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Pharmacogenetics of SGLT2 Inhibitors (SGLT2iPGx)

Primary Purpose

Diabetes Mellitus, Gout, Hyperuricemia

Status
Terminated
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Canagliflozin
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus focused on measuring SGLT2, SLC5A2, SLC5A4, SLC5A9, SLC2A9, GLUT9, SGLT3, SGLT4, pharmacogenomics

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Active Comparator

    Experimental

    Experimental

    Experimental

    Arm Label

    Wild type genotype

    Nonsense mutation in SLC5A4

    Nonsense mutation in SLC5A9

    Missense variant in SLC2A9

    Arm Description

    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.

    Research subjects who are homozygous for nonsense mutation in SLC5A4 (sodium-dependent glucose transporter-3) will be studied before and after canagliflozin treatment.

    Research subjects who are homozygous for nonsense mutation in SLC5A9 (sodium-dependent glucose transporter-4) will be studied before and after canagliflozin treatment.

    Research subjects who are homozygous for nonsynonymous variant in glucose transporter-9 (SLC2A9) will be studied before and after canagliflozin treatment.

    Outcomes

    Primary Outcome Measures

    Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
    The pharmacodynamic response to canagliflozin will be assessed by measuring the increase in 24 hour urinary glucose excretion.
    Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before 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.

    Secondary Outcome Measures

    Canagliflozin-induced Change in Urinary Excretion of Sodium
    The pharmacodynamic response to canagliflozin will be assessed by measuring the % increase in 24 hour urinary excretion of sodium.
    Canagliflozin-induced Change in Serum Creatinine
    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine
    Canagliflozin-induced Change in Serum Uric Acid
    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level
    Canagliflozin-induced Change in Fasting Plasma Glucose
    The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)

    Full Information

    First Posted
    April 24, 2015
    Last Updated
    July 31, 2022
    Sponsor
    University of Maryland, Baltimore
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02462421
    Brief Title
    Pharmacogenetics of SGLT2 Inhibitors
    Acronym
    SGLT2iPGx
    Official Title
    Pharmacogenetics of Sodium-dependent Glucose Transporter-2 (SGLT2) Inhibitors
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2022
    Overall Recruitment Status
    Terminated
    Why Stopped
    Did not meet recruitment targets.
    Study Start Date
    June 1, 2015 (Actual)
    Primary Completion Date
    December 31, 2021 (Actual)
    Study Completion Date
    December 31, 2021 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of Maryland, Baltimore
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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.
    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)).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Diabetes Mellitus, Gout, Hyperuricemia
    Keywords
    SGLT2, SLC5A2, SLC5A4, SLC5A9, SLC2A9, GLUT9, SGLT3, SGLT4, pharmacogenomics

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 4
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    30 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Wild type genotype
    Arm Type
    Active Comparator
    Arm Description
    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.
    Arm Title
    Nonsense mutation in SLC5A4
    Arm Type
    Experimental
    Arm Description
    Research subjects who are homozygous for nonsense mutation in SLC5A4 (sodium-dependent glucose transporter-3) will be studied before and after canagliflozin treatment.
    Arm Title
    Nonsense mutation in SLC5A9
    Arm Type
    Experimental
    Arm Description
    Research subjects who are homozygous for nonsense mutation in SLC5A9 (sodium-dependent glucose transporter-4) will be studied before and after canagliflozin treatment.
    Arm Title
    Missense variant in SLC2A9
    Arm Type
    Experimental
    Arm Description
    Research subjects who are homozygous for nonsynonymous variant in glucose transporter-9 (SLC2A9) will be studied before and after canagliflozin treatment.
    Intervention Type
    Drug
    Intervention Name(s)
    Canagliflozin
    Other Intervention Name(s)
    Invokana
    Intervention Description
    A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
    Primary Outcome Measure Information:
    Title
    Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
    Description
    The pharmacodynamic response to canagliflozin will be assessed by measuring the increase in 24 hour urinary glucose excretion.
    Time Frame
    24 hours after administration of canagliflozin
    Title
    Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
    Description
    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.
    Time Frame
    24 hour urine collection after administration of canagliflozin
    Secondary Outcome Measure Information:
    Title
    Canagliflozin-induced Change in Urinary Excretion of Sodium
    Description
    The pharmacodynamic response to canagliflozin will be assessed by measuring the % increase in 24 hour urinary excretion of sodium.
    Time Frame
    24 hours after administration of canagliflozin
    Title
    Canagliflozin-induced Change in Serum Creatinine
    Description
    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine
    Time Frame
    24 hours after administration of canagliflozin
    Title
    Canagliflozin-induced Change in Serum Uric Acid
    Description
    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level
    Time Frame
    24 hours after administration of canagliflozin
    Title
    Canagliflozin-induced Change in Fasting Plasma Glucose
    Description
    The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)
    Time Frame
    24 hrs

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    21 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    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)
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Simeon I Taylor, MD, PhD
    Organizational Affiliation
    University of Maryland, Baltimore
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    IPD Sharing Plan Description
    Individual participant data will not be shared in order to protect confidentiality of research subjects.

    Learn more about this trial

    Pharmacogenetics of SGLT2 Inhibitors

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