The aim of this randomized trial with a 2-by-2 factorial design is to test the efficacy of the SGLT2 inhibitor empagliflozin and personalized dietary counseling based on 24-hr urine collection results and dietary assessments for kidney stone recurrence prevention in patients with calcium kidney stones.

Study interventions:

• Empagliflozin 10 mg once daily per os for 36 months
• Personalized dietary counseling for 36 months.

Control interventions:

• Placebo once daily per os for 36 months
• Generic dietary counseling for 36 months.

Background and rationale:

Nephrolithiasis is a highly prevalent kidney disorder causing substantial morbidity, reduced quality of life and enormous healthcare expenditures worldwide, in large part related to their frequent recurrence. Existing pharmacological strategies for recurrence prevention are limited, and non-pharmacological measures, predominantly dietary counseling practices, vary widely. In observational studies and post-hoc analyses of cardiovascular outcome trials, Sodium-Glucose Co-Transporter 2 inhibitor (SGLT2i) use was associated with a 26-49 % reduction in kidney stone events in patients with type 2 diabetes. In our recent randomized phase 2 SWEETSTONE trial (NCT04911660), the SGLT2i empagliflozin reduced the urinary relative supersaturation ratio for calcium phosphate by 36 % compared to placebo in non-diabetic patients with idiopathic calcium kidney stones, by far the most common kidney stone type. The therapeutic value of SGLT2is in prevention of kidney stone recurrence is unknown, and the optimal dietary counseling approach for patients with kidney stones is undefined.

Objectives:

The primary objective of the study is to assess the efficacy of empagliflozin and a personalized dietary counseling strategy in the secondary prevention of calcium kidney stones, assessed as radiologic stone recurrence at 3 years.

The secondary objectives of the study are to assess the effect of the interventions (empagliflozin versus placebo and personalized versus generic dietary counseling) on both the recurrence and cumulative number of symptomatic kidney stones within 3 years.

Methodology:

The investigators will include 400adult (≥ 18 years) patients with recurrent (≥ 2 kidney stone episodes in the last 10 years) calcium kidney stones (containing 50% or more of calcium oxalate, calcium phosphate or a mixture of both). Patients with known secondary causes of kidney stones will be excluded. In this randomized trial with a 2-by-2 factorial design, patients will be allocated to either empagliflozin 10mg or placebo once daily, and to either personalized or generic dietary counselling according to 24-hr urine results. Randomization will be stratified according to the number of kidney stone episodes during the 10 years before enrolment.

The primary endpoint will be radiologic kidney stone recurrence (a composite of stone growth or new stones formed assessed by computed tomography) at 3 years. Secondary endpoints will be symptomatic kidney stone recurrence up to 3 years, and the number of symptomatic recurrences over 3 years. Exploratory endpoints will be changes in blood and urine parameters, vital signs and weight; asymptomatic kidney stone passage; patient-reported pain and quality of life; and kidney stone event-related health care utilization and cost. Safety endpoints assessed will be the frequency of serious adverse events and of pre-defined adverse events of special interest.

Inclusion criteria:

1. Written, informed consent.
2. Age 18 years or older.
3. Recurrent kidney stone disease with 2 or more stone episodes in the last 10 years prior to randomization.
4. Last kidney stone containing 50% or more of CaOx, CaP or a mixture of both.
5. If taking guideline-recommended medications for kidney stone prophylaxis (e.g. citrate salts), patients must have been on a stable regimen for at least 60 days before randomization and willing to remain on this stable regimen for the duration of the study.

Exclusion criteria:

1. Known history of secondary or Mendelian causes of calcium nephrolithiasis
2. Type I diabetes mellitus
3. History of ketoacidosis
4. Chronic Kidney Disease (CKD) stage 4 or 5 (defined as CKD-EPI eGFR <30 mL/min)
5. Kidney transplant recipient
6. History of recurrent urinary tract infections, defined as >3 episodes within the year prior to randomization
7. Heart failure. Symptomatic patients with suspected heart failure must be evaluated before study enrollment
8. Treatment with an SGLT2i within 4 weeks prior to randomization.
9. Active cancer treatment
10. Pregnancy and/or breastfeeding. Women of childbearing potential (i.e., premenopausal women who have not undergone surgical sterilization and are sexually active with a male partner) must have a negative urine or blood pregnancy test prior to enrollment
11. Known allergy to the study drug
12. Inability to understand and follow the study procedures
13. Vulnerable individual, e.g. individual incapable of judgement or currently incarcerated or otherwise institutionalized (priosner), or refugee
14. Concomitant participation in another interventional clinical trial within 4 weeks prior to randomization and during the current trial
15. Prior enrollment in the EMPASTONE trial

Once results have been published, trial data will be accessible to external researchers and coded datasets corresponding to each publication will be made available. Investigators wishing to replicate the analyses or to do an individual patient meta-analysis may request the data to the Sponsor-Investigator.