- Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is the most common chronic liver disease, affecting almost 40% of adults worldwide.
- If left untreated, it can lead to more severe liver diseases such as cirrhosis and liver cancer, but there are few drugs available to treat the early stages.
- Now, a study in animal models has found that, in combination, two commonly used heart drugs reverse fat accumulation in the liver.
- The researchers suggest that, if further research confirms their findings, this may be a promising treatment for MASLD.
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), or nonalcoholic fatty liver disease, has increased steadily over past decades. It now affects
The condition is strongly linked to cardiovascular disease, as the conditions share many of the same
MASLD is often associated with overweight or obesity, so one of the most effective non-pharmacological treatments is weight loss. Studies suggest that for people with overweight or obesity losing 3-5% of their bodyweight can reduce the condition, while 10% weight loss can help reverse fibrosis of the liver.
However, if weight loss is ineffective, there are few pharmacological treatments for the condition.
Now, a new study has found that, in animal models of fatty liver disease, two commonly used heart drugs — pemafibrate, which is used to lower blood lipids, and telmisartan, a blood pressure medication — significantly reduced fat buildup.
In their study, published in Pharmacological Research, the researchers suggest that this finding supports the repurposing of telmisartan and pemafibrate for managing MASLD.
Marta Alegret, DPharm, one of the study authors, who is a pharmacology professor in the Department of Pharmacology, Toxicology, and Medicinal Chemistry at the University of Barcelona, in Spain, told Medical News Today:
“We have used a dietary rat model which mimics the initial stage of MASLD, simple steatosis without inflammation or fibrosis. These phases are often neglected because it is believed that they are benign, but the truth is that the risk of mortality is already increased. The importance of our findings is that we demonstrate that telmisartan and pemafibrate, alone or combined, effectively reduce liver lipid levels in this model.”
The researchers used two models of hepatic steatosis — abnormal fat accumulation in the liver — one in rats and the other in zebrafish larvae.
In the rat model, the animals were randomly divided into five groups. For two months, a control group followed a regular diet, and four groups had a high-fat diet with free access to 10% fructose (sugar) solution.
For the third month, three of the high-fat diet groups were treated as follows:
- group 1 received 0.5 milligrams per kilogram per day ( mg/kg/day) of pemafibrate
- group 2 received 10 mg/kg/day of telmisartan
- group 3 received a combination of 0.25 mg/kg/day of pemafibrate and 5 mg/kg/day of telmisartan.
At the end of the 3 months, the researchers collected blood samples for analysis.
Zebrafish have similar carbohydrate/lipid metabolism and liver physiology to mammals, so are often used as a quicker, cheaper alternative to mammal models.
The researchers placed 5-day old zebrafish larvae into tanks with different feeding regimes — standard fed, overfed plus fructose, and overfed plus glucose. They then added telmisartan to the water in the overfed plus glucose tank.
After 5 days of treatment, researchers collected body image data and liver samples from the zebrafish for analysis.
In the rat model of fatty liver without obesity, both pemafibrate (0.5mg/kg/day) and telmisartan (10mg/kg/day) were highly effective in reducing liver triglycerides.
In zebrafish, telmisartan similarly reduced fat accumulation in the liver.
Notably, the researchers found that combining the drugs, each at half the normal dose, was equally effective in reducing fat accumulation in the liver.
Alegret told MNT:
“The rationale of combining pemafibrate with telmisartan is based on their complementary mechanisms of action to reduce liver lipids: Pemafibrate essentially enhances lipid catabolism (breakdown), while telmisartan affects the pathways related to endogenous lipid synthesis in the liver. In addition, cardiovascular risk is high in patients with MASLD, and each one of these compounds target one different cardiovascular risk factor (dyslipidemia and hypertension). Therefore, their combination may result in a lowered cardiovascular risk.”
“Moreover,” she continued, “one of our key findings in the rat model of MASLD is that the combination of pemafibrate and telmisartan at half the dose used of each drug alone is as effective at reducing accumulation of hepatic fat as monotherapy. The possibility of using low doses of the compounds when they are combined would reduce the risk of adverse effects.”
Cheng-Han Chen, MD, a board-certified interventional cardiologist and medical director of the Structural Heart Program at MemorialCare Saddleback Medical Center in Laguna Hills, CA, explained how the drugs are currently used:
“Pemafibrate is a drug closely related to the fibrate class of medications, and telmisartan belongs to the class of medications known as angiotensin II receptor blockers. Both of these categories of medications are commonly used in the treatment of cardiovascular diseases and have a favorable safety and efficacy profile,” Chen, who was not involved in this study, told MNT.
“Developing new drugs is a costly process that frequently ends in failure due to safety concerns. By repurposing drugs that have already demonstrated safety when used for other conditions, it may be possible to find effective treatments for certain unmet medical needs in a more efficient and cost-effective manner.”
– Cheng-Han Chen, MD
Alegret cautioned that their findings are an early stage in developing these drugs as a potential treatment for liver disease.
“From our results only, we can not recommend these drugs, alone or combined for the treatment of MASLD. It would be necessary to demonstrate their beneficial effects in a clinical assay in patients with this disease,“ she said.
“To our knowledge, some small clinical trials have reported improvements in MASLD markers, such as fatty liver index, with pemafibrate or telmisartan,” the study author added.
“However, to approve these drugs for the treatment of MASLD, it is necessary to perform assays with a larger number of patients, longer duration, and specific histologic endpoints — for example, improvement in fibrosis stage and reduction of liver fat content measured by imaging or biopsy,” she pointed out.
