Trial Outcomes & Findings for Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (NCT NCT01762046)

Results Overview

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.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE1

Target enrollment

1033 participants

Primary outcome timeframe

0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1)

Results posted on

2025-05-08

Participant Flow

Participant milestones

Participant milestones
Measure	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. Glipizide Metformin Oral Glucose Tolerance Test
Overall Study STARTED	1033
Overall Study COMPLETED	1033
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

1033 subjects were enrolled and completed the study but some disqualified for various reasons like not fasting for the fasting visit due to having chewed gum, or having had black coffee, and in the end we have 1000 subjects with viable phenotype and genotype data.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Glipizide and Metformin n=1033 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Age, Continuous	47.2 years STANDARD_DEVIATION 16.2 • n=1000 Participants • 1033 subjects were enrolled and completed the study but some disqualified for various reasons like not fasting for the fasting visit due to having chewed gum, or having had black coffee, and in the end we have 1000 subjects with viable phenotype and genotype data.
Sex: Female, Male Female	557 Participants n=1033 Participants
Sex: Female, Male Male	476 Participants n=1033 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=1033 Participants
Race (NIH/OMB) Asian	59 Participants n=1033 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=1033 Participants
Race (NIH/OMB) Black or African American	229 Participants n=1033 Participants
Race (NIH/OMB) White	702 Participants n=1033 Participants
Race (NIH/OMB) More than one race	21 Participants n=1033 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=1033 Participants
Region of Enrollment United States	1033 participants n=1033 Participants
Body Mass Index (BMI)	30.14 kg/m^2 STANDARD_DEVIATION 7.1 • n=1000 Participants • 1033 subjects completed the study but 33 subjects were disqualified for various reasons (such as: having chewed gum before the fasting visits, had coffee before the fasting visit etc.), and in the end we have 1000 subjects with viable phenotype and genotype data.

PRIMARY outcome

Timeframe: 0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1)

Population: 1000 subjects were genotyped for SNP rs7903146 (in the TCF7L2 gene). We are showing Area over the curve for glucose that was measured between time 0 to 240 minutes. 10 subjects didn't pass the QC for genotype analysis.

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.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=990 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype Area over the Glucose curve for TCF7L2 CC genotype	4893.5 mg/dl x time(minutes) Standard Deviation 2079.4
Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype Area over the Glucose curve for TCF7L2 CT genotype	5032.6 mg/dl x time(minutes) Standard Deviation 2161
Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype Area over the Glucose curve for TCF7L2 TT Genotype	6011 mg/dl x time(minutes) Standard Deviation 3204.8

PRIMARY outcome

Timeframe: 0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1)

Population: 1000 subjects were genotyped for SNP rs7903146 (in the TCF7L2 gene). We are showing Area under the curve for Insulin that was measured between time 0 to 240 minutes. 10 subjects didn't pass the QC for genotype analysis.

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.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=990 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype Area under the InsulinCurve for TCF7L2 CC genotype	1141 mU/L x time (minutes) Standard Deviation 1910
Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype Area under the InsulinCurve for TCF7L2 CT genotype	1278 mU/L x time (minutes) Standard Deviation 1455
Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype Area under the InsulinCurve for TCF7L2 TT genotype	1400 mU/L x time (minutes) Standard Deviation 1447

PRIMARY outcome

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

Population: We looked at fasting glucose at Visit 2 minus fasting glucose at visit 1 to see if there are differences by genotype at rs7903146 after Metformin treatment in the 1000 subjects in this study. 10 subjects didn't pass the QC for genotype analysis.

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.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=990 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 FastingGlucose V2-FastingGlucose V1 in CC Genotype	-2.1 mg/dl Standard Deviation 8.1
Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 FastingGlucose V2-FastingGlucose V1 in CT Genotype	-2.2 mg/dl Standard Deviation 8.2
Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 FastingGlucose V2-FastingGlucose V1 in TT Genotype	-6.1 mg/dl Standard Deviation 11

PRIMARY outcome

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

Population: We looked at HOMA-IR at Visit 2 minus HOMA-IR at visit 1 to see if there are differences by genotype at rs7903146 after Metformin treatment in the 1000 subjects in this study. 10 subjects didn't pass the QC for genotype analysis.

