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

Primary Purpose

Diabetes Mellitus, Type 2

Status
Unknown status
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Glipizide
Metformin
Oral Glucose Tolerance Test
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 2 focused on measuring Diabetes Mellitus, Type 2, Pharmacogenetics, Genetics, Obesity

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Massachusetts General Hospital
  • Brigham and Women's Hospital
  • Joslin Diabetes Center

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Glipizide and Metformin

Arm Description

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.

Outcomes

Primary Outcome Measures

Glipizide response
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
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
Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.
Proinsulin, glucagon
Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.
Metabolomics
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
Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.

Full Information

First Posted
December 28, 2012
Last Updated
January 11, 2017
Sponsor
Massachusetts General Hospital
Collaborators
Brigham and Women's Hospital, Joslin Diabetes Center, Broad Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01762046
Brief Title
Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans
Acronym
SUGAR-MGH
Official Title
Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Unknown status
Study Start Date
January 2008 (undefined)
Primary Completion Date
October 2017 (Anticipated)
Study Completion Date
October 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Brigham and Women's Hospital, Joslin Diabetes Center, Broad Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The SUGAR-MGH 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2
Keywords
Diabetes Mellitus, Type 2, Pharmacogenetics, Genetics, Obesity

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Glipizide and Metformin
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Glipizide
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Type
Other
Intervention Name(s)
Oral Glucose Tolerance Test
Primary Outcome Measure Information:
Title
Glipizide response
Description
Investigators will measure insulin and glucose levels for 240 minutes after Glipizide administration on Visit 1, and compare them by genotype at selected loci.
Time Frame
Between 0-240 minutes, Visit 1
Title
Metformin response
Description
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.
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Incretin levels
Description
Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.
Time Frame
120 minutes, Visit 2
Title
Proinsulin, glucagon
Description
Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.
Time Frame
7 days
Title
Metabolomics
Description
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.
Time Frame
7 days
Title
Vitamin D
Description
Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jose C Florez, MD, PhD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02116
Country
United States
Facility Name
Joslin Diabetes Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02116
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
31709648
Citation
Chen L, Li JH, Kaur V, Muhammad A, Fernandez M, Hudson MS, Goldfine AB, Florez JC. The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide. Diabet Med. 2020 Dec;37(12):2124-2130. doi: 10.1111/dme.14176. Epub 2019 Nov 25.
Results Reference
derived
PubMed Identifier
29326107
Citation
Srinivasan S, Kaur V, Chamarthi B, Littleton KR, Chen L, Manning AK, Merino J, Thomas MK, Hudson M, Goldfine A, Florez JC. TCF7L2 Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH). Diabetes Care. 2018 Mar;41(3):554-561. doi: 10.2337/dc17-1386. Epub 2018 Jan 11.
Results Reference
derived
PubMed Identifier
25812009
Citation
Walford GA, Colomo N, Todd JN, Billings LK, Fernandez M, Chamarthi B, Warner AS, Davis J, Littleton KR, Hernandez AM, Fanelli RR, Lanier A, Barbato C, Ackerman RJ, Khan SQ, Bui R, Garber L, Stolerman ES, Moore AF, Huang C, Kaur V, Harden M, Taylor A, Chen L, Manning AK, Huang P, Wexler D, McCarthy RM, Lo J, Thomas MK, Grant RW, Goldfine A, Hudson MS, Florez JC. The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes. PLoS One. 2015 Mar 26;10(3):e0121553. doi: 10.1371/journal.pone.0121553. eCollection 2015.
Results Reference
derived

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Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans

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