# Treatment Resistant Patients with Metabolic Dysfunction-associated Steatohepatitis: Long-term Follow-up Prospective Study

## TL;DR

This study examines long-term outcomes of multidrug therapy in patients with MASH, finding that early treatment with weight control and step-by-step medication stabilizes most patients.

## Contribution

The study introduces a step-by-step multidrug therapy approach and identifies early-stage treatment as crucial for MASH management.

## Key findings

- Weight control and multidrug therapy stabilized over 90% of MASH patients.
- High fibrosis markers like type IV collagen and FIB-4 index correlate with treatment resistance.
- Early treatment before fibrosis worsens is recommended based on baseline marker levels.

## Abstract

Many treatments for patients with metabolic dysfunction-associated steatohepatitis (MASH) have been proposed; however, most studies showed the results for a single medication and a short duration of treatment. The long-term outcomes of the multidrug therapies remain indeterminate. We conducted a study to investigate the usefulness of multidrug combination therapy for every kind of MASH patient and the differences between treatment-sensitive and treatment-resistant patients.

Fifty-one patients (middle-aged, in their 40s to 60s, metabolic generation) with MASH-determined fibrosis staging were enrolled. Primary treatment (weight control and medication of vitamin E and sodium-glucose cotransporter 2 inhibitor (SGLT2i)) was done and then pemafibrate treatment was added.

Regarding responses to the step-by-step multidrug therapy, patients with MASH were divided into 3 groups, with use of 3 markers―alanine aminotransferase (ALT) (hepatitis), elasticity value (E value, liver stiffness measurement) (hepatitis/fibrosis), and type IV collagen (fibrosis); group 1: sensitive to primary treatment (n = 35), group 2: resistant to primary treatment and sensitive to pemafibrate treatment (n = 11), and group 3: resistant to both treatments (n = 5).

To determine the parameters related to treatment resistance, the baseline levels of parameters―obesity (body mass index), metabolic factor (visceral fat, controlled attenuation parameter), diabetes mellitus (DM) (glycated hemoglobulin (HbA1c), fasting immunoreactive insulin), lipid metabolism (triglyceride), and hepatitis (ALT)―were compared between treatment-sensitive group 1+group 2 and treatment-resistant group 3. However, none of them had differences statistically. The same analysis showed that type IV collagen, E value, FIB-4 index (age (year) x AST (IU/L)/platelet count (104/L) x ALT (IU/L)1/2), and MASH fibrosis had differences statistically.

The most effective treatment for patients with MASH could not be determined, according to the baseline levels of characteristics; however, weight control and step-by-step multidrug therapies made it possible to stabilize more than 90% of patient conditions and to solve MASH without worsening fibrosis. Since high levels of liver fibrosis-related markers affected the treatment resistance, MASH treatments should be started in an early stage while the levels of each marker are still low; type IV collagen <5.3 ng/mL, E value <13.7 kPa, FIB-4 index <1.89 and MASH fibrosis stage 2 or less.