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

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

Overview[ - collapse ][ - ]

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	Diabetes Mellitus, Type 2
Intervention	Drug: Glipizide Drug: Metformin Other: Oral Glucose Tolerance Test
Phase	Phase 1
Sponsor	Massachusetts General Hospital
Responsible Party	Massachusetts General Hospital
ClinicalTrials.gov Identifier	NCT01762046
First Received	December 28, 2012
Last Updated	January 4, 2013
Last verified	January 2013

Tracking Information[ + expand ][ + ]

First Received Date	December 28, 2012
Last Updated Date	January 4, 2013
Start Date	January 2008
Estimated Primary Completion Date	Not Provided
Current 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.
Current 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.

Descriptive Information[ + expand ][ + ]

Brief Title	Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans
Official Title	Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans
Brief Summary	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.
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.
Study Type	Interventional
Study Phase	Phase 1
Study Design	Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Condition	Diabetes Mellitus, Type 2
Intervention	Drug: Glipizide Drug: Metformin Other: Oral Glucose Tolerance Test
Study Arm (s)	Other: 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.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	1000
Estimated Completion Date	Not Provided
Estimated Primary Completion Date	December 2014
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
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	Accepts Healthy Volunteers
Contacts	Contact: Amelia Lanier, BA 617-643-5419 sugarmgh@partners.org
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01762046
Other Study ID Numbers	2007p000193
Has Data Monitoring Committee	Yes
Information Provided By	Massachusetts General Hospital
Study Sponsor	Massachusetts General Hospital
Collaborators	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
Verification Date	January 2013

Locations[ + expand ][ + ]

Massachusetts General Hospital	Boston, Massachusetts, United States, 02114 Contact: Amelia Lanier \| sugarmgh@partners.org Principal Investigator: Jose C Florez, MD, PhD Recruiting
Joslin Diabetes Center	Boston, Massachusetts, United States, 02116 Contact: Corinne Barbato, BS \| 617-309-4478 \| Corinne.Barbato@joslin.harvard.edu Principal Investigator: Allison Goldfine, MD Recruiting
Brigham and Women's Hospital	Boston, Massachusetts, United States, 02116 Contact: Marlene Fernandez, BS \| 617-643-5417 \| sugarmgh@partners.org Principal Investigator: Margo Hudson, MD Recruiting