Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers
Condition: Kidney Stone
MeSH terms: Kidney Calculi; Nephrolithiasis
Study type: Interventional
Phase: Phase 2

Summary: 
      The aim of this study is to test the effect of a new drug on the composition of the urine in
      kidney stone patients. This new drug (Jardiance®, substance: empagliflozin) is currently
      approved in Switzerland for the treatment of patients with diabetes. Data from previous
      studies with and without diabetes suggest that it may have a beneficial effect on the
      composition of the urine and thereby reduce the risk of developing kidney stones.
    

Detailed description: 
      Kidney stones - a global epidemic associated with obesity and diabetes

      Kidney stones are a worldwide healthcare problem with a current lifetime risk of ~18.8 % in
      men and ~9.4 % in women in Western civilizations. Recurrence rates are high, up to 40 % and
      75 % at 5 and 10 years, respectively. Hospitalizations, surgery and lost work time associated
      with kidney stones cause enormous healthcare-related expenditures. Although kidney stone
      disease is traditionally considered an isolated renal disorder, there is overwhelming
      evidence that it is in fact a systemic disease. Arterial hypertension, obesity, diabetes
      mellitus, gouty diathesis, dyslipidemia, cardiovascular disease, chronic kidney disease and
      low bone mass are much more prevalent in kidney stone formers than in non-stone formers. It
      is currently unknown if stone disease is a cause of this co-morbidity per se or if it is a
      consequence of the same underlying conditions that lead to these disorders and kidney stones.
      Clearly, however, these co-morbidities contribute significantly to stone-related morbidity
      and mortality.

      The strong, positive and independent association of Body Mass Index (BMI) with kidney stone
      disease is well established. The magnitude of the increased risk is larger in women than in
      men. In addition to BMI, significant weight gain is also associated with a greater risk of
      developing symptomatic kidney stone disease in the future. In recent decades, the prevalence
      of both kidney stone disease and obesity increased significantly, irrespective of age, sex
      and race. In large cross-sectional analyses, the prevalence of both symptomatic and
      asymptomatic kidney stones increased proportionally with the number of metabolic syndrome
      features present. Both calcium and uric acid stones are associated with obesity, but the
      ratio of calcium stones to uric acid stones is lower in obese compared to non-obese stone
      formers, suggesting a disproportionate increase of uric acid stone disease in obesity.
      Absolute urinary excretion rates of stone formation promoters (calcium, phosphate, oxalate
      and uric acid) as well as urinary supersaturation ratios for calcium oxalate and uric acid
      are increased in obese individuals. In addition, there is a well documented negative
      association of BMI with urinary pH in both stone formers and non-stone formers, and low
      urinary pH is the main driver of uric acid stone formation. The latter may be explained by
      insulin resistance which affects the generation of renal ammonium by direct and indirect
      mechanisms. In contrast to urinary pH, urinary calcium excretion (the main driver for calcium
      stone formation) is not independently associated with BMI but rather due to other factors
      known to affect urinary calcium excretion (e.g. secondary to increased sodium and animal
      protein intake).

      Supersaturation - driver of kidney stone formation

      Supersaturation, the presence of a material in solution at a concentration above its own
      solubility, is the driving force for crystallization and therefore kidney stone formation.
      Relevant supersaturations for kidney stones disease in humans include calcium oxalate,
      brushite (calcium phosphate) and uric acid. At a supersaturation <1, crystals dissolve, at a
      supersaturation >1, crystals form. Urinary supersaturations calculated from ambulatory 24 h
      urine collections accurately reflect the long-term average supersaturation values in the
      urine and are highly correlated with the kidney stone composition encountered in the
      individual kidney stone former. Treatments that reduced stone events in Randomized Controlled
      Trials (RCTs) are highly correlated with reductions in urinary supersaturations. A recent
      analysis of a large 5-year kidney stone RCT revealed that as early as 1 week after
      randomization, every 10 % reduction of urinary calcium oxalate supersaturation from baseline
      was associated with an 8 % reduction in the risk of stone recurrence during follow-up.

