Diabetes Mellitus, Gout, Hyperuricemia
Conditions
Keywords
SGLT2, SLC5A2, SLC5A4, SLC5A9, SLC2A9, GLUT9, SGLT3, SGLT4, pharmacogenomics
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)).
Interventions
DRUGCanagliflozin
A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 24 hours after 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Canagliflozin-induced Change in Urinary Excretion of Sodium | 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. |
| Canagliflozin-induced Change in Serum Creatinine | 24 hours after administration of canagliflozin | The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum creatinine |
| Canagliflozin-induced Change in Serum Uric Acid | 24 hours after administration of canagliflozin | The pharmacodynamic response to canagliflozin will be assessed by measuring changes in serum uric acid level |
| Canagliflozin-induced Change in Fasting Plasma Glucose | 24 hrs | The magnitude of the change in fasting plasma glucose 24 hours after administration of canagliflozin (300 mg) |
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Canagliflozin: A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response. | 13 |
| 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.
Canagliflozin: A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response. | 4 |
| 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.
Canagliflozin: A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response. | 6 |
| 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.
Canagliflozin: A single dose of canagliflozin (300 mg, p.o.) will be administered prior to assessing pharmacodynamic response. | 7 |
| Total | 30 |
Baseline characteristics
| Characteristic | Wild Type Genotype | Total | Missense Variant in SLC2A9 | Nonsense Mutation in SLC5A9 | Nonsense Mutation in SLC5A4 |
|---|---|---|---|---|---|
| Age, Continuous | 58.6 Years | 57.8 Years | 56.1 Years | 58.2 Years | 57.5 Years |
| BMI | 28.4 kg/m^2 STANDARD_DEVIATION 5.3 | 28.0 kg/m^2 STANDARD_DEVIATION 4.8 | 25.7 kg/m^2 STANDARD_DEVIATION 3.2 | 28.2 kg/m^2 STANDARD_DEVIATION 5.9 | 30.1 kg/m^2 STANDARD_DEVIATION 3.5 |
| creatinine clearance | 110 mL/min/1.73m^2 STANDARD_DEVIATION 29 | 113 mL/min/1.73m^2 STANDARD_DEVIATION 30 | 126 mL/min/1.73m^2 STANDARD_DEVIATION 37 | 103 mL/min/1.73m^2 STANDARD_DEVIATION 18 | 118 mL/min/1.73m^2 STANDARD_DEVIATION 31 |
| eGFR | 95.3 mL/min/1.73m^2 STANDARD_DEVIATION 14.6 | 96.4 mL/min/1.73m^2 STANDARD_DEVIATION 13.9 | 98.0 mL/min/1.73m^2 STANDARD_DEVIATION 17.1 | 96.0 mL/min/1.73m^2 STANDARD_DEVIATION 14.3 | 96.5 mL/min/1.73m^2 STANDARD_DEVIATION 8.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 30 Participants | 7 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fractional excretion of uric acid | 8.0 % of filtered uric acid that is excreted STANDARD_DEVIATION 1.3 | 8.5 % of filtered uric acid that is excreted STANDARD_DEVIATION 2.4 | 9.8 % of filtered uric acid that is excreted STANDARD_DEVIATION 2.9 | 6.2 % of filtered uric acid that is excreted STANDARD_DEVIATION 1.5 | 9.4 % of filtered uric acid that is excreted STANDARD_DEVIATION 3.7 |
| HbA1c | 5.8 % of total hemoglobin that is glycated STANDARD_DEVIATION 0.2 | 5.7 % of total hemoglobin that is glycated STANDARD_DEVIATION 0.3 | 5.5 % of total hemoglobin that is glycated STANDARD_DEVIATION 0.4 | 5.8 % of total hemoglobin that is glycated STANDARD_DEVIATION 0.2 | 5.7 % of total hemoglobin that is glycated STANDARD_DEVIATION 0.2 |
| Hematocrit | 41.8 % STANDARD_DEVIATION 2.4 | 42.0 % STANDARD_DEVIATION 3.3 | 43.3 % STANDARD_DEVIATION 3.1 | 39.9 % STANDARD_DEVIATION 4.3 | 43.8 % STANDARD_DEVIATION 4.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 30 Participants | 7 Participants | 6 Participants | 4 Participants |
| Region of Enrollment United States | 13 Participants | 30 Participants | 7 Participants | 6 Participants | 4 Participants |
