Drug combo shrinks liver fat in rats and zebrafish: Study
Pemafibrate-telmisartan treatment reduced fat buildup
A combination of pemafibrate and telmisartan, two medications approved in some countries to help manage cardiovascular conditions, may help reduce the buildup of liver fat in people with fatty liver disease, according to a study done in animal models.
The study, “Telmisartan reverses hepatic steatosis via PCK1 upregulation: A novel PPAR-independent mechanism in experimental models of MASLD,” was published in Pharmacological Research.
Metabolic dysfunction-associated steatotic liver disease (MASLD), the most common liver disease, is marked by the abnormal buildup of liver fat in people who typically have cardiometabolic risk factors like high blood pressure, diabetes, or elevated fatty molecules in the blood (hyperlipidemia).
Unchecked, the disease can progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe stage marked by liver inflammation and scarring. This can set the stage for life-threatening complications like liver failure and liver cancer.
Current MASLD treatment options are limited. One strategy that’s being explored is to repurpose drugs that are approved for other conditions. Repurposing existing drugs has some notable advantages over developing a new drug from scratch: It’s usually cheaper, and drugs already on the market usually have well-established safety profiles.
Repurposing seen attractive for use in disease’s early stages
This type of repurposing is especially attractive for treating MASLD in the earliest stages, when patients usually don’t have any obvious symptoms, according to Marta Alegret, the study’s senior author and a professor at the University of Barcelona.
“We have focused on these phases with the aim of preventing the disease from progressing to more severe stages,” Alegret said in a university news story. “But for a drug to be used in these early stages, it must have a good safety profile in humans. That is why we have studied drugs already on the market for other [conditions], which have been shown to be very safe and could have a potential benefit in the treatment of MASLD.”
Alegret and colleagues in Spain and Sweden set out to test the effects of two available therapies, pemafibrate and telmisartan, in MASLD.
Pemafibrate is approved in Japan under the name Parmodia to treat hyperlipidemia. Telmisartan, sold as Micardis and with generics available, is approved in the U.S. and elsewhere to treat hypertension and reduce risk of cardiovascular events.
Their selection was based in part on the fact that they are already often used in people with the disease to manage underlying hyperlipidemia or hypertension.
“Mortality from cardiovascular causes is significant in patients with MASLD, and often these patients also have these two risk factors together,” Alegret said.
The team conducted tests in rat and zebrafish models of MASLD.
“In recent years, zebrafish have emerged as an interesting alternative model that facilitates the study of the [disease mechanisms] of MASLD and the evaluation of treatments,” Alegret said. “These are simpler and cheaper models that allow results to be obtained more quickly and which, although they are not identical to humans, have a [carbohydrate/fat] metabolism and liver physiology similar to those of mammals.”
The researchers found that pemafibrate and telmisartan were each able to reduce liver fat buildup, but they did so through distinct molecular mechanisms. Pemafibrate reduced liver fat by modulating the activity of PPAR-alpha, a protein that helps with the fat breakdown. Telmisartan’s benefits were not mediated by PPAR proteins, but instead by an increase in the levels of a protein called PCK1.
Although pemafibrate was known to act on PPAR proteins, telmisartan’s effect on PCK1 had not been reported before. The researchers found that the observed increase in PCK1 led liver cells to make less fat, instead diverting resources to make more glucose, or blood sugar.
“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,” Alegret said.
Low dose of each to maintain efficacy, minimize side effects
Because pemafibrate and telmisartan reduce liver fat through different mechanisms, the researchers reasoned that combining the two therapies might produce more potent effects. Indeed, experiments in rats showed that a half dose of both therapies was just as effective as a full dose of either one.
Using lower doses in combination instead of single drugs (monotherapy) at higher doses could help minimize side effects while still maintaining efficacy, the scientists noted.
“Combination therapy with drugs acting on different [disease-related] 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,” Alegret said. Synergy refers to a combined effect of two or more agents that is greater than the sum of their separate effects.
“The use of these compounds in a clinical setting could offer the advantage of simultaneously treating liver [disease]” and simultaneous conditions outside the liver, the researchers wrote.
They noted, however, that clinical studies in people with MASLD are needed to confirm the therapeutic potential of this approach.
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