Erik Swain , 2025-05-17 13:00:00
Key takeaways:
- Scientists do not fully understand why response to GLP-1s varies so widely among people prescribed them.
- Some benefits of GLP-1s occur independently of weight loss, so multiple factors are likely in play.
ORLANDO — Much has been learned about GLP-1s over many years, but little is understood about why the degree of response to them varies so widely, Daniel J. Drucker, MD, said in a keynote speech.
Drucker, one of the first researchers to discover the benefits of GLP-1s, made his remarks at the American Association of Clinical Endocrinology Annual Scientific and Clinical Conference, where he received the Kahn-Tan-Faiman Frontiers in Science and Distinction in Endocrinology Award and the first-ever honorary Master of American Association of Clinical Endocrinology designation.
Drucker, who is an endocrinologist, Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology and professor of medicine in the division of endocrinology at University of Toronto and has a laboratory based in the Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, said GLP-1s have gone from scientists questioning why anyone would want to use “an injectable sulfonylurea” to a class of drugs that have numerous benefits, including:
- reductions in albuminuria, atherosclerosis, body weight, blood pressure, cell death, fibrosis, glucose, gut motility, inflammation, oxidative stress, platelet aggregation, postprandial lipemia and thrombosis;
- increases in blood flow, cell survival, natriuresis and plaque stability; and
- positive results in patients with cardiovascular disease, diabetes, kidney disease, liver disease, obesity, osteoarthritis and sleep apnea.
“At the end of the day, we are not just trying to lower blood sugar, we’re trying to reduce the complications of these diseases,” he said.
Benefits independent of weight loss
Despite the extensive research that has gone into GLP-1s, “how does this work? The actual reality is, we don’t fully know,” Drucker said. “Long ago, we discovered that liraglutide (Victoza/Saxenda, Novo Nordisk) reduces heart attacks and strokes, and it doesn’t need to reduce blood sugar or body weight to do that in mice. We have learned that many of the GLP-1 benefits in humans are also weight-loss independent, which is fascinating.”
Even albiglutide (Tanzeum, GlaxoSmithKline), which was taken off the market because it wasn’t as good as other GLP-1s at reducing glucose and weight, reduced risk for major adverse cardiovascular events (MACE) by 22% compared with placebo despite no difference between the groups in weight loss, he said.
“Just 10 years ago, we didn’t have any drugs in diabetes that reduced MACE, and now, a 22% reduction, nah, we’re going to pull it from the market,” he said.
In addition, the 20% reduced risk for MACE seen in the SELECT trial of semaglutide (Wegovy, Novo Nordisk) was the same in patients in the lowest quartile of weight loss and the highest, he said.
A major focus of current research is how GLP-1s affect the brain, as they have been shown to reduce depression, anxiety and substance use disorders in real-world analyses, Drucker said.
Assumptions that GLP-1s work to produce weight loss because they cause nausea, vomiting and diarrhea in patients, which makes them want to eat less, have been proven untrue, he said.
“If you never felt sick whatsoever, you still got 90% of the weight-loss benefits from tirzepatide (Zepbound, Eli Lilly),” Drucker said. “The same data exists with semaglutide. Yes, we need to pay attention to the [gastrointestinal] adverse events, but that is not the whole story.”
‘A great opportunity for future research’
Other key questions about GLP-1s that need to be answered are when or if it is appropriate to stop them, and why there is such wide variation in how patients respond to them.
“The common dogma you hear is ‘everybody gains the weight back pretty quickly [after stopping a GLP-1], and most people gain back even more weight than when they started,’ and that can happen to some people,” he said. “But look at the data from SURMOUNT-4. One year after stopping tirzepatide, 46% of people still managed to keep off at least 10% of their weight, and almost 25% of people kept off at least 15%. Could we one day have a point-of-care test to be able to say ‘I know what’s going to happen to you, you’re going to be a superresponder or a poor responder, you’re going to be a person who gains back the weight quickly or you’re going to be able to maintain.’ This is a great opportunity for future research.”
Genetics-based research has been conducted, “but it could not find a genetic variation that explained these differences” in response to GLP-1s, Drucker said. “That doesn’t mean we’re never going to understand why, but it means today, so far, it’s very difficult, even with very high-powered omics science, to understand this interindividual variation in response.”
Sources/Disclosures
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Drucker DJ. Keynote: Endocrine innovation & obesity breakthroughs. Presented at: American Association of Clinical Endocrinology Annual Scientific and Clinical Conference; May 15-17, 2025; Orlando.
Disclosures:
Drucker reports consulting or speaking for Alnylam, Amgen, AstraZeneca, Crinetics, Kallyope, Merck Research Laboratories, Novo Nordisk and Pfizer and receiving research grants for preclinical studies from Amgen, Eli Lilly, Novo Nordisk, Pfizer and Zealand.
