Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), have traditionally been treated as liver diseases. But what happens in the liver may have profound consequences for the heart — and potentially other organs throughout the body.
Duke researchers are advancing understanding of this liver-heart connection through a new multicenter clinical trial led by Amreen Dinani, MD, associate professor of medicine in the Division of Gastroenterology.
Dinani has spent years arguing that this singular view of liver disease is too narrow – and dangerous – when her clinical experience revealed a recurring pattern: many patients with MASH also showed early signs of heart dysfunction.
Now, her hypothesis is being tested in a new clinical trial funded by Madrigal Pharmaceuticals that is believed to be the first proof-of-concept study specifically designed to examine the safety and impact on heart structure and function of resmetirom in those with MASH and HFpEF — a form of heart failure in which the heart has difficulty filling properly.
Resmetirom is a medication that was conditionally approved in March 2024 to treat patients with MASH and liver scarring. The six-month, double-blind, randomized, placebo-controlled study will enroll 90 patients at approximately 30 sites across the United States, including Duke.
“Historically, we have thought about this as a very liver-centric disease, but if you don't have a healthy liver, you won't have a healthy heart,” said Dinani, the trial’s principal investigator. We really have to think about it as a multi-organ disease and start thinking about this population holistically”
Nearly one in three people worldwide live with metabolic dysfunction-associated steatotic liver disease, or MASLD. In the United States, an estimated 110 million people are affected. The disease has become the fastest-growing cause of both liver transplantation and liver cancer in the country.
A Shared Metabolic Problem
Cardiovascular disease is a leading cause of death among people with MASLD, and one of the strongest cardiovascular associations is HFpEF. While the two diseases share many of the same underlying drivers such as obesity, insulin resistance and chronic inflammation, there is also an independent association between the two.
Dinani believes these overlapping conditions should not be viewed in isolation.
The liver plays a central role in regulating metabolism, filtering toxins, producing bile acids to digest fat, store energy as glycogen and making important proteins. When these processes become disrupted, she explained, the effects can extend far beyond the liver itself. Dysregulated liver metabolism then leads to systemic inflammation leading to changes in the heart and other vital organs that affect the overall metabolic health of the patient.
For Dinani, the question is whether intervening earlier in one part of that system could produce benefits elsewhere. “If you don't have a healthy liver, you won't have a healthy heart,” she said.
Researchers will assess whether treatment with resmetirom affects not only the liver but also the structure and function of the heart. They will also examine changes in liver fat, skeletal fat and muscle, fat distribution, impact on physical capacity and quality of life. Investigators will also study biomarkers associated with heart failure, cardiovascular risk and systemic inflammation.
Looking Beyond a Single Organ
The study represents a shift in how researchers are beginning to think about MASH — not simply as a disease of the liver, but as part of a broader metabolic condition with consequences throughout the body. The implications could be significant given the growing prevalence of both MASH and HFpEF and the limited treatment options available for many patients.
The study can provide important evidence for larger studies—and help establish a new framework for understanding metabolic disease. For Dinani, that means looking beyond the liver to understand the full impact of MASH — and asking whether protecting one organ could ultimately help protect the others.
Her message to patients and families is to understand their risk. People with obesity, diabetes or cardiovascular disease may be at increased risk for metabolic liver disease, Dinani said, and patients should feel empowered to ask their health care providers whether screening is appropriate.
“If you can't keep a liver healthy,” she said, “you can't keep the rest of the organs healthy.”