Metabolic dysfunction-associated steatotic liver disease a multisystem disease: Assessing the cost effectiveness of pharmacotherapies.
Description:Wallace and colleagues have aimed to model the US health and economic impact of a hypothetical pharmacologic therapy which halts metabolic dysfunction-associated steatotic liver disease (MASLD) fibrosis progression.1 In their models, therapy which only reverses steatosis had minimal (<1–2%) effect on severe liver disease events prevented and healthcare costs averted. Over a 20-year timeframe (2024-2044), the scenarios in which a hypothetical therapy halts fibrosis progression (70% response rate) resulted in reduced cases of decompensated cirrhosis (11-39%), hepatocellular carcinoma (10-34%), liver-related deaths (8-31%), a 9-31% reduction in cumulative DALYs (disability adjust life years), and $40-$99 B incremental healthcare costs averted. We congratulate them on their work in addressing this extremely complex issue which has now become very relevant for healthcare providers and clinical practice. MASLD has rapidly become the most common chronic liver disease, causing major adverse liver outcomes, and affects up to ∼38% of the global adult population.2 Thus, MASLD has major implications for healthcare costs and providers of healthcare. A decade ago, we highlighted evidence supporting the notion that MASLD is a multisystem disease, not only affecting the liver; but also having the potential to increase risk of other extrahepatic cardiometabolic diseases.3 Since then, it has become apparent that MASLD also increases the risk of chronic kidney disease (CKD)4 and certain extrahepatic cancers.5 Cardiovascular disease (CVD) is the leading cause of death in people with MASLD, and MASLD is a risk factor for incident type 2 diabetes mellitus (T2DM),6 creating a vicious cycle where MASLD not only increases the risk of T2DM, but the development of T2DM further worsens the risk of liver disease progression.7 Notably, CVD risk may increase further with more severe liver disease, especially with higher fibrosis stages.8 Since MASLD also increases the risk of developing new-onset heart failure9 and atrial fibrillation,10 there is considerable interest in re-purposing drugs shown to reduce body fat and decrease risk of CVD and CKD for the treatment of MASLD. One such potential drug class is glucagon-like peptide-1 receptor agonists (GLP-1RAs) that have considerable utility in attenuating risk of many of these other diseases linked to MASLD.11 Another drug class is sodium-glucose transport protein 2 inhibitors (SGLT2-i), with preliminary evidence of benefit in decreasing adverse liver and cardiovascular events.12,13 Thus, both drug classes have potential utility for liver disease, including attenuating risk of many other diseases linked to MASLD as a complex multisystem disease.11 Wallace and colleagues have modelled the cost effectiveness of GLP-1RAs and SGLT2-i, as well as a future hypothetical therapy that halts fibrosis progression. They used the MASLD disease burden model, a Markov model that incorporates MASLD prevalence, disease progression, mortality and impact. Five scenarios were evaluated: no treatment; antisteatotic therapy of diabetic MASLD F0–F1 patients; and novel antifibrotic therapy for F3, F2–F3, and F2–F4 patients. In the antisteatotic therapy scenario, diabetes diagnosis among the MASLD population remained constant at 22% with treatment constant at 10%. The assumption of constant antisteatotic treatment is problematic as GLP-1RA and SGLT2-i class use is increasing, and will extend into the population without diabetes, because of the need to attenuate a patient’s risk of CVD and CKD and to treat obesity. The authors did assume the total MASLD population will grow as result of obesity trends. Thus, despite constant proportions diagnosed and treated, Wallace and colleagues estimated the number of people on GLP-1RA/SGLT2-i therapies will increase from 2.6 million in 2024 to 3.8 million in 2044. The modelled benefit of GLP-1RA/SGLT2-i drugs was conservative, being limited to antisteatotic effects and use within the F0–F1 population. In the antifibrotic scenarios, progressive increases in diagnosis of MASLD were incorporated, from 3% to 10% for F0-1 to F4 patients at baseline (2022-2024) to 15% to 50% for F0-1 to F4 patients in 2040-2044. Given the 20-year time frame of analysis and slow progression of the disease14,15), changing treatment assumptions in the F0–F1 population would be expected to have limited effect on outcomes. However, the analysis was undertaken prior to the publication of interim results from the ESSENCE trial. The significant benefit on liver fibrosis in trial participants treated with the GLP-1RA semaglutide in ESSENCE may translate into a sustained impact on liver disease outcomes, at least for this class of drugs. In the novel antifibrotic therapy scenarios, it was assumed the pharmacological agent would be used by 80% of those diagnosed with MASLD and successively halt fibrosis with a response rate of 70%. Such high levels of coverage and response do seem optimistic, although the authors additionally evaluated response rates from 30% to 83%, with relatively low impact on outcomes. The impact of antifibrotic therapy is clearly dependent on fibrosis progression parameter estimates and the