Metabolic dysfunction-associated steatotic liver disease has become the leading liver disorder globally, impacting roughly one-third of adults. This condition arises from excessive fat accumulation in liver cells, potentially causing severe organ damage and heightening the chances of death from cardiovascular issues.
A new investigation by the University of Barcelona highlights a promising development with readily available drugs. Scientists discovered that pemafibrate and telmisartan substantially decreased liver fat in animal subjects with the disease. Notably, combining them not only enhanced liver function but also mitigated associated heart risks.
With few current treatments available, these results suggest a potentially safer and more efficient method compared to various investigational options.
The project was directed by Marta Alegret, a professor in the Faculty of Pharmacy and Food Sciences at the University of Barcelona. It included partnerships with entities like the Institute of Biomedicine of the UB (IBUB), the CIBER Area for Physiopathology of Obesity and Nutrition (CIBEROBN), and Uppsala University in Sweden.
Importance of Repurposing Approved Medications
Numerous trial drugs for metabolic dysfunction-associated steatotic liver disease (MASLD), previously called fatty liver disease, have failed clinical testing due to safety issues. This has led researchers to consider repurposing drugs already sanctioned for other uses.
This method offers advantages in speed, affordability, and safety, particularly for asymptomatic early stages of MASLD.
The team aimed at these initial phases to halt progression to advanced forms. For such applications, drugs need proven human safety, prompting the examination of established treatments for other conditions that might benefit MASLD.
They evaluated a cholesterol-reducing agent (pemafibrate) and a hypertension drug (telmisartan), both employed for heart-related risks. Pemafibrate is available solely in Japan, whereas telmisartan is used internationally. Patients with MASLD often face elevated cardiovascular mortality and commonly have these risk factors concurrently.
Significant Outcomes in Animal Testing
To explore the drugs’ mechanisms, the researchers used rats and zebrafish larvae. Zebrafish serve as an effective model for liver studies due to metabolic and functional similarities to humans, enabling quicker and cheaper research.
The findings were impressive. The pemafibrate-telmisartan duo reversed fat accumulation in livers induced by high-fat, high-fructose diets. In rats, half-doses of both combined matched the efficacy of full doses of either alone.
Combining agents targeting distinct disease pathways could outperform single-drug approaches, thanks to synergistic benefits and lower toxicity from reduced dosages.
Additionally, the therapy might decrease blood pressure and cholesterol, contributing to reduced cardiovascular threats.
Distinct Mechanisms of Action
The investigation showed the drugs operate via separate pathways. It newly identified the PCK1 protein’s key role in telmisartan’s fat-reduction effects.
Telmisartan has been tested in advanced MASLD models, with benefits linked to reducing inflammation and scarring. However, early stages lack these issues, featuring only fat buildup.
In MASLD-affected animals, hepatic PCK1 levels dropped below normal. Telmisartan treatment normalized them, altering nutrient processing in the liver.
This PCK1 elevation redirects metabolites from fat production to glucose creation. While increased glucose output might risk diabetes if it enters the bloodstream, observations indicated no such accumulation.
Promising Yet Preliminary
Despite encouraging outcomes, the work remains in early phases, derived from animal models. Further studies are required prior to human trials.
