Diacerein in the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease

Overview

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic progressive liver disease in China, posing a significant risk for hepatic decompensation, cardiovascular disease (CVD), chronic kidney disease (CKD), and various malignancies. It severely impacts patient quality of life and life expectancy, creating a substantial socioeconomic burden. Currently, no safe and effective drug exists to reverse MAFLD. Rhubarb (Dà Huáng), a classic Traditional Chinese Medicine (TCM) herb for liver disorders, has a cold nature, bitter taste, and targets the liver, spleen, stomach, large intestine, and pericardium meridians. Its primary active component, Rhein, demonstrates therapeutic potential by targeting key MAFLD pathological processes-insulin resistance, hepatic steatosis, inflammation, and fibrosis. Supporting this, a previous randomized, double-blind, placebo-controlled trial by our group on diacerein (a Rhein derivative) for simple obesity showed that it not only reduced body weight but also improved liver function, Controlled Attenuation Parameter (CAP), and Liver Stiffness Measurement (LSM). Therefore, this study will investigate diacerein-a marketed drug metabolized to Rhein in vivo-for MAFLD treatment using a randomized, double-blind, placebo-controlled design. The aim is to generate clinical evidence for diacerein and other Rhein derivatives within an integrative medicine framework, providing an evidence-based rationale for expanding the application of rhubarb in MAFLD management.

1. Rhubarb and Its Derivatives Have a Solid Theoretical Basis for Treating MAFLD Metabolic dysfunction-associated fatty liver disease (MAFLD), a chronic progressive liver disease caused by nutritional excess and insulin resistance in genetically susceptible individuals, is now the most common chronic liver disease in China. Despite widespread recognition of its hazards, effective interventions for MAFLD remain lacking. MAFLD's pathogenesis is diverse, involving intertwined factors like insulin resistance, dyslipidemia, inflammation, and fibrosis, making single-target approaches often inadequate. Furthermore, treatment must be tailored to disease stage, addressing metabolic abnormalities, liver injury, and complications concurrently. This complexity means treatment efficacy heavily depends on healthcare resource availability and patient compliance, frequently leading to suboptimal outcomes. Traditional Chinese Medicine (TCM), with its unique multi-target, multi-pathway mechanisms and advantages of being simple, convenient, inexpensive, and effective, offers new strategies for MAFLD. TCM theory attributes MAFLD to dietary irregularities, sedentary habits, phlegm-dampness generation, stagnation transforming into heat, and consequent obstruction of the liver collaterals. Clinical epidemiology suggests internal accumulation of dampness-heat is the primary pathogenesis. Rhubarb (Dà Huáng), with its cold nature and bitter taste, is a classic TCM herb for clearing heat, detoxifying, draining fire, and eliminating dampness. Zhang Yuansu's "Origins of Medicine" from the Jin Dynasty notes four actions of rhubarb: 1) expelling substantial heat, 2) removing dampness from the lower energizer, 3) eliminating the old to bring in the new, and 4) dispersing retained food. Rhubarb often serves as the sovereign herb (君药) in MAFLD formulas. Rhein, a primary active component of rhubarb, has demonstrated pharmacological effects against steatosis, inflammation, and fibrosis, making it a potential candidate drug. Its derivative, diacerein, is deacetylated in the gut to rhein, exerting pharmacological effects. Marketed since 1985 for osteoarthritis due to its anti-inflammatory properties (brand name: Diacerein), diacerein has shown promise in clinical trials by our group and others, improving liver function and steatosis markers in obese and type 2 diabetic patients. As a marketed drug derived from a TCM monomer, diacerein combines the multi-target breadth of TCM with the quantifiable, user-friendly nature of Western medicine, representing a potential strategy against current MAFLD treatment challenges. 2. Solid Experimental Foundation for Diacerein in MAFLD Treatment Current MAFLD management focuses on weight/waist circumference reduction, improving insulin resistance, preventing metabolic syndrome/type 2 diabetes, alleviating steatohepatitis, and reversing fibrosis. Extensive pharmacological studies confirm that diacerein and its lead compound, rhein, simultaneously target liver pathology and metabolic abnormalities, providing a robust experimental basis for this study. Diacerein and rhein counteract hepatic steatosis, inflammation, and fibrosis. Tobar et al. reported that diacerein (20mg/kg for 10 days) ameliorated steatosis, insulin resistance, and inflammation in diet-induced obese (DIO) mice. Further studies showed it reduces hepatic lipid deposition and improves liver function by inhibiting NLRP3 inflammasome activation and JNK-mediated oxidative stress/apoptosis. Another study found 10 mg/kg/day diacerein improved cholestasis-induced liver fibrosis in mice via the HMGB1/RAGE/NF-κB/JNK pathway. Similarly, rhein improved liver lipid deposition and inflammatory factors in DIO and KK/H1J diabetic mice, and reduced carbon tetrachloride-induced liver fibrosis in rats. Our group confirmed that rhein's amelioration of hepatic steatosis in DIO mice likely occurs by inhibiting fatty acid synthase (FASN) expression and de novo lipogenesis. The weight-loss and metabolic benefits of diacerein/rhein are clear. In DIO mice, diacerein reduced body weight and improved insulin sensitivity/glucose tolerance. These metabolic improvements are also documented in type 1 diabetes and PCOS models. Our research further showed rhein reduces fat mass, body weight, and improves insulin resistance in DIO mice by inhibiting macrophage inflammasome activation and promoting adipose tissue thermogenesis. 3. Previous Clinical Studies Suggest Diacerein's Potential for MAFLD Two independent randomized, double-blind, placebo-controlled trials (RCTs) from our group and others, using hepatic steatosis as an efficacy endpoint, suggest diacerein's potential. An RCT by Nathalie et al. involving 84 patients with type 2 diabetes and NAFLD found two years of diacerein treatment significantly improved Liver Stiffness Measurement (LSM) via Fibroscan, suggesting anti-fibrotic effects. Our RCT in obese patients showed 14 weeks of diacerein not only reduced weight and waist circumference and improved insulin sensitivity but also significantly decreased LSM, Controlled Attenuation Parameter (CAP), and serum ALT levels, indicating potential benefits for liver steatosis, fibrosis, and function alongside metabolic improvements. In summary, the TCM monomer derivative diacerein has strong TCM theoretical basis, solid pharmacological foundation, and promising clinical evidence for treating MAFLD. However, its efficacy and safety in MAFLD populations require further investigation. Notably, the aforementioned studies relied on Fibroscan, which can be influenced by factors like subcutaneous fat. Therefore, this study proposes a randomized, double-blind, placebo-controlled clinical trial incorporating proton magnetic resonance spectroscopy (¹H-MRS), the non-invasive gold standard for hepatic fat quantification, to comprehensively and objectively evaluate the efficacy and safety of diacerein for adult MAFLD. This will provide reliable evidence for expanding diacerein's indications and future MAFLD drug development, while offering evidence-based support for using rhubarb-based formulations in MAFLD clinical practice.