MASLD: A Global Liver Disease in Need of Safe, Effective Treatments
Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as the world’s most common liver disorder, affecting roughly one in three adults. The disease is characterized by fat buildup in liver cells, which can progress to liver dysfunction and is closely linked to higher cardiovascular mortality. The search for therapies that are both effective and safe in early stages has intensified in recent years.
Drug Repurposing: A Practical Path Forward
In a study from the University of Barcelona (UB) and collaborators, researchers explored the repurposing of two already-approved drugs: pemafibrate, a lipid-lowering agent, and telmisartan, an antihypertensive. Conducted in collaboration with hospitals in Barcelona and Uppsala University (Sweden), the work was published in Pharmacological Research. Drug repurposing leverages known safety profiles, potentially accelerating access to treatment for MASLD patients while reducing development costs.
What the UB study Investigated
The team examined whether single or combined administration of pemafibrate and telmisartan could curb hepatic fat accumulation. They conducted experiments in a rat model of MASLD and extended the investigation to zebrafish larvae, an increasingly popular model due to its practicality and physiological similarities to human lipid metabolism.
Key Findings: Fat Reduction and Dual Benefits
The results were promising: the combination of pemafibrate and telmisartan reversed diet-induced hepatic steatosis in rats and, in zebrafish, corroborated the fat-reducing effect. Notably, using half-doses of each drug in combination achieved comparable fat-lowering outcomes to a full dose of either drug alone. This suggests potential for synergistic effects with lower toxicity risk from reduced dosages.
Mechanistic Insight: PCK1 and Lipid Flux
The study uncovered distinct mechanisms for each drug, jointly contributing to lipid lowering. A novel finding was the role of the PCK1 protein in telmisartan’s hepatic effects. In MASLD models, PCK1 levels were diminished but telmisartan restored them toward normal. Elevated PCK1 shifts metabolic flux away from lipid synthesis toward glucose production. Although increased glucose could raise concerns about hyperglycemia, the researchers observed no such adverse blood glucose elevation in their models, suggesting a favorable balance in early MASLD stages.
Why This Matters for MASLD Patients
Cardiovascular risk is a major concern for MASLD patients, who frequently exhibit coexisting hypertension and dyslipidemia. A combination therapy that simultaneously lowers liver fat, blood pressure, and cholesterol could address two critical risk factors at once, potentially reducing overall cardiovascular mortality linked to MASLD.
From Lab to Clinic: Next Steps and Considerations
While the findings are encouraging, the researchers caution that clinical application is still distant. The safety, efficacy, and optimal dosing of pemafibrate-telmisartan therapy must be evaluated in human MASLD trials. The study underscores the value of repurposing strategies, which can speed up the translation from bench to bedside, particularly for a disease stage where current therapies are limited.
A New Avenue in MASLD Research
As the landscape of MASLD treatment evolves, this work adds to a growing body of evidence that combination therapies targeting multiple pathogenic pathways may offer superior outcomes. By leveraging safe, well-understood drugs, researchers aim to deliver practical options for patients in the early, asymptomatic phases of MASLD while reducing the burden of related cardiovascular complications.
