SGLT2 Inhibition: Uric Acid Excretion Study (UREX)

Uric Acid Excretion Study: Open-label Randomised Cross Over Study

The current study investigates the effects of SGLT2 inhibitor empagliflozin on uric acid excretion.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Drug: Benzbromaron; Drug: Empagliflozin 25 MG + benzbromarone 100 mg

Detailed Description

SGTL2 inhibitors improve cardiovascular and kidney outcomes. The underlying mechanisms are incompletely understood. SGLT2 inhibitors are known to reduce plasma uric acid likely by enhanced urinary uric acid excretion.

In this study the investigators will study the effects of SGLT2 inhibit on uric acid levels and excretion in detail, linking it to the role of glucosuria and Uric acid transporter (URAT1) which in rodents was indispensable for the glucose-lowering effects of SGLT2 inhibition.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081HV
      • VU University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Caucasian Men or post-menopausal women Age 35 to 75 Diagnosed with T2D HbA1c from 6.5% to 9.0% (48-75 mmol/mol) body mass index >25 kg/m2 Treated with metformin monotherapy (stable dose for ≥3 months) with or without sulfonylurea Well-controlled blood pressure (i.e., <140/90 mm Hg). In case of previously diagnosed hypertension and/or albuminuria treatment at least a stable dose of a renin-angiotensin system (RAS) inhibitor for ≥3 months at maximal tolerable dose.

Exclusion Criteria:

History of gout history of unstable or rapidly progressing renal or malignant disease (excluding basal cell carcinoma) eGFR <60 mL/min/1.73 m2 Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation) Hemoglobin level < 7.0 mmol/L Current urinary tract infection and active nephritis Macroalbuminuria; defined as ACR of >300 mg/g. Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs).

Patients on diuretics will only be excluded when these drugs cannot be stopped 3 months prior randomization and for the duration of the study.

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing Pregnancy History of or actual severe mental disease History of or actual severe somatic disease (e.g. systemic disease) History of or actual malignancy (except basal cell carcinoma) History of or actual pancreatic disease (Unstable) thyroid disease Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) Recent (<6 months) history of cardiovascular disease, including Acute coronary syndrome Stroke or transient ischemic neurologic disorder or chronic heart failure (NYHA grade II-IV) Complaints compatible with or established neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan) Substance abuse (alcohol: defined as >3 units alcohol/day) History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.

Recent blood donation (< 6 months) Allergy to any of the agents used in the study Inability to understand the protocol and/or give informed consent Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No intervention
Experimental: Empagliflozin; Empagliflozin 25 mg once daily for one week	Drug: Empagliflozin 25 MG; 25 once daily one week treatment
Experimental: Benzbromarone; Benzbromarone 100 mg once daily for one week	Drug: Benzbromaron; 100 mg once daily 1 one week treatment
Experimental: Empagliflozin-Benzbromarone; Empagliflozin 25 mg once daily for one week combined with Benzbromarone 100 mg once daily for one week	Drug: Empagliflozin 25 MG + benzbromarone 100 mg; combined treatment once daily for one week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
plasma uric acid	change in plasma uric acid concentrations	1 week
Fractional uric acid excretion	change creatinine-adjusted fractional uric acid excretion	one week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
urinary glucose levels	glucose concentration urine	one week

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Suijk DLS, van Baar MJB, van Bommel EJM, Iqbal Z, Krebber MM, Vallon V, Touw D, Hoorn EJ, Nieuwdorp M, Kramer MMH, Joles JA, Bjornstad P, van Raalte DH. SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function. Clin J Am Soc Nephrol. 2022 May;17(5):663-671. doi: 10.2215/CJN.11480821. Epub 2022 Mar 23.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Actual): June 8, 2021
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Sodium-Glucose Transporter 2 Inhibitors; Gout Suppressants; Renal Agents; Uricosuric Agents; Empagliflozin; Benzbromarone
• Other Study ID Numbers: DCUREX2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No