Two common drugs can reverse fatty liver disease

Researchers at the University of Barcelona have now found a promising approach that could change how this condition is treated. Their study was published in Pharmaceutical researchReports indicate that two existing drugs, pemafibrate and telmisartan, significantly reduced lipid accumulation in animal models of metabolic liver disease. The results also suggest that using these medications together can mitigate liver damage while reducing related cardiovascular complications. Since available treatments for this disease are still very limited, the results suggest a safer and more effective treatment option.

The research was led by Marta Allegret, professor at the Faculty of Pharmacy and Food Sciences of the University of Barcelona, ​​and member of the Institute of Biomedicine at the University of UB (IBUB) and the CIBER Area for Physiological Pathology of Obesity and Nutrition (CIBEROBN). The work was carried out in collaboration with scientists from the Santa Creu i Sant Pau Hospital Research Institute, Hospital Clínic de Barcelona, ​​CIBER Cardiovascular Region (CIBERCV), and Uppsala University (Sweden).

Drug reuse is a promising and cost-effective strategy

To date, most new experimental compounds developed to treat metabolic syndrome-associated fatty liver disease (MASLD) — formerly known as steatosis — have failed during clinical trials, often due to safety concerns. This has shifted attention towards drug repurposing, a strategy that explores new uses for drugs that have already been proven safe in humans. Such an approach is not only faster and less expensive, but is also particularly valuable for treating the early stages of MASLD, which are often symptom-free.

“We focused on these stages with the aim of preventing the disease from progressing to more serious stages,” explains Marta Allegret. “But for the drug to be used in these early stages, it must have a good safety profile in humans.” “That’s why we studied drugs that are already on the market to treat other diseases, which have been shown to be very safe and could have potential benefit in treating MASLD,” she adds.

In this study, the team evaluated the potential of two approved drugs, given separately and together: a lipid-lowering agent (pemafibrate) and an antihypertensive drug (telmisartan). The former is marketed only in Japan, while the latter is widely used to treat high blood pressure. Both are prescribed to reduce cardiovascular risks. “Cardiovascular mortality is greater in patients with MASLD, and these patients also often have both of these risk factors together,” Allgret emphasizes.

Zebrafish larvae are an alternative model for studying disease

To confirm the drugs’ effectiveness and explore their mechanism of action, the researchers applied them to a mouse model of the disease and, later, to a zebrafish larval model. “In recent years, zebrafish have emerged as an interesting alternative model that facilitates the study of the pathophysiology of MASLD and the evaluation of treatments. These are simpler and cheaper models that allow results to be obtained more quickly, and although they are not identical to humans, they have a carbohydrate/lipid metabolism and liver physiology similar to those in mammals,” says the UB professor.

The results showed that the combination of the two drugs reversed the accumulation of fat in the liver caused by a diet high in fat and fructose. Additionally, in a rat model, co-administration of half a dose of pemafibrate and half a dose of telmisartan was found to be as effective as a full dose of either drug in reducing fat accumulation. “Combination therapy with drugs that act on different pathogenic pathways may be a better strategy than monotherapy, thanks to potential synergistic effects and reduced toxicity associated with using lower doses of each drug,” Allgret points out.

She stressed that combining these two drugs would be beneficial not only for liver disease, but also because it “lowers blood pressure and cholesterol levels, all of which would lead to a lower risk of cardiovascular disease.”

​​​​​​Different mechanisms of fat reduction The study also found that each drug acts through different mechanisms and describes, for the first time, a key role for PCK1 in telmisartan-derived hepatic fat reduction. “Telmisartan is a drug that has been used in other models of MASLD, but mostly in more advanced stages of the disease, and its beneficial effects are mainly attributed to anti-inflammatory and anti-fibrotic effects. But in the early stages of the disease there is no inflammation or fibrosis yet, only fat accumulation,” explains the researcher.

Researchers have now found that the amount of PCK1 protein in the livers of MASLD animals decreased and that treatment with telmisartan returned its levels to normal. “This increase in PCK1 switches the flow of metabolites from fat synthesis to glucose synthesis. This increase in glucose production could be negative if glucose is exported and accumulates in the blood, where it can lead to diabetes, but we have observed that this is not the case,” says the UCLA professor.

It is still far from clinical application

Despite these promising results, the researchers point out that since this is a study using animal models, it is still a long way from patients. “In order to translate it into a treatment for MASLD patients, clinical studies will be needed to show that the benefits observed in animal models also occur in humans,” Allegret says. However, the findings raise new questions, such as whether the drugs will be equally effective in more advanced stages of the disease, when fibrosis is present. So the research team is already working on new studies in animal models of diet-induced liver fibrosis. “In addition, we will develop a dual model including liver fibrosis and cardiovascular disease to see if a beneficial effect is observed not only in the liver, but also in reducing atherosclerosis,” he concludes.