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TerminatedNCT02462421SGLT2iPGxUpdated Aug 2, 2022Results posted

Pharmacogenetics of SGLT2 Inhibitors

A Phase 4 interventional study of Canagliflozin in Diabetes Mellitus, Gout and Hyperuricemia, sponsored by University of Maryland, Baltimore. Terminated. Open to participants aged 21 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-08-02.

Sponsored by University of Maryland, Baltimore · Phase 4, Interventional, and Basic science

Why this study was terminated
Did not meet recruitment targets.
Phase
Phase 4
Study type
Interventional
Enrollment
30
Allocation
Non-randomized
Ages
21 Years and older
Sex
All
01

Study 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.

Read the 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)).

02

Conditions studied

  • Diabetes Mellitus
  • Gout
  • Hyperuricemia

Keywords

  • SGLT2
  • SLC5A2
  • SLC5A4
  • SLC5A9
  • SLC2A9
  • GLUT9
  • SGLT3
  • SGLT4
  • pharmacogenomics
03

In context

Diabetes Mellitus

11,089 studies on the registry are indexed under Diabetes Mellitus; 1,319 are open to participants now.

This study's enrollment of 30 is below the median of 80 across 8,491 interventional studies indexed under Diabetes Mellitus.

Browse Diabetes Mellitus studies →

Lead sponsor

University of Maryland, Baltimore is the lead sponsor of 696 studies on the registry; 131 are open to participants now.

Of its 91 completed or terminated interventional studies of FDA-regulated products, 63 (69%) have results posted.

Browse University of Maryland, Baltimore studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
21 Years and older
Sexes eligible
All
Accepts healthy volunteers
Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

  • Of Amish descent
  • Age 21 or older
  • BMI 18-40 kg/m2

Exclusion criteria

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)
05

Study design

Phase
Phase 4
Primary purpose
Basic science
Allocation
Non-randomized
Intervention model
Single group
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • 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.

    Drug: Canagliflozin

  • 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.

    Drug: Canagliflozin

  • 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.

    Drug: Canagliflozin

  • 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.

    Drug: Canagliflozin

Interventions

  • DrugCanagliflozin

    A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.

    Also known as: Invokana

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 24 hours after administration of canagliflozin

  2. 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.

    Time frame: 24 hour urine collection after administration of canagliflozin

Secondary outcomes

  1. 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.

    Time frame: 24 hours after administration of canagliflozin

  2. Canagliflozin-induced Change in Serum Creatinine

    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine

    Time frame: 24 hours after administration of canagliflozin

  3. Canagliflozin-induced Change in Serum Uric Acid

    The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level

    Time frame: 24 hours after administration of canagliflozin

  4. Canagliflozin-induced Change in Fasting Plasma Glucose

    The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)

    Time frame: 24 hrs

07

Results

Posted Aug 1, 2022
Limitations and caveats
Small sample size: We had hoped to recruit more participants, but the need to collect two 24 hour urine samples turned out to be a major obstacle. Small pilot study conducted in healthy volunteers rather than the target population for SGLT2 inhibitors. Genetic studiy conducted in a Founder Population (Old Order Amish living in Lancaster County). Lancaster Amish chosen because of the availability of genotyping data and existence of infrastructure enabling genotype-directed "call-back" studies.

Participant flow

We over-estimated the percentage of people who would agree to participate in this clinical trial. Ultimately, we terminated the study after 30 participants had completed the clinical trial.

Participant flow — Overall Study
MilestoneWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9
Started13467
Completed13467
Not completed0000

Outcome measures

PrimaryUrinary 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.

