The Effect of Sodium-glucose Cotransporter (SGLT) 2 Inhibitors on Cystine Stone Formation: A Preliminary Study

Cystinuria is an inherited autosomal recessive disorder of the kidney that is the result of an inability to reabsorb cystine from the urine. Supersaturation of cystine in the urine produces crystals that precipitate and form stones in the kidney, which can be a cause of obstruction, infection, and chronic kidney disease. Cystine stones constitute a major health challenge for affected individuals with cystinuria because of the frequent recurrence of painful symptoms and the current absence of effective, patient-accepting treatment.

A mainstay of therapy is breaking or preventing the cystine bond on the molecular level such that cystine (which is formed from the joining of two cysteine amino acids and their corresponding sulfur atoms) cannot precipitate in the urine. It is hypothesized that a glucose molecule may be able to do this if introduced into the urine. SGLT-2 inhibitors are a class of drug that are FDA approved to treat diabetes mellitus (DM) and heart failure by inhibiting an enzyme in the kidney that allows for reabsorption of glucose from the urine. This effectively increases the concentration of glucose in the urine. Our hypothesis suggests that administration of this drug to patients with cystine will introduce sufficient glucose into the urine to prevent the formation of cystine stones. To date, there has been no published data on the effectiveness of this therapy for this indication, although the dosage and administration would be identical to that already approved by the FDA for the treatment of DM and heart failure.

Study Overview

• Status: Recruiting
• Conditions: Cystinuria
• Intervention / Treatment: Drug: Dapagliflozin

Detailed Description

This is a single center, proof of concept prospective cohort trial designed to assess the effect of daily oral administration of dapagliflozin on cystine formation in freshly voided urine. Five subjects are planned, each with previously diagnosed cystinuria and without current treatment except with potassium citrate medication.

Total duration of subject participation with be up to four weeks. Total duration of the study is expected to be 6 months.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Victoria Hogue; Phone Number: 415-302-7443; Email: victoria.hogue@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Sub-Investigator: Max Bowman, MD
      • Contact: Victoria Hogue; Phone Number: 415-302-7443; Email: victoria.hogue@ucsf.edu
      • Principal Investigator: Marshall Stoller, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• males and females age 18 or older
• documented cystinuria on prior 24-hour urine collection and/or stone analysis
• history of previous cystine kidney stones
• able and willing to provide consent

Exclusion Criteria:

• prior diagnosis of diabetes mellitus (type I or type II)
• current SGLT-2 inhibitor administration at the time of screening
• SGLT-2 inhibitor administration within the last year prior to screening
• vulnerable populations including incarceration status
• anticipation of pregnancy during the study duration
• unable to give informed consent
• non-English primary language
• pregnancy, lactation, or child- bearing age without birth control devices
• serious illness likely to cause death within the next 5 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Drug; The study drug Dapagliflozin	Drug: Dapagliflozin; Dapagliflozin is to lower blood sugar levels in adults with type 2 diabetes.; Other Names: FARXIGA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cysteine level in freshly voided urine	Utilizing mass spectrometry, the research team will determine the effect of SGLT-2 inhibitor therapy on quantitative sulfur as a surrogate for presence of cysteine in freshly voided urine in patients with cystinuria. This will be assessed by comparing the qualitative and quantitative differences between the mass spectrometry output data between the participants' freshly voided urine at the initial visit and at the follow up visit after initiation of SGLT-2 inhibitor therapy, specifically examining the quantitative sulfur content between the two samples as a surrogate for cysteine in the urine.	Samples collected at Initial visit and Day 7 visit, preserved and stored; mass spectometry analysis done over the course of 6 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Marshall Stoller, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Estimated): May 2, 2025
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 17, 2021
• First Submitted That Met QC Criteria: March 23, 2021
• First Posted (Actual): March 26, 2021

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Renal Tubular Transport, Inborn Errors; Renal Aminoacidurias; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cystinuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: SGLT2

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No