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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Metformin; Drug: Glipizide; 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.

• Study Type: Interventional
• Enrollment (Actual): 1033
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02116
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02116
      • Joslin Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Metformin; Drug: Glipizide; Other: Oral Glucose Tolerance Test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Brigham and Women's Hospital; Joslin Diabetes Center; Broad Institute of MIT and Harvard
• Investigators: Principal Investigator: Jose C Florez, MD, PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2008
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2025

Study Registration Dates

• First Submitted: December 28, 2012
• First Submitted That Met QC Criteria: January 4, 2013
• First Posted (Estimated): January 7, 2013

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Genetics; Obesity; Diabetes Mellitus, Type 2; Pharmacogenetics
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Diabetes Mellitus; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Diabetes Mellitus, Type 2; Sulfur Compounds; Organic Chemicals; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Biguanides; Guanidines; Amidines; Sulfones; Blood Chemical Analysis; Clinical Chemistry Tests; Sulfonylurea Compounds; Diagnostic Techniques, Endocrine; Metformin; Glipizide; Glucose Tolerance Test
• Other Study ID Numbers: 2007p000193