      SGLT2 inhibitors - a promising new drug class for kidney stone formers

      Inhibitors of the sodium/glucose co-transporter isoform 2 (SLC5A2 or SGLT2) belong to a new
      class of oral hypoglycemic drugs. SGLT2 resides in the brush border membrane of proximal
      tubular cells in the kidney and reabsorbs ~90 % of glucose filtered at the glomerulus. SGLT2
      inhibitors block the physiological glucose reabsorption in the proximal tubule from the
      glomerular filtrate, thereby inducing significant glucosuria accompanied by a reduction of
      blood glucose levels. Empagliflozin, the clinically best characterized SGLT2 inhibitor to
      date, decreases cardiovascular mortality, death from any cause, hospitalizations for heart
      failure, decline of GFR and need for renal replacement therapy in patients with type 2
      diabetes. Some of these findings were also observed with two other SGLT2 inhibitors
      canagliflozin and dapagliflozin in large outcome trials. Due to their unique mode of action,
      SGLT2 inhibitors induce weight loss, decrease blood pressure and increase urinary volume, the
      latter being a very effective measure to reduce stone recurrence. Driven by promising results
      in RCTs, SGLT2 inhibitors are currently widely tested in non-diabetics e.g. for the treatment
      of heart failure, non-diabetic kidney disease, arterial hypertension or obesity
      (www.clinicaltrials.gov). The pleiotropic beneficial effects make SGLT2 inhibitors also a
      very attractive class of drugs for kidney stone formers, which often suffer concomitantly
      from arterial hypertension, CKD, obesity and diabetes.

      Effect of SGLT2 inhibitors on bone fractures, mineral metabolism and kidney stone events

      Therapy with SGLT2 inhibitors as monotherapy or add-on therapy to various glucose-lowering
      agents is generally well tolerated. An increased incidence of genital infections and
      (although rare) euglycemic ketoacidosis are known side effects of this new class of
      medications. The latter is mainly observed in type I diabetics and less frequently in type II
      diabetics. To the best of our knowledge, no cases of euglycemic ketoacidosis in individuals
      without diabetes treated with SGLT2 inhibitors have been reported.

      In the large canagliflozin outcome study CANVAS, an increased incidence of lower extremity
      amputations was noted. This adverse effect has not been reported with other SGLT2 inhibitors.
      In addition, both canagliflozin and dapagliflozin have been associated with an increased risk
      of bone fractures compared to placebo. In a short term study in healthy volunteers,
      canagliflozin increased serum phosphate, plasma fibroblast growth factor 23 (FGF23) and
      plasma parathyroid hormone (PTH) and decreased the level of 1,25-dihydroxyvitamin D. Similar
      results were obtained in individuals with diabetes treated with dapagliflozin. In contrast,
      pooled analyses of phase I, II and III trials of patients with type 2 diabetes treated with
      empagliflozin encompassing > 15'000 patient-years of exposure did not reveal an increased
      rate of bone fractures, alterations of blood electrolytes, PTH, 25-dihydroxyvitamin D or bone
      turnover markers.

      While blood electrolyte and mineral metabolism parameters in patients treated with SGLT2
      inhibitors have been well studied in healthy volunteers and patients with diabetes, there is
      a lack of data on the impact of SGLT2 inhibition on urinary parameters, especially on
      parameters that influence the kidney stone formation rate. Also, to our knowledge, no studies
      have been conducted thus far with SGLT2 inhibitors in kidney stone formers.

      Interestingly, in pooled analyses of phase I, II and III trials, the rate of kidney stone
      events tended to be 30-50 % lower in patients treated with 10 or 25 mg empagliflozin versus
      placebo. However, detailed analyses for kidney stone events in empagliflozin outcome trials
      have not been reported. Reported stone event rates in these pooled empagliflozin trials (0.5
      - 1/100 person years) are similar to what has been observed in individuals with diabetes in
      three large prospective US cohorts (Nurses' Health Study I, the Nurses' Health Study II and
      the Health Professionals Follow-up Study. In contrast, stone event rates are considerably (10
      - 100-fold) higher in patients with a history of kidney stone disease. RCTs testing dietary
      or pharmacologic measures for recurrence prevention typically included patients with stone
      event rates between 20 and 200 events/100 person-years.

      In summary, SGLT2 inhibitors represent a promising new drug class for kidney stone formers.
      Kidney stone formers are likely to profit from the metabolic and cardiovascular effects of
      SGLT2 inhibition. In addition, SGLT2 inhibitors may decrease the stone formation rate. Based
      on the overall experience thus far, empagliflozin seems to have by far the most favorable
      side effect profile. Clearly, there is a dire need for clinical studies with SGLT2 inhibitors
      in kidney stone formers.
    

Intervention name(s): Empagliflozin 25 MG; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 1 empagliflozin 25 mg capsule per day for 14 days; 1 placebo capsule per day for 14 days
Intervention MeSH terms: Empagliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Eligible individuals will be randomized in equal proportions to 25 mg empagliflozin or placebo, taken once daily per os in the morning. Placebo will be administered to individuals randomized to that treatment in a form identical to empagliflozin. Patients will remain on the assigned IMP for 14 days. The following 14 days (days 15 - 28) will be a wash out period without IMP intake; this wash out time can be extended to up to 6 weeks if necessary. On day 29 of the study (or later according to the length of the wash out phase), a second 14 days period with IMP intake starts (empagliflozin or placebo, whichever was not received initially).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Kidney stones; Empagliflozin; Supersaturation