Clinical trial NCT02462421: Pharmacogenetics of SGLT2 Inhibitors
Official title: Pharmacogenetics of Sodium-dependent Glucose Transporter-2 (SGLT2) Inhibitors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Diabetes Mellitus
Gout
Hyperuricemia
Keywords: SGLT2
SLC5A2
SLC5A4
SLC5A9
SLC2A9
GLUT9
SGLT3
SGLT4
pharmacogenomics
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2015-06-04
Enrollment: 30
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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)).

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)

Primary outcomes:
measure: Urinary Excretion of Glucose (Measured During the 24 Hours Following Administration of Canagliflozin)
timeFrame: 24 hours after administration of canagliflozin
measure: Change in Fractional Excretion of Uric Acid (the Difference Between Data After Administration of Canagliflozin Minus Data Before Administration of Canagliflozin)
timeFrame: 24 hour urine collection after administration of canagliflozin
Secondary outcomes:
measure: Canagliflozin-induced Change in Urinary Excretion of Sodium
timeFrame: 24 hours after administration of canagliflozin
measure: Canagliflozin-induced Change in Serum Creatinine
timeFrame: 24 hours after administration of canagliflozin
measure: Canagliflozin-induced Change in Serum Uric Acid
timeFrame: 24 hours after administration of canagliflozin
measure: Canagliflozin-induced Change in Fasting Plasma Glucose
timeFrame: 24 hrs
Other outcomes:
Locations:
Study officials:
affiliation: University of Maryland, Baltimore
name: Simeon I Taylor, MD, PhD
role: STUDY_CHAIR
References: