Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined as steatotic liver disease in the presence of one or more cardiometabolic risk factors and the absence of increased alcohol intake. MASLD comprises a disease spectrum ranging from simple steatosis to its more severe and aggressive form, metabolic dysfunction-associated steatohepatitis (MASH). Regression of hepatic fibrosis was set as a histological primary endpoint in clinical trials on the treatment of MASH. Two United States Food and Drug Administration (FDA)-approved pharmacological therapies for MASH with F2-3 fibrosis, resmetirom and semaglutide, achieved a placebo-adjusted difference of 11.7% and 14.4% in fibrosis improvement, respectively [
1,
2]. However, determining the clinical utility of a new drug remains a challenge, considering its significance in histological improvement as well as associated costs and impact on the long-term outcomes. Yoon et al. [
3] utilized a Markov model to reflect the natural history of MASLD, a new hypothetical drug’s efficacy and the factors associated with the cost-effectiveness of the drug, using the incremental cost-effectiveness ratio (ICER) as the primary outcome. This study established a generalized framework applicable to novel MASLD drugs, providing a valuable reference for policymakers, pharmaceutical companies, and hepatologists in drug development.
One-way sensitivity analysis identified the initial placebo-adjusted difference in fibrosis regression, the distribution of baseline fibrosis stage, and the rate of annual treatment effect waning as the most influential parameters on ICER. As expected, a greater initial gap in regression compared to the placebo reflected the drug’s effectiveness and directly reduced ICER. Notably, it was most cost-effectiveness of when treating only patients with F4 fibrosis, while targeting F2 fibrosis alone produced an ICER exceeding $100,000/quality-adjusted life years (QALYs), which was not considered as cost-effective. The results underscore the necessity of defining the target population based on the liver fibrosis grading when assessing the cost-effectiveness of a drug.
To avoid overestimating the durability of drug effects, the authors incorporated a range of annual waning rates of treatment effectiveness in the analyses. They considered scenarios where the initial treatment effect was maintained until the third year, alongside variations in adherence across different fibrosis stages. However, sensitivity analyses for varying medication adherence in F2-F4 patients from 70% to 90% reflected a situation in which increased medication costs (due to better adherence) were offset by reduced costs for managing advanced diseases and by gains in QALYs (due to fewer incidence of advanced diseases), likely resulting in a lower instead of higher ICER. Maintaining good drug adherence would be important for good cost-effectiveness. However, real-world adherence can be hindered by factors such as severe adverse effects leading to discontinuation [
1] and inconvenient drug administration routes [
4].
The prognostic interplay between MASLD and cardiovascular diseases (CVD) risks [
5] complicated the economic modeling, as the impact of the drug on CVD outcomes should be considered in estimating cost-effectiveness. The authors addressed this limitation by incorporating a distinct CVD morbidity state into the Markov model. Interestingly, sensitivity analysis demonstrated that CVD incidence had a minimal impact on the ICER. Nevertheless, the robustness of the result is subject to the inherent challenges in representing the complex interactions between MASLD and CVD.
The model captured the impact of CVD on ICER, but it is also important to account for other extrahepatic complications including multiple metabolic disorders. Notably, in the phase 3 trial of resmetirom [
1], eligible patients presented at least three of five metabolic risk factors. Furthermore, the effect of the drugs like glucagon-like peptide 1 receptor agonists on fibrosis regression is accompanied by weight reduction and metabolic improvements [
6,
7], and relevant interventions such as lifestyle modifications, anti-diabetic medications, antihypertensives, lipid lowering agents, or other cardiometabolic risk management could influence both liver-related and extrahepatic outcomes. These considerations may not be reflected in a general evaluation framework; in real-world practice, however, coexisting metabolic disorders and pharmaceutical therapies should be considered to avoid overestimation of the drug efficacy.
A 1-year cycle length was chosen for the model, which aligns with the timeframe required to observe treatment effects in Phase 3 clinical trials for MASLD [
1], ensuring the model captures the clinical transition.
