Trial to Assess the Efficacy of EMPAgliflozin and Personalized Dietary Counseling for Kidney STONE Prevention

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 25 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:

Nephrolithiasis is a highly prevalent kidney disorder that causes substantial morbidity, reduced quality of life and enormous healthcare expenditures worldwide. Kidney stones recur frequently, with 10-year recurrence rates of up to 80 %. Existing pharmacological strategies for the prevention of kidney stone recurrence are limited, and dietary counselling practices for patients with kidney stones vary widely. In observational studies and post-hoc analyses of cardiovascular outcome trials, sodium-glucose cotransporter 2 inhibitor (SGLT2i) use was associated with a reduction in kidney stone events in patients with type 2 diabetes. In the recent randomized phase 2 trial SWEETSTONE (NCT04911660), the SGLT2i empagliflozin significantly improved the urinary lithogenic risk profile compared to placebo in non-diabetic patients with calcium kidney stones, by far the most common kidney stone type.

Rationale:

The efficacy of SGLT2is in the prevention of kidney stone recurrence in patients with kidney stones is unknown. Furthermore, the optimal dietary counseling approach for individuals with kidney stones remains unclear.

Objective:

The investigators plan to conduct a 3-year multicentric, double-blind, placebo-controlled factorial trial to assess the efficacy of empagliflozin with either a personalized or generic dietary counselling strategy for recurrence prevention in patients with calcium kidney stones.

Methodology:

The investigators will include 380 adult (≥ 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 25 mg 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.

Eligibility Criteria:
Inclusion criteria:

1. Written, informed consent.
2. Age 18 years or older.
3. Recurrent kidney stone disease (2 or more stone episodes in the last 10 years).
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. Patients with a known history of secondary or Mendelian causes of calcium nephrolithiasis
2. Type I diabetes mellitus
3. History of ketoacidosis
4. Treatment with SGLT2 Inhibitor
5. CKD (defined as CKD-EPI eGFR \<30 mL/min)
6. Kidney transplant recipient
7. History of recurrent urinary tract infections (\>3 episodes/year)
8. Active cancer treatment
9. Less than 3-year life expectancy
10. Pregnancy and breastfeeding
11. Inability to understand and follow the study protocol
12. Known allergy to the study drug
13. Concomitant participation in another interventional clinical trial