Fatty liver disease, which is associated with metabolic dysfunction, is currently the most common liver disease worldwide, affecting approximately one in three adults. It occurs when excess fat accumulates within liver cells, which can lead to severe liver damage and an increased risk of death from heart and blood vessel disease.
Recent research from the University of Barcelona suggests that breakthroughs could be made using drugs that are already available. Researchers found that two drugs, pemafibrate and telmisartan, were able to significantly reduce liver fat in animal models of the disease. Even more encouraging, the two appear to not only improve liver health when used together, but also reduce associated cardiovascular risks.
Treatment options for this condition remain limited, so our findings point to a new approach that may be safer and more effective than many experimental treatments.
The study was led by Professor Marta Allegretto from the Faculty of Pharmacy and Food Sciences at the University of Barcelona, and was carried out in collaboration with several leading research institutions, including the UB Biomedical Research Institute (IBUB), the CIBER Area of Physiology and Pathology of Obesity and Nutrition (CIBEROBN), and Uppsala University (Sweden).
Why reusing existing medicines is important
Many investigational drugs for metabolic dysfunction-associated fatty liver disease (MASLD), formerly known as fatty liver disease, have failed to advance through clinical trials, often due to safety concerns. This has led scientists to consider drug repurposing, which involves using drugs already approved for other diseases.
This strategy is faster, more cost-effective, and safer, especially in the early stages of MASLD, when symptoms are usually not present.
“We have focused on these stages, with the aim of preventing the disease from progressing to more severe stages. However, the drugs used in these early stages must have a good safety profile in humans,” explains Marta Alegre. “Therefore, we are studying drugs that are already on the market for other medical conditions and have shown that they are very safe and have potential benefits in the treatment of MASLD,” she added.
The research team tested a lipid-lowering drug (pemafibrate) and a blood pressure drug (telmisartan) used to manage cardiovascular risk. Pemafibrate is currently only sold in Japan, while telmisartan is widely prescribed around the world. “Patients with MASLD have a high mortality rate from cardiovascular disease, and these patients often have these two risk factors at the same time,” Dr. Alegre emphasizes.
Animal models reveal powerful effects
To better understand how the drug works, researchers tested it in both rats and zebrafish larvae. Zebrafish have become a valuable model for studying liver diseases because their metabolism and liver function share important similarities with humans, while allowing for faster and cheaper experiments.
The results were amazing. The combination of pemafibrate and telmisartan reversed hepatic fat accumulation caused by a diet high in fat and fructose. In rats, half a dose of both drugs together was as effective as a full dose of either drug alone.
“Combination therapy with drugs that act on different pathogenic pathways may be a better strategy than monotherapy due to the potential for synergy and reduced toxicity associated with the use of low doses of each drug,” Alegre noted.
This treatment not only improves liver health but may also lower blood pressure and cholesterol levels. “It lowers blood pressure and cholesterol levels, all of which lead to lower cardiovascular risk,” she emphasizes.
Differences in drug action
The study also revealed that the two drugs act through different biological pathways. Researchers have for the first time identified a key role for the PCK1 protein in how telmisartan reduces liver fat.
“Telmisartan is a drug that has also been used in other models of MASLD, but it is mainly used in more advanced stages of the disease, and its beneficial effects are thought to be mainly due to its anti-inflammatory and anti-fibrotic effects. However, in the early stages of the disease there is still no inflammation or fibrosis, just lipid accumulation,” the researchers explain.
In animals with MASLD, PCK1 levels in the liver were lower than normal. Treatment with telmisartan restored these levels and changed the way the liver processes nutrients.
“This increase in PCK1 diverts the flow of metabolites from lipid synthesis to glucose synthesis. This increase in glucose production could be negative because if glucose is exported and accumulated in the blood it could lead to diabetes, but we found that this is not the case,” says the UB professor.
It’s still early days, but it’s encouraging.
Although the results are promising, the research is still in its early stages. The findings came from animal studies, and more research is needed before the treatment can be tested in humans.
“Clinical studies will be needed to show that the benefits observed in animal models also occur in humans before they can be translated into treatments for patients with MASLD,” Alegre says.
The research team is now looking at whether the same drug combination might be effective in more advanced stages of the disease, particularly when liver fibrosis is present. They are also developing new models that include both liver and cardiovascular disease to see if the benefits extend beyond the liver.
“Furthermore, we plan to develop a dual model that includes liver fibrosis and cardiovascular disease to see if beneficial effects are observed not only in the liver but also in reducing atherosclerosis,” he concludes.
