The Canadian researcher whose discovery led to Ozempic is still making breakthroughs. Inside a nondescript research tower behind Toronto’s Mount Sinai Hospital, Daniel Drucker, his scientist colleagues, and their lab mice are unraveling mysteries about one of the biggest medical breakthroughs of the last 30 years. They are studying the mechanisms behind the seemingly endless uses of Ozempic and its cousins in the class known as glucagon-like peptide-1 receptor agonists, or GLP-1s. These drugs have already been proven to be highly effective in controlling blood sugar and promoting weight loss. But study after study is showing that they may reduce the risks for everything from strokes and heart attacks to kidney and liver disease, sleep apnea, and arthritis. What makes these drugs so powerful? The answer is not straightforward, explained Dr. Drucker, a senior investigator at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital and a pioneer of GLP-1 science. Some of the benefits of GLP-1 medicines appear to be independent of blood-sugar control and weight loss. That means that, to take one example, patients on semaglutide, the drug sold as Ozempic for Type 2 diabetes and Wegovy for weight loss, can see liver disease improve even if they don’t shed many pounds. We can do experiments where we can make sure that the mice we’re treating have no weight loss. They’re getting the GLP-1 medicine and they still have these tremendous benefits in improving liver health, despite the fact that they’re losing no weight. How and why that happens is one of the pre-occupations of Dr. Drucker’s lab, a hub for GLP-1 science in Canada where 11 postdoctoral fellows, students, and associate scientists are researching topics that range from how the popular drugs affect chronic inflammation to how they stave off kidney disease. By now, Dr. Drucker’s role in isolating a stable version of glucagon-like peptide-1 is familiar to Canadians who’ve followed the Ozempic craze – a craze that is set to become a mania when cheaper generic versions of the medicine are released in Canada this year. The human version of GLP-1 degrades too rapidly to be repurposed as a drug, so, in the mid-1990s, Dr. Drucker decided to follow the discovery of a reptile GLP-1-related molecule by an American scientist. Dr. Drucker got his hands on a source through the Royal Ontario Museum in Toronto: a Gila monster, the portly lizard native to the deserts of the southern U.S. and Mexico. Dr. Drucker analyzed the Gila monster’s venom and cloned the reptile genes for GLP-1 and a peptide called exendin-4. Both act on GLP-1 receptors, and exendin-4 was more stable than the human equivalent. His discovery, published in 1997, helped pave the way for short-acting versions of GLP-1s for diabetes, and eventually, for the long-acting blockbuster that is Ozempic. Dr. Drucker pays homage to the lizard by keeping a bottle of Gila brand tequila in his office and the body of the original monster in his lab’s freezer, shrouded lovingly in plastic wrap. The reptile also made a mark on Chi Kin Wong, a postdoctoral scientist in Dr. Drucker’s lab who studies how GLP-1s affect inflammation. He got a tattoo of the Gila monster on his forearm to celebrate the publication in 2022 of his study that found semaglutide works directly on certain immune cells to tame inflammation. We found that there’s a population of immune cells in the gut that the drug can directly act on and reduce inflammation there. I got really excited, and then I was like, ‘Oh, I’ve got to commemorate it in some way.’ Later, Dr. Wong led a follow-up study that found semaglutide acts directly on GLP-1 receptors in the brain in a way that dampens inflammation throughout the body, even though GLP-1 receptors haven’t been found widely on immune cells outside the gut. The results held in short-term experiments before lab mice had time to lose weight, suggesting GLP-1s may directly reduce damaging inflammation broadly before weight loss happens. It’s one of the reasons the drugs are being studied as possible treatments for inflammatory diseases such as rheumatoid arthritis. The question of where in the body and under what conditions GLP-1 receptors are active is critical to grasping how Ozempic and its peer drugs work. It’s well-understood that the drugs act directly on the cells in the pancreas and the brain, where GLP-1 receptors are plentiful, to regulate blood glucose and control appetite. But the receptors are harder for scientists to spot elsewhere. Dr. Drucker likens it to scanning a Where’s Waldo book. Just because the striped-shirted character isn’t visible at first glance, doesn’t mean he’s not there. Consider the liver, as Maria Jesus Gonzalez-Rellan has spent the past three years doing. She has been experimenting on mice to figure out why semaglutide improves liver function in people with severe fatty liver disease, which now goes by the unwieldly name of metabolic dysfunction–associated steatohepatitis, or MASH. Health Canada conditionally approved Wegovy for MASH late last year. Dr. Gonzalez-Rellan, who moved from Spain to work in Dr. Drucker’s lab, set out to answer the question with two groups of mice. One was comprised of wild-type mice, the other of mice genetically modified to block the GLP-1 receptors in their brains. She and her colleagues fed all the mice pellet diets engineered to make them obese. Once the rodents had packed on weight and developed fatty liver disease, Dr. Gonzalez-Rellan divided the groups again. Half received injections of semaglutide, the rest jabs of saline, a placebo. The wild-type mice lost weight on semaglutide and their liver function improved, according to blood tests and examinations of their liver tissue. The mice without working GLP-1 receptors in their brains did not lose weight but their liver function also improved. That means that, in reality, both weight-loss dependent mechanisms and weight-loss independent mechanisms are important for liver health, Dr. Gonzalez-Rellan said. And this was a surprise. Her findings, which have been submitted to a scientific journal but have yet to be published, were unexpected because most of the GLP-1 research community thought the critical receptors weren’t present in the liver, and that better liver health was just a side benefit of weight loss. The GLP-1 receptor isn’t expressed on hepatocytes, the cells that make up 80 per cent of the liver. To investigate further, Dr. Gonzalez-Rellan’s and her colleagues looked more carefully inside the liver itself. They discovered that GLP-1 receptors are present on a specialized group of endothelial cells in the liver’s tiny blood vessels. When obese mice were engineered so that these cells, which play a crucial part in liver health, no longer had GLP-1 receptors, semaglutide still helped them lose weight. But many of liver health benefits disappeared. Canada will be a launching pad in the global race for generic Ozempic. These kinds of findings are more than academic, said Dr. Drucker, who also holds the Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology at the University of Toronto. Their insights could help medical scientists and pharmaceutical companies design better Ozempic offshoots in the future, or help explain why the GLP-1 class doesn’t seem to work for Parkinson’s or Alzheimer’s disease, as early observational studies suggested they might. In the meantime, Rola Hammoud, another postdoctoral scientist in Dr. Drucker’s lab, is pleased with what the current generation of drugs is already capable of. As a dietician working in the pre-Ozempic era in her native Lebanon, she often encountered patients who blamed themselves – or were blamed by others – when they couldn’t lose weight. She moved to the University of Toronto for a PhD in nutritional science and is now studying the mechanism of the gut hormone abbreviated as GIP, which works with GLP-1 in tirzepatide, the drug sold as Mounjaro for diabetes and Zepbound for weight loss. These GLP-1 drugs really just highlight how, if you can just override your biology, how much of an effect you get. Weight loss and appetite control is not simply a will-power problem, but it is actually a more complex physiological process.
