Pharmacogenetics of SGLT2 Inhibitors

NCT ID: NCT02462421

Last Updated: 2022-08-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-01
• Study Completion Date: 2021-12-31

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)).

Conditions

Diabetes Mellitus; Gout; Hyperuricemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Canagliflozin

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Canagliflozin

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Canagliflozin

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Canagliflozin

Intervention Type: DRUG

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

Interventions

Canagliflozin

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

Intervention Type: DRUG

Other Intervention Names

Invokana

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)

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Simeon I. Taylor

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Simeon I Taylor, MD, PhD

Role: STUDY_CHAIR

University of Maryland, Baltimore

References

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.

Reference Type: DERIVED

PMID: 36993363 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36945579 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R21DK105401

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HP-00058350

Identifier Type: -

Identifier Source: org_study_id