinolones
  • Planned radiologic or angiographic study requiring contrast within one week of completion of this study
  • Established coronary artery disease (CAD), defined as:
  • History of myocardial infarction.
  • History of revascularization (coronary artery bypass grafting, percutaneous coronary intervention (e.g. stenting or balloon angioplasty).
  • Evidence of ischemia on cardiac stress test.
  • Enrolled in any other interventional study at time of screening through completion of study protocol
  • History of bariatric surgery
  • History of seizures
  • History of stroke/CVA
  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: NCT01762046

Contacts
Contact: Amelia Lanier, BA 617-643-5419 sugarmgh@partners.org
Contact: Marlene Fernandez, BS 617-643-5417 sugarmgh@partners.org

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Amelia Lanier       sugarmgh@partners.org   
Contact: Marlene Fernandez       sugarmgh@partners.org   
Principal Investigator: Jose C Florez, MD, PhD         
Sub-Investigator: Geoffrey Walford, MD         
Sub-Investigator: Liana K Billings, MD, MMSc         
Joslin Diabetes Center Recruiting
Boston, Massachusetts, United States, 02116
Contact: Corinne Barbato, BS    617-309-4478    Corinne.Barbato@joslin.harvard.edu   
Principal Investigator: Allison Goldfine, MD         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02116
Contact: Marlene Fernandez, BS    617-643-5417    sugarmgh@partners.org   
Principal Investigator: Margo Hudson, MD         
Sub-Investigator: Bindu Chamarthi, MD, MMSc         
Sponsors and Collaborators
Massachusetts General Hospital
Brigham and Women's Hospital
Joslin Diabetes Center
Broad Institute of Harvard and Massachusetts Institute of Technology
Investigators
Principal Investigator: Jose C Florez, MD, PhD Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Jose C. Florez, MD, PhD, Assistant Physician in Endocrinology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01762046     History of Changes
Other Study ID Numbers: 2007p000193
Study First Received: December 28, 2012
Last Updated: January 4, 2013
Health Authority: United States: Federal Government

Keywords provided by Massachusetts General Hospital:
Diabetes Mellitus, Type 2
Pharmacogenetics
Genetics
Obesity

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glipizide
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014