Key Takeaways & Executive Findings
- •• • Pioglitazone significantly improved NAFLD activity score (NAS) by a mean difference of -1.2 (95% CI -1.8 to -0.6, p<0.001) and resolved steatohepatitis in 2.1 times more patients (RR 2.1, 95% CI 1.4-3.1), underscoring its histological benefit in clinical practice. • • GLP-1 receptor agonists reduced hepatic fat content by a mean difference of -4.5% (p<0.01) and serum ALT by -15 U/L (p<0.001), indicating robust biochemical and steatotic improvements. • • Novel agents, such as resmetirom, demonstrated a significant reduction in fibrosis stage (MD -0.3, p=0.02), offering a potential anti-fibrotic effect beyond existing therapies. • • Adverse events were predominantly mild gastrointestinal symptoms, with no significant increase in serious adverse events, supporting acceptable tolerability for chronic use.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, with no approved pharmacotherapy. This systematic review and meta-analysis evaluated the efficacy of metabolic dysfunction-associated steatotic liver disease (MASLD) pharmacotherapies, including pioglitazone, GLP-1 receptor agonists, and novel agents, in patients with biopsy-proven NAFLD. We searched PubMed, Embase, and Cochrane Library through March 2025. Randomized controlled trials (RCTs) comparing active treatment with placebo or standard care were included. Primary outcomes were histological improvement (≥1-point reduction in NAFLD activity score [NAS]) and resolution of steatohepatitis without worsening of fibrosis. Secondary outcomes included changes in liver fat content, serum alanine aminotransferase (ALT), and body weight. Meta-analysis used random-effects models. We identified 12 RCTs (n=1,847). Pioglitazone significantly improved NAS (mean difference [MD] -1.2, 95% CI -1.8 to -0.6, p<0.001) and resolved steatohepatitis (RR 2.1, 95% CI 1.4-3.1). GLP-1 receptor agonists reduced liver fat (MD -4.5%, p<0.01) and ALT (MD -15 U/L, p<0.001). Novel agents, including resmetirom, showed promising effects on fibrosis (MD -0.3 stage, p=0.02). Adverse events were generally mild, with gastrointestinal symptoms most common. These findings support the use of MASLD pharmacotherapies in NAFLD, particularly pioglitazone and GLP-1 receptor agonists, though long-term safety and cost-effectiveness require further investigation.
1. Introduction
Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the global population and is a major driver of cirrhosis and hepatocellular carcinoma. Despite its prevalence, no pharmacologic agent has received regulatory approval for NAFLD, leaving lifestyle modification as the sole standard of care. The failure of previous drug candidates, such as obeticholic acid, due to safety concerns and modest efficacy, underscores the urgent need for effective and tolerable therapies. The recent redefinition of NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD) has refocused attention on metabolic pathways, leading to the repurposing of insulin sensitizers, incretin-based therapies, and the development of thyroid hormone receptor-beta agonists.
This systematic review and meta-analysis synthesizes evidence from randomized controlled trials evaluating MASLD pharmacotherapies in biopsy-proven NAFLD. By pooling data on histological, biochemical, and imaging outcomes, we provide quantitative estimates of treatment effects and safety profiles. Our findings directly address the clinical bottleneck of limited therapeutic options by identifying agents with significant histological benefit, thereby informing evidence-based treatment decisions and guiding future drug development.
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ZHANG Wei, LI Ming, WANG Fang (2025). Efficacy of Metabolic Dysfunction-Associated Steatotic Liver Disease Pharmacotherapies in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Chinese Journal of New Drugs. https://doi.org/pub_80__articleID_218
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Frequently Asked Questions
What is the comparative histological efficacy of pioglitazone versus GLP-1 receptor agonists in biopsy-proven NASH?
Pioglitazone demonstrated a significant improvement in NAS (MD -1.2, 95% CI -1.8 to -0.6) and resolution of steatohepatitis (RR 2.1, 95% CI 1.4-3.1). GLP-1 receptor agonists primarily reduced liver fat (MD -4.5%) and ALT (MD -15 U/L) but did not show significant fibrosis improvement in our analysis. Thus, pioglitazone appears more effective for histological endpoints.
What are the long-term safety concerns associated with pioglitazone in NAFLD patients, particularly regarding weight gain and bone density?
Pioglitazone is associated with dose-dependent weight gain (average 2-4 kg) and potential bone density loss, especially in postmenopausal women. In our meta-analysis, adverse events were mostly mild gastrointestinal, but long-term safety data beyond 2 years are limited. Clinicians should monitor weight and bone health, especially in high-risk populations.
How does resmetirom's anti-fibrotic effect compare to placebo in terms of clinical significance?
Resmetirom reduced fibrosis stage by a mean difference of -0.3 (p=0.02) compared to placebo. While statistically significant, the clinical relevance of a 0.3-stage reduction is modest; however, it represents a step forward as no other agent has shown significant anti-fibrotic activity in phase 3 trials.
What are the cost-effectiveness implications of adopting GLP-1 receptor agonists for NAFLD treatment?
GLP-1 receptor agonists are expensive (annual cost >$10,000) and require subcutaneous injection. Their benefit in reducing liver fat and ALT may translate to delayed disease progression, but formal cost-effectiveness analyses are lacking. Given the high prevalence of NAFLD, widespread use would impose significant economic burden, necessitating patient selection based on severity and metabolic comorbidities.
What are the main limitations of the current meta-analysis, and how might they affect clinical decision-making?
Limitations include heterogeneity in trial designs, varying definitions of histological improvement, and short follow-up durations (mostly ≤1 year). Publication bias may overestimate effects. These factors warrant cautious interpretation, and head-to-head trials with longer-term outcomes are needed to refine treatment algorithms.
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