| Serum creatinine | 0.72 mg/dL STANDARD_DEVIATION 0.15 | 0.74 mg/dL STANDARD_DEVIATION 0.12 | 0.75 mg/dL STANDARD_DEVIATION 0.11 | 0.74 mg/dL STANDARD_DEVIATION 0.13 | 0.79 mg/dL STANDARD_DEVIATION 0.08 |
| Serum sodium | 138.8 mEq/L STANDARD_DEVIATION 1.3 | 138.4 mEq/L STANDARD_DEVIATION 1.4 | 137.6 mEq/L STANDARD_DEVIATION 1.5 | 138.7 mEq/L STANDARD_DEVIATION 1.2 | 138.0 mEq/L STANDARD_DEVIATION 1.8 |
| Serum uric acid level | 4.60 mg/dL STANDARD_DEVIATION 0.72 | 4.38 mg/dL STANDARD_DEVIATION 0.93 | 3.74 mg/dL STANDARD_DEVIATION 0.71 | 4.05 mg/dL STANDARD_DEVIATION 1.53 | 5.25 mg/dL STANDARD_DEVIATION 0.55 |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 13 Participants | 4 Participants | 2 Participants | 3 Participants |
| Urinary sodium excretion (24 hr) | 196 mEq/day STANDARD_DEVIATION 50 | 208 mEq/day STANDARD_DEVIATION 67 | 247 mEq/day STANDARD_DEVIATION 68 | 208 mEq/day STANDARD_DEVIATION 105 | 182 mEq/day STANDARD_DEVIATION 38 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 2 / 30 |
| serious Total, serious adverse events | 0 / 30 |
Outcome results
Primary
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
Population: Data from all 30 patients are summarized. The primary statistical analysis is based on comparison of the 13 wild type genotype versus the 7 patients who are homozygous for the variant in SLC2A9 (GLUT9).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin) | 0.25 absolute change in fractional excretion | Standard Error 0.02 |
| Nonsense Mutation in SLC5A4 | Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin) | 0.25 absolute change in fractional excretion | Standard Error 0.02 |
| Nonsense Mutation in SLC5A9 | Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin) | 0.28 absolute change in fractional excretion | Standard Error 0.04 |
| Missense Variant in SLC2A9 | Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin) | 0.38 absolute change in fractional excretion | Standard Error 0.05 |
| Total Population | Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin) | 0.29 absolute change in fractional excretion | Standard Error 0.02 |
Comparison: The study was terminated early because of slow recruitment. As a result the study did not achieve the statistical power that had been planned.p-value: 0.04t-test, 2 sided
Primary
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
Population: The entire population of 30 research participants comprised the database for this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 37.6 glucose (g)/creatinine (g) | Standard Error 2.1 |
| Nonsense Mutation in SLC5A4 | Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 37.1 glucose (g)/creatinine (g) | Standard Error 3.3 |
| Nonsense Mutation in SLC5A9 | Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 39.1 glucose (g)/creatinine (g) | Standard Error 2.5 |
| Missense Variant in SLC2A9 | Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 36.9 glucose (g)/creatinine (g) | Standard Error 2.7 |
| Total Population | Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin) | 37.7 glucose (g)/creatinine (g) | Standard Error 1.2 |
Comparison: Each of the variant genotypes was compared to the control group (homozygous for major alleles at all three genetic loci) in an unpaired t-test. The study was terminated early because it was clear that we would not meet our recruitment targets and that the study was likely underpowered.~Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.92t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.63t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.86t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Canagliflozin-induced Change in Fasting Plasma Glucose | -5.0 mg/dL | Standard Error 1.5 |
