The Systemic Burden of Metabolic Liver Dysfunction
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a primary global health challenge, currently affecting approximately one in three adults. The condition is characterized by the accumulation of excess fat within liver cells, a process that can trigger a cascade of hepatic damage and significantly elevate the risk of mortality stemming from heart and blood vessel disease.
The scale of this prevalence places substantial pressure on healthcare systems, as MASLD often progresses silently. Because early stages frequently lack overt symptoms, the disease often goes undetected until significant damage has occurred, necessitating a shift toward preventive pharmacological interventions that can be deployed safely across broad populations. For health ministries and payers, the condition is increasingly being framed as a systems-level challenge that cuts across primary care, cardiology, endocrinology, and liver services.
| Risk Factor / Driver | Pathological Impact | Systemic Outcome |
|---|---|---|
| Intracellular Lipid Accumulation | Hepatic inflammation and cellular stress | Potential for liver fibrosis and cirrhosis |
| Metabolic Dysfunction | Dyslipidemia and insulin resistance | Elevated cardiovascular morbidity |
| Asymptomatic Progression | Delayed clinical diagnosis | Increased reliance on high-cost late-stage care |
Strategic Drug Repurposing in Hepatology
The development of novel therapies for metabolic dysfunction-associated steatotic liver disease has been hindered by a high attrition rate in clinical trials, where many experimental candidates failed due to inadequate safety profiles. In response, researchers are increasingly pivoting toward drug repurposing-the process of identifying new therapeutic uses for medications already approved by regulatory bodies such as the European Medicines Agency or the U.S. Food and Drug Administration for other conditions.
From a public health and economic perspective, repurposing offers a streamlined pathway to treatment. Since these drugs have already undergone rigorous safety testing in humans, the time and cost associated with early-phase clinical trials are significantly reduced, allowing regulators and health systems to respond more nimbly to population-level health crises without compromising established safety standards.
“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,” explains Marta Alegret, a professor at the University of Barcelona’s Faculty of Pharmacy and Food Sciences. “That is why we have studied drugs already on the market for other pathologies, which have been shown to be very safe and could have a potential benefit in the treatment of MASLD,” she adds.
Synergistic Effects of Combination Therapy
Recent research conducted by the University of Barcelona, in collaboration with the Institute of Biomedicine of the UB (IBUB), the CIBER Area for Physiopathology of Obesity and Nutrition (CIBEROBN), and Uppsala University, has examined the efficacy of combining pemafibrate, a lipid-lowering agent, with telmisartan, a medication used to manage blood pressure.
The study utilized zebrafish larvae and rat models to analyze how these drugs interact. The results indicated that the combination therapy was more effective than monotherapy, demonstrating a synergistic effect that allowed for lower dosages without sacrificing efficacy and pointing to a potential future role in multi-morbidity management strategies for patients with overlapping liver and cardiovascular risk.
- Liver Fat Reduction: The combination successfully reversed fat buildup induced by diets high in fructose and fat.
- Dosage Efficiency: In rat models, half-doses of both drugs combined matched the efficacy of a full dose of either drug used alone.
- Cardiovascular Mitigation: The treatment demonstrated a dual benefit by lowering both cholesterol and blood pressure.
“Mortality from cardiovascular causes is significant in patients with MASLD, and often these patients also have these two risk factors together,” Alegret stresses. “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,” she points out.
“It lowers blood pressure and cholesterol levels, and all this would result in a lower cardiovascular risk,” she stresses.
Biochemical Pathways and the Role of PCK1
A critical component of this research is the identification of the biological mechanisms that drive the reduction of liver fat. While telmisartan has been utilized in advanced MASLD models for its anti-inflammatory and anti-fibrotic properties, this study highlights its role in the early, non-inflammatory stages of the disease.
“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 have been attributed mainly to anti-inflammatory and anti-fibrotic effects. But in the early stages of the disease there is no inflammation or fibrosis yet, only lipid accumulation,” explains the researcher.
The researchers identified that telmisartan restores the levels of the PCK1 protein in the liver, which had been abnormally low in the animal models. This restoration alters the liver’s metabolic processing by rebalancing how energy substrates are used within hepatocytes.
“This increase in PCK1 diverts the flux of metabolites from lipid synthesis to glucose synthesis. This increase in glucose production could be negative if the glucose were exported and accumulated in the blood, as it could lead to diabetes, but we have noticed that this is not the case,” says the UB professor.
Translating Animal Models to Clinical Practice
While these findings provide a promising theoretical framework for treating MASLD, the transition from animal models to human patients requires strict regulatory oversight and extensive clinical validation. Under existing medicinal product frameworks, any repurposed use would still need to pass through formal clinical development and post-market safety monitoring before clinicians could adopt it at scale.
“In order to be translated into a treatment for MASLD patients, clinical studies would be needed to show that the benefits observed in animal models also occur in humans,” says Alegret.
Current research efforts are expanding to determine if this drug combination remains effective in patients who have already developed liver fibrosis. Furthermore, the team is developing integrated models to observe the impact on atherosclerosis, aiming to confirm if the benefits extend fully to the vascular system and could, in time, influence how guideline committees frame combined liver-cardiovascular risk management.
“In addition, we will develop a dual model involving liver fibrosis and cardiovascular disease to see if the beneficial action is observed not only in the liver, but also in the reduction of atherosclerosis,” she concludes.
