- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02462421
Pharmacogenetics of SGLT2 Inhibitors (SGLT2iPGx)
July 31, 2022 updated by: Simeon I. Taylor, University of Maryland, Baltimore
Pharmacogenetics of Sodium-dependent Glucose Transporter-2 (SGLT2) Inhibitors
Sodium-dependent glucose transporter-2 (SGLT2) inhibitors are a new class of anti-diabetic drugs, which increase urinary glucose excretion thereby promoting weight loss and decreasing plasma glucose levels.
We hypothesize that the pharmacodynamic response to SGLT2 inhibitors (specifically canagliflozin) varies among individuals, and that a proportion of this inter-individual variation can be explained by genetic variation.
This is a pilot study in healthy, non-diabetic subjects in whom glucose and other related metabolites in the urine and plasma will be measured before and after administration of a single dose of canagliflozin.
This will allow us to characterize the inter-individual variation in the pharmacodynamic response to canagliflozin as well as determine if changes in glucose and other related metabolite levels are associated with variants in various candidate genes.
Study Overview
Status
Terminated
Conditions
Intervention / Treatment
Detailed Description
Sodium-dependent glucose transporters (SGLTs) are a family of glucose transporters expressed on the apical surface of epithelial cells in the intestines and kidneys.
Their function is to actively transport glucose across epithelia into the blood.
Members of the SGLT-family of transporters include sodium-dependent glucose transporters-1, -2, -3, and -4 (SGLT1, SGLT2, SGLT3 and SGLT4), with SGLT2 being the primary glucose transporter in the kidney.
SGLT2 inhibitors are a new class of anti-diabetic drug approved as treatments for type 2 diabetes (T2DM).
These drugs inhibit SGLT2-mediated reabsorption of glucose in the renal proximal tubule -- thereby increasing urinary glucose excretion and decreasing plasma glucose levels.
We hypothesize that the pharmacodynamic response to SGLT2 inhibitors (specifically canagliflozin) varies among individuals, and that a proportion of this inter-individual variation can be explained by genetic variation.
To explore this hypothesis, we will conduct a pilot study in healthy, non-diabetic subjects in whom glucose and other related metabolites in the urine and plasma will be measured before and after administration of a single dose of canagliflozin.
This will allow us to characterize the inter-individual variation in the pharmacodynamic response to canagliflozin as well as determine if changes in glucose and other related metabolite levels are associated with variants in candidate genes (SGLT3, SGLT4, and glucose transporter-2 (abbreviated as either GLUT9 or SLC2A9)).
Study Type
Interventional
Enrollment (Actual)
30
Phase
- Phase 4
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
21 years and older (ADULT, OLDER_ADULT)
Accepts Healthy Volunteers
Yes
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Of Amish descent
- Age 21 or older
- BMI 18-40 kg/m2
Exclusion Criteria:
- Known allergy to canagliflozin
- History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5%
- Currently taking diuretics, antihypertensive medication, uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult
- Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
- Seizure disorder
- Positive urine human chorionic gonadotropin (hCG) test or known pregnancy within 3 months of the start of the study
- Estimated glomerular filtration rate less than 60 mL/min
- Currently breast feeding or breast feeding within 3 month of the start of the study
- Liver function tests greater than 2 times the upper limit of normal
- Hematocrit less than 35%
- Currently symptomatic for urinary tract or yeast infection or history of two or more urinary tract or yeast infections in the past 12 months.
- Abnormal thyroid stimulating hormone (TSH)
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: NON_RANDOMIZED
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Wild type genotype
Research subjects with wild type genotypes at three candidate genes encoding sodium-dependent glucose transporter-3, sodium-dependent glucose transporter-4, and glucose transporter-9 (abbreviated as SLC5A4, SLC5A9, SLC2A9, respectively) will be studied before and after canagliflozin treatment.
|
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
Other Names:
|
EXPERIMENTAL: Nonsense mutation in SLC5A4
Research subjects who are homozygous for nonsense mutation in SLC5A4 (sodium-dependent glucose transporter-3) will be studied before and after canagliflozin treatment.
|
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
Other Names:
|
EXPERIMENTAL: Nonsense mutation in SLC5A9
Research subjects who are homozygous for nonsense mutation in SLC5A9 (sodium-dependent glucose transporter-4) will be studied before and after canagliflozin treatment.
|
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
Other Names:
|
EXPERIMENTAL: Missense variant in SLC2A9
Research subjects who are homozygous for nonsynonymous variant in glucose transporter-9 (SLC2A9) will be studied before and after canagliflozin treatment.
|
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
Time Frame: 24 hours after administration of canagliflozin
|
The pharmacodynamic response to canagliflozin will be assessed by measuring the increase in 24 hour urinary glucose excretion.
|
24 hours after administration of canagliflozin
|
Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
Time Frame: 24 hour urine collection after administration of canagliflozin
|
For the study arm focused on individuals with a genetic variant in SLC2A9, the pharmacodynamic response to canagliflozin will be assessed by measuring the absolute change in fractional excretion of uric acid in the urine.
Fractional excretion of uric acid represents the fraction of the calculated filtered uric acid load (serum uric acid level multiplied by the measured creatinine clearance rate) that was excreted in the urine.
|
24 hour urine collection after administration of canagliflozin
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Canagliflozin-induced Change in Urinary Excretion of Sodium
Time Frame: 24 hours after administration of canagliflozin
|
The pharmacodynamic response to canagliflozin will be assessed by measuring the % increase in 24 hour urinary excretion of sodium.
|
24 hours after administration of canagliflozin
|
Canagliflozin-induced Change in Serum Creatinine
Time Frame: 24 hours after administration of canagliflozin
|
The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine
|
24 hours after administration of canagliflozin
|
Canagliflozin-induced Change in Serum Uric Acid
Time Frame: 24 hours after administration of canagliflozin
|
The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level
|
24 hours after administration of canagliflozin
|
Canagliflozin-induced Change in Fasting Plasma Glucose
Time Frame: 24 hrs
|
The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)
|
24 hrs
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Study Chair: Simeon I Taylor, MD, PhD, University of Maryland School of Medicine
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (ACTUAL)
June 1, 2015
Primary Completion (ACTUAL)
December 31, 2021
Study Completion (ACTUAL)
December 31, 2021
Study Registration Dates
First Submitted
April 24, 2015
First Submitted That Met QC Criteria
June 1, 2015
First Posted (ESTIMATE)
June 4, 2015
Study Record Updates
Last Update Posted (ACTUAL)
August 2, 2022
Last Update Submitted That Met QC Criteria
July 31, 2022
Last Verified
July 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- HP-00058350
- R21DK105401 (NIH)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
IPD Plan Description
Individual participant data will not be shared in order to protect confidentiality of research subjects.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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