Time frame:
24 hours after administration of canagliflozin
Reported as:
Mean · glucose (g)/creatinine (g)
Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
glucose (g)/creatinine (g)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Population
Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)37.6 ± 2.137.1 ± 3.339.1 ± 2.536.9 ± 2.737.7 ± 1.2
Statistical analysis
  • Wild Type Genotype vs Nonsense Mutation in SLC5A4 · t-test, 2 sided · p = 0.92 (No adjustment for multiple comparisons. Viewed as unnecessary inasmuch as none of the comparisons achieved p\<0.05.)
  • Wild Type Genotype vs Nonsense Mutation in SLC5A9 · t-test, 2 sided · p = 0.63 (Not corrected for multiple comparisons)
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.86 (Not adjusted for multiple comparisons)
PrimaryChange 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.

Time frame:
24 hour urine collection after administration of canagliflozin
Reported as:
Mean · absolute change in fractional excretion
Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
absolute change in fractional excretionWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Population
Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)0.25 ± 0.020.25 ± 0.020.28 ± 0.040.38 ± 0.050.29 ± 0.02
Statistical analysis
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.04 (Because the study was terminated early, we did not have sufficient statistical power to adjust for multiple comparisons. We are reporting a nominal p-value without adjusting for multiple comparisons)
SecondaryCanagliflozin-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.

Time frame:
24 hours after administration of canagliflozin
Reported as:
Mean · % increase in urinary Na excretion
Canagliflozin-induced Change in Urinary Excretion of Sodium
% increase in urinary Na excretionWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Population
Canagliflozin-induced Change in Urinary Excretion of Sodium20 ± 1266 ± 1718 ± 1048 ± 4132 ± 11
Statistical analysis
  • Wild Type Genotype vs Nonsense Mutation in SLC5A4 · t-test, 2 sided · p = 0.07 (Not corrected for multiple comparisons)
  • Wild Type Genotype vs Nonsense Mutation in SLC5A9 · t-test, 2 sided · p = 0.53 (Not corrected for multiple comparisons.)
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.92 (Not corrected for multiple comparisons.)
SecondaryCanagliflozin-induced Change in Serum Creatinine

The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine

Time frame:
24 hours after administration of canagliflozin
Reported as:
Mean · mg/dL
Canagliflozin-induced Change in Serum Creatinine
mg/dLWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Population
Canagliflozin-induced Change in Serum Creatinine0.06 ± 0.02-0.03 ± 0.020.07 ± 0.020.05 ± 0.020.04 ± 0.01
Statistical analysis
  • Wild Type Genotype vs Nonsense Mutation in SLC5A4 · t-test, 2 sided · p = <0.01 (Not corrected for multiple comparisons.)
  • Wild Type Genotype vs Nonsense Mutation in SLC5A9 · t-test, 2 sided · p = 0.77 (Not corrected for multiple comparisons.)
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.65 (Not corrected for multiple comparisons.)
SecondaryCanagliflozin-induced Change in Serum Uric Acid

The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level

Time frame:
24 hours after administration of canagliflozin
Reported as:
Mean · % change in serum uric acid level
Canagliflozin-induced Change in Serum Uric Acid
% change in serum uric acid levelWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Study Population
Canagliflozin-induced Change in Serum Uric Acid-22 ± 1.9-29 ± 4.2-12 ± 2.6-17 ± 3.0-20 ± 1.6
Statistical analysis
  • Wild Type Genotype vs Nonsense Mutation in SLC5A4 · t-test, 2 sided · p = 0.20 (Because the study was terminated early, the study does not have sufficient statistical power to adjust for multiple comparisons. Accordingly, nominal p-values are reported.)
  • Wild Type Genotype vs Nonsense Mutation in SLC5A9 · t-test, 2 sided · p = 0.01
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.16 (Not corrected for multiple comparisons.)
SecondaryCanagliflozin-induced Change in Fasting Plasma Glucose

The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg)

Time frame:
24 hrs
Reported as:
Mean · mg/dL
Canagliflozin-induced Change in Fasting Plasma Glucose
mg/dLWild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total Study Population
Canagliflozin-induced Change in Fasting Plasma Glucose-5.0 ± 1.5-2.0 ± 1.6-4.7 ± 2.8-3.4 ± 1.0-4.2 ± 0.9
Statistical analysis
  • Wild Type Genotype vs Nonsense Mutation in SLC5A4 · t-test, 2 sided · p = 0.21 (Not corrected for multiple comparisons.)
  • Wild Type Genotype vs Nonsense Mutation in SLC5A9 · t-test, 2 sided · p = 0.92 (Not corrected for multiple comparisons.)
  • Wild Type Genotype vs Missense Variant in SLC2A9 · t-test, 2 sided · p = 0.39 (Not corrected for multiple comparisons.)

