Associations of Topiramate and Zonisamide Use With Kidney Stones: A Retrospective Cohort Study

Abstract

Rationale & Objective

Driven by expanding indications, topiramate and zonisamide utilization has increased over time, a trend that may be associated with greater occurrence of kidney stones given the effects of these medications on urine chemistries. We examined the relationship between topiramate and zonisamide use and kidney stone risk.

Study Design

Retrospective cohort study.

Setting & Participants

Individuals in Optum’s deidentified Clinformatics Data Mart Database (CDM) and Medicare enrollees with at least 1 prescription filled for topiramate or zonisamide between January 1, 2011, and September 30, 2019, and age- and sex-matched controls.

Exposure

New topiramate or zonisamide use.

Outcome

Symptomatic stone event defined as an emergency department visit, hospitalization, or surgery for kidney stones.

Analytical Approach

Cox proportional hazards regression.

Results

Among 1,122,301 study participants, 187,032 filled a prescription for topiramate or zonisamide at some point during the study period. The unadjusted cumulative incidence of symptomatic stone events between 3 months and 3 years after the first filled prescription were 2.9% and 2.0% among users of topiramate or zonisamide versus 1.2% and 1.3% among nonusers in the CDM and Medicare cohorts, respectively (P < 0.001 for each comparison). After controlling for covariates, users had a significantly higher hazard than nonusers of experiencing a symptomatic stone event (CDM cohort: HR, 1.58 [95% CI, 1.49-1.68]; Medicare cohort: HR, 1.22 [95% CI, 1.11-1.34]). There was a stronger association with stone risk among younger adults receiving either topiramate or zonisamide and the hazard of a symptomatic stone event increased with higher topiramate doses.

Limitations

Potential bias in unmeasured differences between users of topiramate or zonisamide and nonusers. Participants may have been diagnosed with kidney stone disease before the study period.

Conclusions

Use of topiramate or zonisamide was associated with an increased hazard of symptomatic stone events. These findings inform the consideration of risks and benefits of these medications.

Plain-Language Summary

Topiramate and zonisamide are increasingly prescribed for uses other than seizure prophylaxis. These agents may cause kidney stones. In this retrospective cohort study of adults with either Medicare or commercial health insurance, we assessed the relationship between use of topiramate or zonisamide and kidney stone events requiring clinical intervention. Between 3 months and 3 years after first use of these drugs, stone events occurred more often among users of topiramate or zonisamide than nonusers. Our analysis also demonstrated a stronger association with stone risk among younger adults receiving either topiramate or zonisamide. These findings are consistent with the magnitude of association reported previously in the literature and the association was independent of treatment indication in younger adults.