| Nonsense Mutation in SLC5A4 | Canagliflozin-induced Change in Fasting Plasma Glucose | -2.0 mg/dL | Standard Error 1.6 |
| Nonsense Mutation in SLC5A9 | Canagliflozin-induced Change in Fasting Plasma Glucose | -4.7 mg/dL | Standard Error 2.8 |
| Missense Variant in SLC2A9 | Canagliflozin-induced Change in Fasting Plasma Glucose | -3.4 mg/dL | Standard Error 1 |
| Total Population | Canagliflozin-induced Change in Fasting Plasma Glucose | -4.2 mg/dL | Standard Error 0.9 |
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.21t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.92t-test, 2 sided
Comparison: Not corrected for multiple comparisons.p-value: 0.39t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Canagliflozin-induced Change in Serum Creatinine | 0.06 mg/dL | Standard Error 0.02 |
| Nonsense Mutation in SLC5A4 | Canagliflozin-induced Change in Serum Creatinine | -0.03 mg/dL | Standard Error 0.02 |
| Nonsense Mutation in SLC5A9 | Canagliflozin-induced Change in Serum Creatinine | 0.07 mg/dL | Standard Error 0.02 |
| Missense Variant in SLC2A9 | Canagliflozin-induced Change in Serum Creatinine | 0.05 mg/dL | Standard Error 0.02 |
| Total Population | Canagliflozin-induced Change in Serum Creatinine | 0.04 mg/dL | Standard Error 0.01 |
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: <0.01t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.77t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.65t-test, 2 sided
Secondary
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
Population: Data from all 30 research participants will be summarized. Statistical analysis will focus on comparisons between the 13 participants who are homozygous for the major alleles at all three loci versus the three groups who are homozygous for each of the three other genetic variants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Canagliflozin-induced Change in Serum Uric Acid | -22 % change in serum uric acid level | Standard Error 1.9 |
| Nonsense Mutation in SLC5A4 | Canagliflozin-induced Change in Serum Uric Acid | -29 % change in serum uric acid level | Standard Error 4.2 |
| Nonsense Mutation in SLC5A9 | Canagliflozin-induced Change in Serum Uric Acid | -12 % change in serum uric acid level | Standard Error 2.6 |
| Missense Variant in SLC2A9 | Canagliflozin-induced Change in Serum Uric Acid | -17 % change in serum uric acid level | Standard Error 3 |
| Total Population | Canagliflozin-induced Change in Serum Uric Acid | -20 % change in serum uric acid level | Standard Error 1.6 |
Comparison: The wild type genotype group was compared to homozygotes for each of the three other genotypes.p-value: 0.2t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.01t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.16t-test, 2 sided
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wild Type Genotype | Canagliflozin-induced Change in Urinary Excretion of Sodium | 20 % increase in urinary Na excretion | Standard Error 12 |
| Nonsense Mutation in SLC5A4 | Canagliflozin-induced Change in Urinary Excretion of Sodium | 66 % increase in urinary Na excretion | Standard Error 17 |
| Nonsense Mutation in SLC5A9 | Canagliflozin-induced Change in Urinary Excretion of Sodium | 18 % increase in urinary Na excretion | Standard Error 10 |
| Missense Variant in SLC2A9 | Canagliflozin-induced Change in Urinary Excretion of Sodium | 48 % increase in urinary Na excretion | Standard Error 41 |
| Total Population | Canagliflozin-induced Change in Urinary Excretion of Sodium | 32 % increase in urinary Na excretion | Standard Error 11 |
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.07t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.53t-test, 2 sided
Comparison: Null hypothesis: pharmacodynamic response is the same in the control group and homozygotes for the genetic variant.p-value: 0.92t-test, 2 sided