Most people have heard of fatty liver disease in passing, but fewer know about its more serious cousin: metabolic dysfunction-associated steatohepatitis, or MASH. In MASH, fat does not just sit passively inside liver cells. It triggers inflammation, and over time that inflammation can leave behind scar tissue, a process called fibrosis. Enough fibrosis, and the liver struggles to do its job. Researchers have long searched for drugs that can interrupt this process before it reaches that point.
A 2026 systematic review published in a European pharmacology journal set out to take stock of where the evidence stands. The authors pulled together 12 clinical studies testing two classes of metabolic therapy in people with MASH: drugs that work through the incretin system, a hormonal signaling pathway tied to blood sugar and appetite, and drugs called SGLT2 inhibitors, which act on the kidney to influence how the body handles glucose. The numbers they assembled paint a cautiously encouraging picture, though the researchers are careful to point out where the evidence still has gaps.
This article walks through what the review found, what the measured outcomes actually mean, and why researchers are paying close attention to the fibrosis question in particular.
What MASH is and why fibrosis matters
The liver is one of the few organs that can regenerate, but its repair toolkit has limits. When liver cells are repeatedly injured, the organ patches the damage with fibrous connective tissue. A small amount of fibrosis is manageable, but extensive scarring changes the liver's architecture and impairs its ability to filter toxins, regulate metabolism, and produce essential proteins.
MASH sits in a continuum. The earliest stage is simple fat accumulation, sometimes called steatosis. When inflammation is added to that fat, the condition becomes steatohepatitis. Add progressive fibrosis and the trajectory can lead toward cirrhosis. The review authors focused specifically on patients who had already crossed into the steatohepatitis stage, meaning their liver was actively inflamed, not just fatty.
Researchers use two related but distinct measures in MASH trials. One is whether the steatohepatitis itself resolves, meaning inflammation and cell injury calm down. The other is whether fibrosis improves, regresses, or at least does not worsen. A therapy can clear inflammation without necessarily reversing existing scar tissue, which is why published trials track both outcomes separately.
How incretin-based peptides performed
The incretin system involves hormones released from the gut after eating. These hormones normally signal the pancreas, the brain, and various other tissues to regulate appetite and glucose. Researchers have developed peptide drugs that mimic or amplify these hormonal signals, and the systematic review found that this class showed particularly strong results in MASH trials.
A GLP-1 receptor agonist peptide was tested in both a phase 2 and a phase 3 trial included in the review. In the phase 3 trial, 62.9 percent of patients in the treatment group achieved steatohepatitis resolution without worsening of fibrosis, compared with 34.3 percent in the placebo group. That is a statistically robust separation, with a p-value below 0.001. The phase 2 trial found NASH resolution in 59 percent of treated patients versus 17 percent receiving placebo, again a strongly significant result. However, that earlier trial did not show a significant improvement in fibrosis scores, with 43 percent of treated patients showing fibrosis improvement compared with 33 percent on placebo, a difference that did not reach statistical significance.
A dual-receptor peptide targeting both GLP-1 and GIP pathways was studied in a separate trial. Depending on the dose tested, between 44 and 62 percent of patients achieved MASH resolution without worsening of fibrosis, compared with 10 percent on placebo. Fibrosis improvement was seen in 51 to 55 percent of treated patients versus 30 percent on placebo. The review authors note that the incretin-based agents consistently produced reductions in body weight and improvements in markers of liver inflammation and fat content across the studies reviewed.
How SGLT2 inhibitors performed
SGLT2 inhibitors work through a different pathway entirely. Rather than targeting hormonal signaling, they act on a protein in the kidney that normally recaptures glucose from filtered urine. By blocking this protein, the drugs cause more glucose to leave the body through urine, which lowers blood sugar and also tends to reduce body weight and fluid retention. The review included trials testing at least one drug from this class in MASH patients.
The most detailed histological data came from trials of a specific SGLT2 inhibitor. In one trial, 53 percent of treated patients showed MASH improvement without worsening of fibrosis, compared with 30 percent on placebo. MASH resolution was observed in 23 percent of the treatment group versus 8 percent with placebo. Perhaps notably for this class, fibrosis improvement reached 45 percent in the treatment group compared with 20 percent in the placebo group, and all three of those differences were statistically significant.
The review authors suggest that SGLT2 inhibitors may offer what they describe as complementary metabolic and cardiometabolic benefits alongside the liver effects. This framing points toward a potential role for combination approaches in future research, though the review itself does not evaluate combination regimens in detail.
The fibrosis question remains open
One of the clearer conclusions from the systematic review is that inflammation resolution and fibrosis regression do not always move together. Several trials showed strong effects on steatohepatitis without corresponding effects on scarring. The authors describe the evidence for durable fibrosis regression as heterogeneous, meaning results vary enough across studies that no firm conclusion can be drawn.
There are a few possible explanations. Fibrosis tends to lag behind inflammation, so short-duration trials may capture inflammation improvement while missing later scar regression. Histological endpoints also require liver biopsies, which are invasive and can introduce sampling variability. Some trials did not include paired biopsies, meaning they measured liver fat or enzyme levels through blood tests or imaging rather than direct tissue examination.
The review calls explicitly for future trials to include paired histological endpoints, longer follow-up periods, and outcomes that matter to patients in a direct clinical sense, such as avoiding cirrhosis or liver failure. This is a fairly standard call in systematic review conclusions, but the authors frame it with enough specificity to suggest that the current evidence base has real and identifiable limits.
Shared metabolic effects across both classes
Beyond the liver-specific outcomes, the review documents consistent improvements in several metabolic parameters across both drug classes. Body weight fell in treated groups across multiple trials. Measures of blood sugar control improved. Markers of liver fat and disease activity, which are often tracked via imaging or blood-based scores, also moved in favorable directions.
The review authors interpret these findings as evidence that both classes act at least partly through systemic metabolic improvement rather than through direct liver-targeted mechanisms. Reducing fat in the liver by improving the broader metabolic environment may be as important as any action the drugs take on liver cells directly. This systemic framing also helps explain why researchers are interested in whether combining the two classes might produce additive or synergistic effects, though that question was outside the scope of this review.
Early data across both classes also pointed toward acceptable safety profiles in the populations studied, though the review notes that long-term safety data specifically in MASH populations remains limited. Most of the adverse events documented in the source trials were consistent with what is already known about these drug classes from their use in metabolic disorders more broadly.
What the review means for the research landscape
Systematic reviews like this one serve a particular function in medical research. They aggregate findings that would otherwise be scattered across separate publications and ask whether a pattern holds across studies. The conclusion here is that metabolic therapies, particularly those working through the incretin system, show meaningful effects on liver inflammation in MASH, but that the story on fibrosis is not yet fully written.
The review included 12 clinical studies, which is a meaningful but still limited evidence base. The trials included range from phase 2 exploratory work to larger phase 3 confirmatory studies, which means the quality and statistical power of the underlying evidence varies. The authors do not draw a single sweeping conclusion about which approach is superior, and the data do not clearly support one.
For researchers and clinicians following this space, the review's most actionable contribution may be its mapping of where the evidence is solid and where the gaps are. Steatohepatitis resolution data looks reliable. Fibrosis data needs longer trials and more consistent histological endpoints. Combination regimens, optimal dosing, and effects in patients without diabetes remain questions that the current literature has not answered.
