Key takeaways:
- Scientists don’t absolutely perceive why response to GLP-1s varies so extensively amongst folks prescribed them.
- Some advantages of GLP-1s happen independently of weight reduction, so a number of elements are seemingly in play.
ORLANDO — A lot has been discovered about GLP-1s over a few years, however little is known about why the diploma of response to them varies so extensively, Daniel J. Drucker, MD, mentioned in a keynote speech.
Drucker, one of many first researchers to find the advantages of GLP-1s, made his remarks on the American Affiliation of Scientific Endocrinology Annual Scientific and Scientific Convention, the place he acquired the Kahn-Tan-Faiman Frontiers in Science and Distinction in Endocrinology Award and the first-ever honorary Grasp of American Affiliation of Scientific Endocrinology designation.
Drucker, who’s an endocrinologist, Banting and Finest Diabetes Centre-Novo Nordisk Chair in Incretin Biology and professor of medication within the division of endocrinology at College of Toronto and has a laboratory based mostly within the Lunenfeld Tanenbaum Analysis Institute at Mount Sinai Hospital in Toronto, mentioned GLP-1s have gone from scientists questioning why anybody would wish to use “an injectable sulfonylurea” to a category of medication which have quite a few advantages, together with:
- reductions in albuminuria, atherosclerosis, physique weight, blood stress, cell demise, fibrosis, glucose, intestine motility, irritation, oxidative stress, platelet aggregation, postprandial lipemia and thrombosis;
- will increase in blood movement, cell survival, natriuresis and plaque stability; and
- constructive ends in sufferers with heart problems, diabetes, kidney illness, liver illness, weight problems, osteoarthritis and sleep apnea.
“On the finish of the day, we’re not simply attempting to decrease blood sugar, we’re attempting to cut back the issues of those illnesses,” he mentioned.
Advantages impartial of weight reduction
Regardless of the intensive analysis that has gone into GLP-1s, “how does this work? The precise actuality is, we don’t absolutely know,” Drucker mentioned. “Way back, we found that liraglutide (Victoza/Saxenda, Novo Nordisk) reduces coronary heart assaults and strokes, and it doesn’t want to cut back blood sugar or physique weight to try this in mice. We now have discovered that lots of the GLP-1 advantages in people are additionally weight-loss impartial, which is fascinating.”
Even albiglutide (Tanzeum, GlaxoSmithKline), which was taken off the market as a result of it wasn’t pretty much as good as different GLP-1s at decreasing glucose and weight, lowered danger for main adversarial cardiovascular occasions (MACE) by 22% in contrast with placebo regardless of no distinction between the teams in weight reduction, he mentioned.
“Simply 10 years in the past, we didn’t have any medication in diabetes that lowered MACE, and now, a 22% discount, nah, we’re going to tug it from the market,” he mentioned.
As well as, the 20% lowered danger for MACE seen within the SELECT trial of semaglutide (Wegovy, Novo Nordisk) was the identical in sufferers within the lowest quartile of weight reduction and the very best, he mentioned.
A serious focus of present analysis is how GLP-1s have an effect on the mind, as they’ve been proven to cut back despair, nervousness and substance use problems in real-world analyses, Drucker mentioned.
Assumptions that GLP-1s work to provide weight reduction as a result of they trigger nausea, vomiting and diarrhea in sufferers, which makes them wish to eat much less, have been confirmed unfaithful, he mentioned.
“In case you by no means felt sick in anyway, you continue to bought 90% of the weight-loss advantages from tirzepatide (Zepbound, Eli Lilly),” Drucker mentioned. “The identical knowledge exists with semaglutide. Sure, we have to take note of the [gastrointestinal] adversarial occasions, however that isn’t the entire story.”
‘An important alternative for future analysis’
Different key questions on GLP-1s that should be answered are when or whether it is acceptable to cease them, and why there’s such vast variation in how sufferers reply to them.
“The frequent dogma you hear is ‘all people positive factors the load again fairly shortly [after stopping a GLP-1], and most of the people achieve again much more weight than after they began,’ and that may occur to some folks,” he mentioned. “However take a look at the info from SURMOUNT-4. One yr after stopping tirzepatide, 46% of individuals nonetheless managed to maintain off at the least 10% of their weight, and nearly 25% of individuals saved off at the least 15%. Might we in the future have a point-of-care check to have the ability to say ‘I do know what’s going to occur to you, you’re going to be a superresponder or a poor responder, you’re going to be an individual who positive factors again the load shortly otherwise you’re going to have the ability to keep.’ It is a nice alternative for future analysis.”
Genetics-based analysis has been performed, “but it surely couldn’t discover a genetic variation that defined these variations” in response to GLP-1s, Drucker mentioned. “That doesn’t imply we’re by no means going to grasp why, but it surely means right now, thus far, it’s very troublesome, even with very high-powered omics science, to grasp this interindividual variation in response.”
Sources/Disclosures
Collapse
Drucker DJ. Keynote: Endocrine innovation & weight problems breakthroughs. Offered at: American Affiliation of Scientific Endocrinology Annual Scientific and Scientific Convention; Could 15-17, 2025; Orlando.
Disclosures:
Drucker reviews consulting or talking for Alnylam, Amgen, AstraZeneca, Crinetics, Kallyope, Merck Analysis Laboratories, Novo Nordisk and Pfizer and receiving analysis grants for preclinical research from Amgen, Eli Lilly, Novo Nordisk, Pfizer and Zealand.
