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

NCT01762046 | Completed Phase 1 Results DMC

• 1 other identifier: 2007p000193
• Study Type: interventional
• Target: 1,033
• Locations: 1 country
• Sites: 3

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.

Conditions

Diabetes Mellitus, Type 2

Keywords

Diabetes Mellitus, Type 2; Pharmacogenetics; Genetics; Obesity

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (3)

• Incretin Levels

  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

  Day 1 (Visit 1) and Day 8 (Visit 2)

• Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146

  Day 1 (Visit 1) and Day 8 (Visit 2)

Study Arms (1)

Glipizide and Metformin

OTHER

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

Interventions

Glipizide DRUG

Glipizide and Metformin

Metformin DRUG

Glipizide and Metformin

Oral Glucose Tolerance Test OTHER

Glipizide and Metformin

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Brigham and Women's Hospital: collaborator
• Joslin Diabetes Center: collaborator
• Broad Institute of MIT and Harvard: collaborator

Study Sites (3)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02116, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02116, United States

Location

Related Publications (3)

• 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.

  PMID: 31709648 DERIVED

• 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.

  PMID: 29326107 DERIVED

• 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.

  PMID: 25812009 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Interventions

Glipizide; Metformin; Glucose Tolerance Test

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonylurea Compounds; Sulfones; Sulfur Compounds; Organic Chemicals; Biguanides; Guanidines; Amidines; Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Investigative Techniques

Results Point of Contact

• Title: Jose C. Florez, MD, PhD
• Organization: Massachusetts General Hospital

jcflorez@partners.org

6176433308

Study Officials

• Jose C Florez, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Physician in Endocrinology

Study Record Dates

• First Submitted: December 28, 2012
• First Posted: January 7, 2013
• Study Start: January 1, 2008
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2025
• Last Updated: May 6, 2026
• Results First Posted: May 1, 2024

Record last verified: 2026-04

Locations

US (3)