Impact on urinary oxalate levels with use of ezetimibe

Abstract Background Calcium oxalate stones are the most common cause of nephrolithiasis in the United States. Smaller studies of <15 patients investigating ezetimibe, a selective cholesterol absorption inhibitor, have suggested increased urine oxalate levels with use of the drug. We attempt to better define this relationship of ezetimibe on urinary oxalate using a larger patient sample analysing multiple urine collections on and off treatment. Materials and Methods We retrospectively reviewed all consecutive patients from 01/2018 through 04/2019 evaluated for nephrolithiasis with use of ezetimibe documented in their medical record at Mayo Clinic Florida. Primary outcomes included increase in urinary oxalate with use of ezetimibe and reduction in urinary oxalate with discontinuation of medication. Results Of 57 reviewed patients, 30 (53%) met inclusion criteria yielding 117 24‐h urine measurements either on ezetimibe (72 measurements) or off ezetimibe (41 measurements). The mean urinary oxalate level off ezetimibe was 39.86 mg versus 40.45 mg with ezetimibe. After adjusting for age and sex, the estimated difference was 1.239 mg (95% CI, −4.856 to 7.335 mg; p = 0.93). A subset of six patients with urinary oxalate values both on and off ezetimibe showed a difference in 24‐h urinary oxalate levels ranged from −16.40 to 14.95 mg (mean difference = 0.93 mg; median difference = 3.84 mg). Conclusion Use of ezetimibe does not provide clear evidence of a difference in urinary oxalate levels.

precipitate enteric hyperoxaluria along with drugs such as orlistat, an oral lipase inhibitor indicated for weight loss via reducing absorption of dietary fat. 5 In 2004, the Food and Drug Administration (FDA) approved the first selective cholesterol absorption inhibitor, ezetimibe, for treatment of hyperlipidemia. 6 This drug acts on intestinal lumen limiting the transport of biliary and dietary cholesterol into enterocytes and reducing chylomicron synthesis causing reductions in serum low-density lipoprotein (LDL) levels. 7 Subsequently, this increases the concentration of free cholesterol in the intestinal tract which may impact oxalate absorption. Previous analysis in a small number of cases has suggested increased urine oxalate levels with use of ezetimibe. In the present study, we examined a relationship of ezetimibe and urinary oxalate, in patients with urinary stone disease, analysing results of multiple urine collections while on and off treatment with ezetimibe.

| MATERIAL S AND ME THODS
Institutional review board (IRB) approval was obtained for this study.
We retrospectively reviewed all consecutive patients from January

| Statistical analysis
Means and standard deviations were calculated for continuous variables, counts and percentages for categorical data. Urinary oxalate values were calculated using the arithmetic mean for those who had more than one. Dot plots were constructed to graphically display

| RE SULTS
A total of 57 patients were reviewed over the 16 month time interval with 30 (53%) patients meeting inclusion criteria. Most common reasons for exclusion from analysis were incomplete urine supersaturation profile or non-collection of urine despite recommendation and electronic order during nephrology clinic visit. Patient characteris-  (Figure 1).

| DISCUSS ION
Urinary oxalate is a key factor in the development of kidney stones, a common malady, and has been shown to be increased in the setting of fat malabsorption. Ezetimibe is a cholesterol absorption inhibitor and is widely used as a lipid lowering compound.
Preliminary findings suggesting a link between ezetimibe use and This retrospective study had a number of limitations. This single centre study was limited by modest patient sample size.
Furthermore, the study was not designed to determine cause and effect and did not control for confounding variables such as dietary changes. In these cases, the use of ezetimibe was inferred by chart review of medication list as medication compliance was not closely In conclusion, this study provided no evidence of effect of ezetimibe use on urinary oxalate levels in patients with nephrolithiasis being evaluated in the nephrology clinic setting. Note: The differences in mean urinary oxalate levels were estimated from single generalized estimating equations to account for the repeated measurement of urinary oxalate levels within patient.

CO N FLI C T O F I NTE R E S T
Abbreviation: CI, confidence interval.
F I G U R E 1 Urinary oxalate levels according to ezetimibe use. Grey circles represent the 113 24-h urine oxalate measurements (N = 28 patients), the patient-averaged 24-h urine oxalate measures are represented by black triangles, and connected lines represent the patient-averaged 24-h urine oxalate for the 6 patients who had measurements both on and off ezetimibe