Researchers at the University of Barcelona have discovered that combining two existing medications, pemafibrate and telmisartan, significantly reduces liver fat in animal models of metabolic dysfunction-associated steatotic liver disease (MASLD). This approach could offer a safer treatment option for the condition, which affects about one in three adults worldwide. The findings highlight the potential of drug repurposing to address a disease with limited current therapies.
Metabolic dysfunction-associated steatotic liver disease, formerly known as fatty liver disease, is the most common liver disorder globally, impacting roughly one in three adults. It involves excess fat buildup in liver cells, raising risks of severe liver damage and cardiovascular death. Current treatments are scarce, with many experimental drugs failing clinical trials due to safety issues, prompting a shift toward repurposing proven medications.
A study led by Marta Alegret, a professor at the University of Barcelona's Faculty of Pharmacy and Food Sciences, explored this strategy. Published in Pharmacological Research, the research tested pemafibrate—a lipid-lowering agent available in Japan—and telmisartan, a widely used antihypertensive drug. Both are approved for reducing cardiovascular risk, which is a major concern in MASLD patients.
In rat and zebrafish larval models of the disease, induced by high-fat and fructose diets, the drugs were applied separately and together. The combination reversed fat accumulation in the liver, proving as effective as full doses of either drug alone, even at half doses. "Combination therapy with drugs acting on different pathogenic pathways may be a better strategy than monotherapy, thanks to possible synergistic effects and reduced toxicity related to the use of lower doses of each drug," Alegret explained.
The study revealed complementary mechanisms: pemafibrate lowers lipids, while telmisartan restores levels of the PCK1 protein, diverting metabolites from fat to glucose synthesis without causing hyperglycemia. This addresses early-stage lipid buildup, before inflammation or fibrosis develops. Additionally, the duo lowers blood pressure and cholesterol, potentially cutting cardiovascular risks.
"We have focused on these phases with the aim of preventing the disease from progressing to more severe stages. But for a drug to be used in these early stages, it must have a good safety profile in humans," Alegret noted. Conducted with collaborators including the Santa Creu i Sant Pau Hospital Research Institute and Uppsala University, the work used zebrafish as a cost-effective model with metabolism similar to mammals.
Though promising, the results are from animal models. "In order to be translated into a treatment for MASLD patients, clinical studies would be needed," Alegret cautioned. The team plans further research on advanced stages involving fibrosis and atherosclerosis.