Metabolic dysfunction-associated steatotic liver disease has emerged as the most prevalent liver disorder globally, impacting roughly one in three adults. This condition arises when excess fat accumulates in liver cells, which can lead to significant liver damage and heighten the risk of cardiovascular disease.
A study conducted by researchers at the University of Barcelona presents a promising development with medications that are already on the market. The investigation revealed that two drugs, pemafibrate and telmisartan, significantly reduced liver fat in animal models of this condition. Additionally, combining these two medications seemed to not only enhance liver health but also diminish cardiovascular risks associated with the disease.
Given the limited treatment options for this liver condition, these findings indicate a potentially safer and more effective approach compared to several experimental therapies currently available.
The research was spearheaded by Marta Alegret, a professor at the University of Barcelona’s Faculty of Pharmacy and Food Sciences, in collaboration with major research institutions such as the Institute of Biomedicine of the UB, the CIBER Area for Physiopathology of Obesity and Nutrition, and Uppsala University.
Importance of Repurposing Existing Drugs
Many experimental medications targeting metabolic dysfunction-associated steatotic liver disease (previously known as fatty liver disease) have struggled to pass clinical trials, often due to safety issues. This has prompted researchers to consider repurposing existing drugs that have already been approved for different health concerns.
This approach can be quicker, more cost-effective, and safer, particularly for early stages of MASLD, which typically don’t present symptoms.
“We have prioritized these early phases to prevent the disease from escalating to more severe levels. However, for a drug to be used effectively in these situations, it must have a solid safety profile,” Marta Alegret explains. “That’s why we looked into drugs that are already established for other conditions, with a proven safety record and potential benefits for MASLD treatment,” she adds.
The research tested pemafibrate, a lipid-lowering agent, alongside telmisartan, a medication for hypertension. Pemafibrate is currently marketed only in Japan, while telmisartan is widely prescribed globally. “Mortality rates due to cardiovascular issues are notably high among MASLD patients, many of whom exhibit both of these risk factors,” Alegret stresses.
Animal Models Show Significant Impact
To deepen their understanding of the drugs’ mechanisms, researchers conducted tests on rats and zebrafish larvae. Zebrafish are particularly useful for liver disease studies due to their metabolic and liver function similarities with humans, and they allow more rapid and economical experiments.
The results were impressive. The combination of pemafibrate and telmisartan reversed fat accumulation in the liver due to a high-fat, high-fructose diet. In rats, using half doses of both drugs together proved just as effective as the full dose of either medication alone.
“Utilizing a combination therapy that targets different biological pathways might be a more effective strategy than monotherapy, likely due to potential synergistic effects and the reduced toxicity associated with lower doses,” Alegret notes.
Additionally, this treatment may help lower blood pressure and cholesterol levels. “The reduction in these factors could lead to diminished cardiovascular risks,” she emphasizes.
Distinct Mechanisms of Action
The study also uncovered that these two drugs operate through separate biological pathways. For the first time, researchers highlighted the role of the PCK1 protein in how telmisartan reduces liver fat.
“Telmisartan has previously been used in other MASLD models, mainly during more advanced stages, and its benefits have often been linked to its anti-inflammatory and anti-fibrotic properties. However, in the early stages, inflammation or fibrosis typically isn’t present, only fat accumulation,” the researcher clarifies.
In animals exhibiting MASLD, PCK1 levels in the liver were found to be abnormally low. Treatment with telmisartan brought these levels back to normal, altering the liver’s nutrient processing.
“This increase in PCK1 shifts the metabolic flow from fat creation to glucose production. While this could lead to elevated blood sugar if not managed, we haven’t observed that happening in this study,” the UB professor explains.
Still Preliminary, but Hopeful
While the findings are promising, they stem from early-stage research. Further work is necessary before any potential treatments are tested on humans.
“To translate these results into a treatment for MASLD patients, we would need clinical studies to verify that the benefits seen in animal models also translate to humans,” Alegret states.
The research team is now investigating whether this drug combination would be effective in more advanced stages of the disease, especially where liver fibrosis is present. They’re also working on new models that integrate both liver disease and cardiovascular issues to assess if the benefits can extend beyond just liver health.
“Additionally, we plan to create a model that combines liver fibrosis and cardiovascular disease, to explore whether the positive effects are observed not only in liver improvement but also in the reduction of atherosclerosis,” she concludes.
