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

Overview

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.