New hope for MASLD through drug repurposing
Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the world’s most common liver disorder, affecting roughly one in three adults. It involves fat buildup in liver cells and is linked to serious liver outcomes and a heightened risk of cardiovascular mortality. A recent study from the University of Barcelona, published in Pharmacological Research, suggests that two existing drugs—pemafibrate and telmisartan—could help curb liver fat accumulation and reduce cardiovascular risk in MASLD. The findings, derived from rat and zebrafish models, signal a potential shift toward safer, more accessible therapies for a disease that currently lacks widely effective treatments.
Drugs already on the market, new in MASLD
The UB team, led by Professor Marta Alegret, examined the repurposing potential of pemafibrate (a lipid-lowering agent) and telmisartan (an antihypertensive). Both drugs have well-established safety profiles for other conditions, making them attractive candidates for MASLD, especially in its early, often asymptomatic stages. “Drug repurposing offers a cost-effective, safer strategy, particularly for patients in the early stages where progression can be slowed or prevented,” Alegret explains.
In experiments with a high-fat, high-fructose diet model that mimics MASLD, the combination of pemafibrate and telmisartan demonstrated a notable reversal of hepatic fat accumulation. Importantly, using half-doses of each drug produced effects comparable to full doses of either drug alone. This suggests the potential for synergistic action while potentially minimizing side effects, a key consideration for long-term management of MASLD.
From rat models to zebrafish: a versatile research approach
The study’s researchers used two complementary models to investigate mechanisms and efficacy. Rat models provided a controlled mammalian context to assess lipid metabolism and liver fat, while zebrafish larvae offered a rapid, cost-efficient platform to study disease pathways. Zebrafish have emerged as a useful surrogate for MASLD research due to similarities in carbohydrate and lipid metabolism and liver physiology with mammals, despite being more experimentally tractable than larger animals.
Professor Alegret notes that this two-pronged approach helps illuminate how these drugs act across different biological systems, reinforcing the translational potential of the findings. While results in animals do not immediately translate to humans, they lay essential groundwork for future clinical trials, particularly in early MASLD where safety and tolerability are paramount.
Different mechanisms, shared goal: reducing liver fat and cardiovascular risk
The research highlights that pemafibrate and telmisartan operate via distinct mechanisms, offering a complementary strategy. A novel insight from the study is the role of the PCK1 protein in telmisartan-driven hepatic lipid lowering. In MASLD models, PCK1 levels were reduced; treatment with telmisartan restored normal PCK1 expression. This shift appears to divert metabolic flux away from lipid synthesis toward glucose production, without causing harmful elevations in blood glucose, a finding that warrants further exploration in human studies.
Beyond liver fat, the combined regimen could address cardiovascular risk, a major concern for MASLD patients who frequently exhibit hypertension and dyslipidemia. By improving lipid and blood pressure profiles, this approach holds the promise of a two-pronged gain: better liver health and lower cardiovascular mortality.
Looking ahead: challenges and cautious optimism
Despite the encouraging results, the researchers acknowledge that clinical application remains distant. Safety, efficacy, and optimal dosing must be established in human trials, and the interaction of these drugs in diverse patient populations requires careful evaluation. The UB team emphasizes that repurposing is a practical route, but it must be validated through rigorous clinical research before changes in standard MASLD care can be recommended.
Conclusion
The study from the University of Barcelona adds to a growing momentum around drug repurposing as a viable path for MASLD therapy. By combining pemafibrate and telmisartan, researchers have opened a potential avenue to reduce liver fat and cardiovascular risk using familiar drugs, with a safety profile suitable for early intervention. As MASLD remains a global health challenge, such innovative approaches are welcome steps toward safer, more effective treatments.