time-horizon employed. The overall impact would be enhanced if progression was more rapid than estimated and a lifetime horizon was employed. The health economic analysis is affected by healthcare costs, including MASLD screening and monitoring costs, and estimation of health-related quality of life at liver disease stages. The cost of following up someone with F0–F1 was not that different from following up someone at much higher risk with more severe disease. The authors comment that reducing annual imaging to a less frequent schedule would produce cost savings without affecting quality of care, due to slow disease progression, particularly in the earlier stages (F0–F2) of disease. Consequently, identification of the subset of patients who are more likely to rapidly progress to advanced disease and those with known risk factors for progression (e.g. T2DM obesity, or hypertension as key metabolic syndrome traits), will be key to ensure those who may require more frequent monitoring receive it. The disability weights for liver disease were only applied to decompensated cirrhosis, hepatocellular carcinoma and liver transplant cases. Thus, fibrosis reversal from antifibrotic therapy intervention for patients with F2–F4 prior to these events had limited impact on DALYs. Again, longer-term follow-up would presumably alter this situation. Evaluation of the potential impact, including cost effectiveness, of pharmacological interventions for MASLD is a complex undertaking for several reasons. First, liver disease generally resides within a multimorbidity clinical situation, with CVD a particularly important determinant of patient outcomes. Second, the relatively short-term improvements in surrogate markers (hepatic inflammation and fibrosis) may not translate into longer-term clinical event impact, since liver disease progresses slowly. Third, treatment adherence and lifestyle will clearly impact on temporal changes in weight, development or resolution of T2DM, and thereby influence liver disease outcomes. MASLD as a multisystem disease does however present opportunities, particularly in relation to T2DM diagnosis and management. Among people living with MASLD, T2DM is associated with substantially higher morbidity and mortality, making case finding for MASLD particularly important in this group. Thus, therapeutic targeting of people living with MASLD and T2DM is likely to be more cost effective, particularly if one considers the benefits of these drug classes beyond the liver and on extrahepatic organs and diseases linked to MASLD. Together with MASLD patient selection for treatment, a key challenge in 2025 is how to monitor liver treatment responses, so that clear stopping rules can be introduced for new and expensive licensed treatments. The emergence of various non-invasive testing modalities, including transient elastography and magnetic resonance-based techniques, has improved the ability to monitor patients; however, the accuracy and reproducibility of these modalities can be affected by obesity, liver congestion and acute inflammation, and access to these diagnostic tools remains variable across healthcare systems.16 Other imaging modalities such as magnetic resonance elastography (MRE) show promise but require further validation for routine clinical use and present additional resource challenges.17 Serum biomarker panels, including the enhanced liver fibrosis (ELF) test, have demonstrated utility in risk stratification, though their accuracy in diagnosing MASH and staging fibrosis vary considerably.18 Following the FDA licensing of resmetirom in 2024, there has been a useful update to the AASLD Practice Guidance in 2025 to introduce guidance on monitoring of therapeutic responses.19 This guidance introduces a ‘traffic light’ system, with a ‘green light’ for continuing resmetirom therapy beyond 12 months (i.e. improvement in vibration-controlled transient elastography [VCTE] kPa by 25% or MRE by ≥20% from baseline or normalization or significant improvement in alanine aminotransferase [ALT]), an ‘amber’ light for re-evaluating therapy (i.e. VCTE kPa improvement by <25%, or MRE improvement <20% from baseline or normalization, and no significant improvement in ALT, or <30% reduction in MRI-PDFF [proton density fat fraction]), and a ‘red’ light for stopping treatment (i.e. worsening of the same imaging or blood-based biomarker tests, or a consistent increase in ALT).19 Although this Guideline mentions the use of MRI-PDFF and MRE, both are costly tests that are not likely to be cost effective. However, the Guideline could be followed with the use of ALT, serum fibrosis biomarkers and VCTE, which is likely to be a more cost-effective strategy for monitoring the efficacy of newly licensed treatments. In conclusion, we are witnessing the dawn of a new era in the treatment of MASLD, with new drug classes not only showing promise for treating liver steatosis, inflammation and fibrosis, but also for having extrahepatic benefits in treating MASLD as a multisystem disease.5 We welcome the work of Wallace and colleagues, but the future challenge will also be to consider the extrahepatic benefits of these drugs, as well as the costs per quality-adjusted life years, in order to develop cost effective strategies for a condition that affects millions across the globe.
