Endocrinologist Dr. Daniel Drucker, pictured in Toronto last October, and his research team used mouse models and sophisticated technologies to explain the link between GLP-1 drugs and improved liver function.Sammy Kogan/The Globe and Mail
Researchers from Toronto’s Sinai Health have published a study that answers a central mystery for scientists studying the liver benefits of drugs such as Ozempic and Wegovy: how exactly they improve liver health, even in patients who don’t lose weight.
Published Tuesday in the journal Cell Metabolism, the study is the latest research to come out of the laboratory of Daniel Drucker, the Canadian scientist renowned for his pioneering research into glucagon-like peptide-1 receptor agonists, or GLP-1s.
While GLP-1s were originally developed for treating diabetes, they’ve achieved blockbuster status thanks to their weight-loss effects. And now, they’re being feverishly studied as a potential treatment for a host of other disorders and chronic diseases.
One of those is metabolic dysfunction-associated steatohepatitis, or MASH, a severe form of fatty liver disease that can lead to cirrhosis or liver cancer. Last December, the GLP-1 drug Wegovy was conditionally approved by Health Canada as the country’s first-ever pharmaceutical treatment for MASH.
Dr. María Jesús González-Rellán and Dr. Daniel Drucker at Toronto’s Sinai Health.Supplied
But an enduring mystery has been how these drugs actually work to improve health in the liver. In their latest paper, Dr. Drucker and his team used mouse models and sophisticated technologies to provide an answer to that long-running question – one that challenged widespread assumptions in the hepatology field around GLP-1s and liver function.
“It’s a very impressive study, and a very important study,” said Mamatha Bhat, a liver specialist with the University Health Network and associate professor of gastroenterology and hepatology at the University of Toronto, who was not involved with the paper.
“This study is very helpful to convince both clinicians and patients that maybe it is worth continuing a medication – even without the weight loss.”
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MASH is the more serious form of metabolic dysfunction-associated steatotic liver disease, or MASLD, which affects about 25 per cent of the adult population in Canada. On Monday, the Lancet Gastroenterology and Hepatology published new research estimating that 1.3 billion people worldwide had MASLD in 2023 – a figure projected to balloon to 1.8 billion by 2050, largely driven by population growth.
About 20 per cent of people with the condition have MASH, which, in serious cases, can lead to cirrhosis or cancer.
For years, MASH had no drug treatments. But in the early aughts, emerging GLP-1 research showed promising signals that these drugs could have benefits for those with the disease, according to Dr. Bhat.
Evidence has mounted over the past decade and in 2021, clinical trials funded by the Danish pharmaceutical company Novo Nordisk started demonstrating significant improvements for MASH patients treated with semaglutide (sold by the company as Ozempic for Type 2 diabetes and Wegovy for weight loss).
Most hepatologists believed these liver benefits were a downstream effect of the weight loss induced by these medicines.
This assumption was fuelled, in part, by the fact that nobody had ever found GLP-1 receptors in the liver – until 2021, when Dr. Drucker published a paper identifying them in a rare population of liver cells, called sinusoidal endothelial cells. (Dr. Drucker and his lab have received funding over the years from Novo Nordisk and other drug companies.) GLP-1 medications work by binding to receptors and triggering the effects of the natural hormone they mimic.
“The prevailing dogma, until very recently, has been that weight loss drives the benefit in people with liver disease,” said Dr. Drucker, a senior investigator with the Lunenfeld-Tanenbaum Research Institute. “Weight loss is helpful, but it’s by no means the entire story.”
Dr. Drucker points to his GLP-1-research-related X posts at Toronto’s Mount Sinai Hospital last October.Sammy Kogan/The Globe and Mail
In Dr. Drucker’s lab, postdoctoral fellow María Jesús González-Rellán began digging deeper to learn what these cells were up to. She started by comparing regular mice with genetically modified mice that lacked GLP-1 receptors in their brains, thus making them resistant to weight loss after taking semaglutide.
All mice were fed a special diet designed to induce liver disease. After being treated with semaglutide, both groups of mice showed liver improvements – even the ones that didn’t lose weight.
She then conducted a similar experiment, this time using genetically modified mice that lacked GLP-1 receptors in their livers. These mice showed no liver improvements with semaglutide, even after losing 20 per cent of their body weight – a “big surprise,” according to Dr. González-Rellán.
Using sophisticated RNA sequencing analysis, the researchers showed that these endothelial cells – once activated by GLP-1s – acted as a kind of air traffic controller, sending signals to other liver cells and co-ordinating their actions to reduce inflammation, a key characteristic of MASH.
While the paper’s findings are based on mouse models, Dr. Drucker said they align with unpublished clinical trial data that Novo Nordisk previously presented at conferences, showing that patients who barely lost weight on semaglutide still saw liver improvements.
For Dr. González-Rellán, the paper underscores the extraordinary potential of GLP-1s, which she prefers to think of as “metabolic medicines.”
“This field makes us stay very humble, because we think we understand how they work,” she said. “Understanding these weight loss-independent effects is quite important, because many people can benefit from them.”