Adverse events

Collected over Participants received a single dose of canagliflozin (300 mg). The primary assessment of adverse events was during the 48 hours in which people were actively participating in the clinical trial (encompassing the two 24-hour urine collections).. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Total Population of Participants in the Clinical Trial0/30 (0%)0/30 (0%)2/30 (6.7%)
Most frequent other events
Most frequent other events
EventTotal Population of Participants in the Clinical Trial
Accident while driving a horse-drawn buggyMusculoskeletal and connective tissue disorders1/30
Loose stoolsGastrointestinal disorders1/30

Baseline characteristics

Age, Continuous
Age, Continuous(Years)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Mean58.6 (35 to 77)57.5 (49 to 70)58.2 (37 to 82)56.1 (37 to 73)57.8 (35 to 82)
Sex: Female, Male
Sex: Female, Male(Participants)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Female914317
Male432413
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Hispanic or Latino00000
Not Hispanic or Latino1346730
Unknown or Not Reported00000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
American Indian or Alaska Native00000
Asian00000
Native Hawaiian or Other Pacific Islander00000
Black or African American00000
White1346730
More than one race00000
Unknown or Not Reported00000
Region of Enrollment
Region of Enrollment(Participants)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
United States1346730
BMI
BMI(kg/m^2)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Mean28.4 ± 5.330.1 ± 3.528.2 ± 5.925.7 ± 3.228.0 ± 4.8
Serum creatinine
Serum creatinine(mg/dL)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Mean0.72 ± 0.150.79 ± 0.080.74 ± 0.130.75 ± 0.110.74 ± 0.12
eGFR
eGFR(mL/min/1.73m^2)Wild Type GenotypeNonsense Mutation in SLC5A4Nonsense Mutation in SLC5A9Missense Variant in SLC2A9Total
Mean95.3 ± 14.696.5 ± 8.396.0 ± 14.398.0 ± 17.196.4 ± 13.9

7 further baseline measures are reported on the registry.

08

Study locations

No study locations are listed for this record.

09

References and documents

Publications

  • Taylor SI, Montasser ME, Yuen AH, Fan H, Yazdi ZS, Whitlatch HB, Mitchell BD, Shuldiner AR, Muniyappa R, Streeten EA, Beitelshees AL. Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness. medRxiv [Preprint]. 2023 May 3:2023.03.15.23287166. doi: 10.1101/2023.03.15.23287166. PubMed 36993363 ↗
  • Taylor SI, Cherng HR, Yazdi ZS, Montasser ME, Whitlatch HB, Mitchell BD, Shuldiner AR, Streeten EA, Beitelshees AL. Pharmacogenetics of SGLT2 Inhibitors: Validation of a sex-agnostic pharmacodynamic biomarker. medRxiv [Preprint]. 2023 Jun 12:2023.03.07.23286875. doi: 10.1101/2023.03.07.23286875. PubMed 36945579 ↗

Study documents

  • Protocol and statistical analysis plan · May 16, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — Individual participant data will not be shared in order to protect confidentiality of research subjects.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 2, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02462421
Lead sponsor
University of Maryland, Baltimore
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Responsible party
Simeon I. Taylor (Professor of Medicine, University of Maryland, Baltimore) — Principal investigator
First posted
Jun 4, 2015
Start date
Jun 1, 2015
Primary completion
Dec 31, 2021
Completion
Dec 31, 2021
Results posted
Aug 1, 2022
Last update
Aug 2, 2022

Study contacts

Simeon I Taylor, MD, PhD
study chair · University of Maryland, Baltimore

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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