Comparative Effectiveness of Lubiprostone and Stool Softeners on Risk of Kidney Outcomes in Patients with Chronic Kidney Disease

Background: Lubiprostone, a chloride channel activator used to treat constipation, has been suggested to exert kidney protective effects by improving the gut microbiome. However, little is known about the comparative effectiveness of lubiprostone vs. conventional laxatives on the risk of kidney outcomes in patients with chronic kidney disease (CKD). Methods: Among United States Veterans with CKD and constipation receiving care from the Veterans Administration healthcare system over 2004-2019, we identified incident users of lubiprostone vs. stool softeners (docusate sodium or calcium), excluding combined users of the examined drugs. We used a target trial emulation approach to examine the association of lubiprostone vs. stool softener use with subsequent risk of a composite kidney outcome (incident end-stage kidney disease, incident estimated glomerular filtration rate [eGFR] <15 mL/min/1.73m 2 , or 57% reduction in eGFR, as primary) and change in eGFR (as secondary). The associations were examined using weighted Cox models for the composite kidney outcome and weighted multinomial logistic regression models for change in eGFR, applying a propensity score (PS)-overlap weighting method to minimize confounding by indication. Results: Among 52,231 patients who met eligibility criteria, 551 (1%) and 51,680 (99%) were incident users of lubiprostone and stool softeners, respectively. Compared with incident stool softener users, incident lubiprostone users had significantly lower risk of a composite kidney outcome (hazard ratio [95% Confidence Interval (CI)], 0.70 [0.51-0.97]) and lower risk of experiencing more progressive eGFR decline (multinomial odds ratios [95% CI] for eGFR slope <-3 and -3 to <-1 [vs. -1 to <0] mL/min/1.73m 2 /year, 0.39 [0.23-0.68] and 0.73 [0.53-1.01], respectively). Conclusion: Incident lubiprostone (vs. stool softener) use was independently associated with lower risk of progressive kidney function decline in patients with CKD and constipation. Further studies are needed to refine the comparative effectiveness of different laxative types on kidney outcomes in clinical trials.