Abstract

Background: Effective treatment for alcohol use disorder (AUD) is the cornerstone of preventing the development of alcohol-associated liver disease (ALD). Recent preclinical and epidemiological data suggest spironolactone, a mineralocorticoid receptor antagonist, reduces alcohol consumption (PMID: 36123420) and may be a promising option to treat AUD. However, its impact on the development of ALD in high risk patients is unknown.

Methods: This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127 480 patients at the time of this study. International Statistical Classification of Diseases and Related Health Problems, Ninth and Tenth Revision diagnosis codes were used to identify patients with AUD and no ALD at study entry, as well as the primary outcome of incident ALD during study follow-up. Patients with ascites were excluded from study enrollment. Treatment with spironolactone was defined by documentation of > 3 prescriptions. Patients were considered to be treated if they initiated spironolactone before the relevant outcome. Alcohol use was assessed through a one-time questionnaire that included a linear scale of standard drink consumption, with higher scores correlating with more alcohol use. Cox proportional hazards models adjusting for potential confounders were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs).

Results: The cohort comprised 9635 patients with AUD, of whom 566 (5.9%) were treated with spironolactone before a diagnosis of ALD. In total, 1135 patients (11.8%) developed ALD over a median follow-up time of 9.7 years. Patients treated with spironolactone were more likely to be older, obese, and receive concurrent medical addiction therapy and less likely to receive psychotherapy and have a concurrent substance use disorder compared to patients never receiving therapy. Treatment groups were similar in viral hepatitis status, homelessness, ethnicity, and sex. In a multivariable analysis accounting for age, sex, ethnicity, BMI, viral hepatitis status, receipt of alcohol therapy, concurrent substance disorder, psychiatric disease, congestive heart failure, and hypertension, spironolactone therapy was associated with a decreased incidence of ALD (HR: 0.68; 95% CI, 0.38-0.93; P = 0.02). We did not observe a dose-dependent association between spironolactone and likelihood of ALD (HR: 0.99; 95% CI: 0.98-1.00; P = 0.27). Notably, AUD patients treated with spironolactone reported less alcohol use compared to those not receiving treatment (linear drinking score of 3.2 in treated group versus 3.9 in the untreated group, P = 0.02).

Conclusion: Spironolactone therapy is associated with reduced alcohol use and incident ALD in patients with AUD and may offer a novel therapeutic strategy in limiting the development of ALD in high-risk patients.