Silymarin for adults with metabolic dysfunction-associated steatotic liver disease.

RATIONALE

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health challenge, with approximately 32.4% of adults globally diagnosed with the condition and a steadily increasing prevalence. Currently, no specific medicines are approved to manage MASLD effectively. Silymarin, a common herbal agent with antioxidant, anti-inflammatory, and antifibrotic properties, presents potential therapeutic benefits for MASLD in both its monotherapy and complex forms (complexation with solubilising agents, such as vitamin E, phosphatidyl choline, etc.).

OBJECTIVES

To evaluate the benefits and harms of silymarin monotherapy and silymarin complex in adults with MASLD.

SEARCH METHODS

We searched CENTRAL, MEDLINE, Embase, LILACS, Web of Science, three Chinese regional bibliographic databases, and two trial registries; we also performed reference checking and contacted trial authors for relevant studies (search date: 15 May 2024).

ELIGIBILITY CRITERIA

We included randomised clinical trials comparing silymarin monotherapy or silymarin complex versus no intervention, placebo, or other interventions in adults with MASLD. We excluded quasi-randomised and observational studies. There were no restrictions on the publication language, date, or status.

OUTCOMES

Critical outcomes were the proportion of people with serious adverse events, all-cause mortality, and quality of life. Some of the most important outcomes were liver enzymes (i.e. alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transpeptidase (GGT)), and the proportion of people with adverse events considered non-serious. We analysed these outcomes at the end of treatment and during maximal follow-up.

RISK OF BIAS

We assessed the risk of bias using the RoB 2 tool.

SYNTHESIS METHODS

We conducted meta-analyses of available data at maximal follow-up, using the random-effects model as our primary analysis. We calculated risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, both with 95% confidence intervals (CI). For rare events, we used the Peto odds ratio (OR) and 95% CI. When meta-analysis was not feasible, we synthesised the data narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes.

INCLUDED STUDIES

We included 17 RCTs with 2069 participants having MASLD (78 participants were diagnosed with MASLD, 423 with metabolic-associated steatohepatitis (MASH), and the diagnosis of 1568 participants was not classified). Four trials were multicentre and 13 were single-centre trials. Twelve trials were conducted in Asia, four in Europe, and one in North America. Silymarin monotherapy (nine trials) and silymarin complex (eight trials) were compared with no intervention, placebo, or other interventions. The number of participants ranged from 36 to 494 (median: 90). Participants' mean age was 43.2 years with a mean proportion of males of 55.6% in the trials reporting on this. The follow-up ranged from four weeks to 48 weeks.

SYNTHESIS OF RESULTS

The evidence suggests that silymarin monotherapy versus no intervention or placebo may result in little to no difference in serious adverse events (Peto OR 1.55, 95% CI 0.26 to 9.28; 4 trials, 304 participants; low-certainty evidence). The evidence is very uncertain about the effect of silymarin monotherapy versus no intervention or placebo on non-serious adverse events (RR 1.29, 95% CI 0.88 to 1.89; 4 trials, 282 participants; very low-certainty evidence). Silymarin monotherapy versus no intervention or placebo may decrease ALT (MD -7.21 U/L, 95% CI -10.62 to -3.80; 6 trials, 409 participants; very low-certainty evidence) and GGT (MD -8.30 U/L, 95% CI -12.43 to -4.17; 1 trial, 45 participants; very low-certainty evidence), but the evidence is very uncertain. We did not perform a meta-analysis for AST due to considerable heterogeneity (I = 77%). The evidence is very uncertain about the effect of silymarin monotherapy versus other interventions on serious adverse events (Peto OR not estimable, no events observed; 1 trial, 45 participants; very low-certainty evidence), non-serious adverse events (RR 0.67, 95% CI 0.08 to 5.88; 1 trial, 45 participants; very low-certainty evidence), ALT (MD -0.89 U/L, 95% CI -3.78 to 2.00; 2 trials, 111 participants; very low-certainty evidence), AST (MD 0.09 U/L, 95% CI -3.94 to 4.12; 2 trials, 111 participants; very low-certainty evidence), and GGT (MD 2.79 U/L, 95% CI -1.04 to 6.62; 1 trial, 45 participants; very low-certainty evidence). The evidence is very uncertain about the effect of silymarin complex versus no intervention or placebo on serious adverse events (Peto OR not estimable, no events observed; 2 trials, 179 participants; very low-certainty evidence), ALT (MD -1.10 U/L, 95% CI -8.12 to 5.92; 4 trials, 309 participants; very low-certainty evidence), AST (MD 0.84 U/L, 95% CI -1.03 to 2.71; 4 trials, 309 participants; very low-certainty evidence), GGT (MD -1.21 U/L, 95% CI -6.76 to 4.35; 3 trials, 249 participants; very low-certainty evidence), and non-serious adverse events (RR 0.73, 95% CI 0.42 to 1.27; 2 trials, 157 participants; very low-certainty evidence). Silymarin complex versus other interventions probably results in little to no difference in serious adverse events (Peto OR not estimable, no events observed; 3 trials, 920 participants; moderate-certainty evidence). The evidence suggests that silymarin complex may result in little to no difference in GGT (MD 11.60 U/L, 95% CI -12.11 to 35.31; 1 trial, 126 participants; low-certainty evidence). We did not perform meta-analyses for ALT, AST, and non-serious adverse events due to considerable heterogeneity (I = 77%, I = 82%, and I = 90%, respectively). None of the trials included in the comparisons reported all-cause mortality and quality of life.

AUTHORS' CONCLUSIONS: The benefits and harms of silymarin in adults with MASLD are unclear. Although one trial reported the occurrence of serious adverse events, none were deemed to be related to the study drugs. When compared with no intervention or placebo, silymarin monotherapy, rather than silymarin complex, may decrease liver enzymes. However, neither silymarin monotherapy nor silymarin complex showed a reduction in liver enzyme levels compared with other interventions. The certainty of evidence for these findings varied from low to very low due to insufficient power, serious risk of bias, and moderate-to-substantial heterogeneity across studies. Well-designed clinical trials that consider people-related important clinical outcomes, such as all-cause mortality and quality of life, are needed.

FUNDING

This Cochrane review had no dedicated funding.

REGISTRATION

Protocol available via doi.org/10.1002/14651858.CD015524.