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.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=990 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 HOMA-IR Visit 1 - HOMA IR Visit 2 in CC Gentoype	0.09 (mg/dl*uU/ml²) Standard Deviation 1.9
Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 HOMA-IR Visit 1 - HOMA IR Visit 2 in CT Gentoype	0.04 (mg/dl*uU/ml²) Standard Deviation 1.98
Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 HOMA-IR Visit 1 - HOMA IR Visit 2 in TT Gentoype	-0.45 (mg/dl*uU/ml²) Standard Deviation 0.29

SECONDARY outcome

Timeframe: 0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2)

Population: We only measured GLP-1 and GIP in a subset of the study population. We are showing Area under the curve results for GLP-1 total, GLP-1 active, and GIP by genotype at rs7903146 in TCF7L2.

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.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=168 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Incretin Levels GLP-1 Total AUC at CC genotype	1176.2 pmol/L x time (minutes) Standard Deviation 523
Incretin Levels GLP-1 Total AUC at CT genotype	1286.4 pmol/L x time (minutes) Standard Deviation 540.4
Incretin Levels GLP-1 Total AUC at TT genotype	1749.3 pmol/L x time (minutes) Standard Deviation 1399
Incretin Levels GLP-1 Active AUC at CC genotype	879 pmol/L x time (minutes) Standard Deviation 316.6
Incretin Levels GLP-1 Active AUC at CT genotype	1060.8 pmol/L x time (minutes) Standard Deviation 687.3
Incretin Levels GLP-1 Active AUC at TT genotype	1415.7 pmol/L x time (minutes) Standard Deviation 1681.2
Incretin Levels GIP AUC at CC genotype	23523 pmol/L x time (minutes) Standard Deviation 8227
Incretin Levels GIP AUC at CT genotype	24041.2 pmol/L x time (minutes) Standard Deviation 8126
Incretin Levels GIP AUC at TT genotype	20183.1 pmol/L x time (minutes) Standard Deviation 5892.8

SECONDARY outcome

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

Population: Fasting Proinsulin were measured only in a subset of study samples. We are showing fasting data at Day 1, Visit 1 and Day 8, Visit 2 by genotype at rs7903146 (in TCF7L2).

Investigators will measure proinsulin levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=589 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 1 at CC Genotype	20.5 pmol/L Standard Deviation 21.2
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 1 at CT Genotype	23.4 pmol/L Standard Deviation 25.2
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 1 at TT Genotype	25.1 pmol/L Standard Deviation 21.2
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 2 at CC Genotype	19.4 pmol/L Standard Deviation 21.6
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 2 at CT Genotype	19.1 pmol/L Standard Deviation 19
Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 ProInsulin at Visit 2 at TT Genotype	21.4 pmol/L Standard Deviation 20.9

SECONDARY outcome

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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline

Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

Population: Fasting glucagon were measured only in a subset of study samples. We are showing fasting data at Day 1, Visit 1 and Day 8, Visit 2 by genotype at rs7903146 (in TCF7L2).

Investigators will measure glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.

Outcome measures

Outcome measures
Measure	Glipizide and Metformin n=556 Participants 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. Glipizide Metformin Oral Glucose Tolerance Test
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 2 at CT Genotype	28 pg/ml Standard Deviation 15.9
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 1 at CC Genotype	29.9 pg/ml Standard Deviation 18.0
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 1 at CT Genotype	28.4 pg/ml Standard Deviation 19.7
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 1 at TT Genotype	25.7 pg/ml Standard Deviation 16.3
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 2 at CC Genotype	28.4 pg/ml Standard Deviation 16.4
Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 Glucagon at Visit 2 at TT Genotype	28.5 pg/ml Standard Deviation 17.5

Adverse Events

Glipizide and Metformin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Jose C. Florez, MD, PhD

Massachusetts General Hospital

Phone: 6176433308

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place