While high medication costs directly contribute to higher ICER, ‘time preference’ has to be considered in this context: patients value immediate health gains more than equivalent gains in the distant future. Furthermore, future costs and benefits are valued less than present ones due to inflation and investment returns. The authors addressed this by applying a discount rate to both costs and QALYs in line with guidelines for economic evaluation. This approach also inherently mitigated the projected impact of future disease events in terms of suboptimal adherence, as their weight in the present-value calculation was reduced.
While the current model is valid in reflecting the conditions across MASLD population starting at approximately 40 years of age, its applicability to older patients remains investigated. Older patients with MASLD are characterized by increased comorbidities, and a higher risk of progression to hepatocellular carcinoma and cardiovascular events [
8]. These age-related risks complicated the estimation of the cost-effectiveness for the intervention drug targeting the elderly population. Adherence also poses a significant concern in the elderly, particularly for those requiring long-term community support and residential care. In this study, sensitivity analyses were conducted with the cohort starting age of 60 years and showed the estimated ICER was less than the threshold of $100,000/QALY ($92,080/QALY). Although regarded as cost-effective, the borderline value combined with the above considerations raises uncertainty about the conclusions in older populations.
This model’s assumption of the initial fibrosis stage-independent regression lacks strong empirical support. Pharmacological interventions like semaglutide showed limited efficacy in directly targeting liver damage and reversing established cirrhosis (F4) [
9]. However, the hypothetical cohort in the base analysis had a relatively high distribution of F4 (20%), which was not under the recommendation for FDA-approved MASH drugs [
10]. It can thus be inferred that the hypothesized drug represents the future drug with treatment potential for F4 fibrosis, such as fibroblast growth factor 21 analogues [
11]. Treating patients with F4 cirrhosis was suggested to yield greater cost-effectiveness in the analysis. Nevertheless, worse histological stages were associated with a higher burden of comorbidities and extra-hepatic mortality, complicating the reversal [
12]. Future studies must determine whether the magnitude of therapeutic effects differs in patients with cirrhosis. Otherwise, assuming identical therapeutic effects across fibrosis stages would introduce bias and falsely favor treating patients with more severe fibrosis. Additionally, F4 cirrhosis encompasses a broad spectrum of diseases, depending on the compensated/decompensated state and the presence of portal hypertension. Treatment response, complication incidences, and the potential for regression vary substantially across this spectrum.
Drug dose-related side effects remain another issue. Higher dose results in reduced costs for advanced treatment due to early recovery as well as gains in QALYs, however, more severe side effects may impair the tolerability and adherence [
13]. The efficacy of the drug should be interpreted with caution in terms of dosage and target fibrosis stage in real scenarios. This is particularly critical for patients with F4 cirrhosis with higher risk of side effects, making safety a paramount concern.
Yoon et al. [
3] provided a practical economic model to evaluate the cost-effective of new MASLD/MASH drugs and revealed key factors such as initial response and sustained durability. The results, however, need to be interpreted with caution considering variations in target population and metabolic confounders.
FOOTNOTES
-
Authors’ contribution
Sherlot Song contributed to the writing and editing of the editorial. Vincent Wong and Terry Yip contributed to the editing and reviewing of the letter. All authors contributed to the approval of the final manuscript before submission.
-
Conflicts of Interest
Dr. Song has no COI. Prof. Wong reports personal fees from AbbVie, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Echosens, personal fees from Eli Lilly, grants and personal fees from Gilead Sciences, personal fees from Merck, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Pfizer, personal fees from Roche Diagnostics, personal fees from TARGET Pharma Solutions, personal fees from Abbott, other from Furui, other from Illuminatio Medical Technology, outside the submitted work. Prof. Yip reports personal fees from Altimmune, grants and personal fees from Gilead Sciences, personal fees from GSK, outside the submitted work.
Abbreviations
United States Food and Drug Administration
incremental cost-effectiveness ratio
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
quality-adjusted life years
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Citations
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