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

Diabetes Mellitus, Type 2 Clinical Trial

— SUGAR-MGH  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01762046
• Other study ID #: 2007p000193
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 2008
• Est. completion date: December 2025

Study information

• Verified date: April 2024
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1033
• Est. completion date: December 2025
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Glipizide

• Metformin

Other:
• Oral Glucose Tolerance Test

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Brigham and Women's Hospital, Broad Institute, Joslin Diabetes Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype	Investigators will measure glucose levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci.	0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1)
Primary	Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype	Investigators will measure insulin levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci.	0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1)
Primary	Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2	Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula.	Day 1 (Visit 1) and Day 8 (Visit 2)
Primary	Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2	Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula. A bigger difference/drop between visit 1 and visit 2 will show that metformin had an effect on insulin resistance index for these participants. The higher the HOMA-IR, the more insulin resistant you are.	Day 1 (Visit 1) and Day 8 (Visit 2)
Secondary	Incretin Levels	Investigators will measure GLP-1 and GIP during the OGTT from 0 to 120 minutes of Visit 2, and compare them by genotype at selected loci.	0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2)
Secondary	Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146	Investigators will measure proinsulin levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.	Day 1 (Visit 1) and Day 8 (Visit 2)
Secondary	Metabolomics	Investigators will perform metabolomic profiling of plasma samples at regular intervals during 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 study interventions.	Day 1 (Visit 1) and Day 8 (Visit 2)
Secondary	Vitamin D	Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.	Baseline
Secondary	Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146	Investigators will measure glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.	Day 1 (Visit 1) and Day 8 (Visit 2)