DPP-4

iStock, hapabapa A retrospective cohort study of more than 33,000 patients with type 2 diabetes showed that Novo Nordisk’s GLP-1 may lower the risk of opioid overdose by 42% to up to 68%. Novo Nordisk ’s blockbuster diabetes drug Ozempic (semaglutide) appears to lower the risk of opioid overdose in patients with type 2 diabetes, according to a study published Wednesday in JAMA Network Open . Leveraging the federated health research network TriNetX Analytics Platform, the cohort study looked at the electronic health records of more than 33,000 patients with comorbid type 2 diabetes and opioid use disorder. Just over 3,000 patients were given semaglutide, while the remaining 30,000 were taking other anti-diabetic agents such as insulin, metformin and liraglutide. After propensity-score matching—in which study participants were balanced according to age, sex, ethnicity and comorbidities—patients on semaglutide demonstrated a significantly lower risk of opioid overdose versus other treatment groups. Compared with insulin, semaglutide suppressed the risk of overdoses by 58% while the GLP-1 receptor agonist held a 54% advantage over metformin. Semaglutide’s benefits were strongest against thiazolidinediones and dipeptidyl peptidase-4 inhibitors, resulting in a 68% and 63% reduction in the risk of overdoses, respectively. Semaglutide also performed significantly better when compared against other GLP-1 therapies. Relative to liraglutide, semaglutide resulted in a statistically significant 55% reduction in overdoses. The only other anti-diabetic medication that semaglutide was not significantly better against was Eli Lilly’s Trulicity (dulaglutide). Despite these promising data, however, the study’s authors acknowledged that their findings have several methodological limitations, such as potentially unmeasured and uncontrolled confounders and other biases inherent in observational studies. “Results need validation from other data resources and study populations,” the researchers said, noting that further studies are needed to “investigate the underlying mechanisms” of semaglutide’s effects on opioid use. Clinical trials are also necessary to better confirm the clinical benefits of semaglutide in this patient population. Despite these uncertainties, Wednesday’s study adds to the growing list of potential therapeutic benefits of semaglutide and GLP-1 treatments. Last week, a paper published in JAMA Internal Medicine showed that these incretin therapies could potentially help patients with metabolic dysfunction-associated steatotic liver disease reduce their risk of progressing to cirrhosis and its related complications. In July 2024, a separate study in the Annals of Internal Medicine showed that semaglutide may lower tobacco use disorder in diabetes patients . Meanwhile, a Phase II study suggested that GLP-1 therapies could also have cognitive benefits in neurodegenerative disorders, with Alzheimer’s disease patients on liraglutide showing slower cognitive decline versus placebo.

Three scientists whose work paved the way to the multibillion-dollar obesity drug boom have won the Lasker Award for “the discovery and development of GLP-1-based drugs that have revolutionized the treatment of obesity,” the Lasker Foundation announced Thursday. Joel Habener from Massachusetts General Hospital and Svetlana Mojsov from The Rockefeller University were honored for unraveling the molecular mysteries of the natural version of GLP-1 made by the body. And Lotte Bjerre Knudsen from Novo Nordisk was honored for figuring out how to turn the short-lived natural molecule into a longer-lasting drug. The trio will split the $250,000 that comes with the 2024 Lasker-DeBakey Clinical Medical Research Award, which is sometimes viewed as a stepping stone to a Nobel Prize. But while the Nobel committee at times seems to pride itself on honoring esoteric discoveries that, while foundational to science, are rarely known to the general public, several recent Lasker Awards have gone to researchers whose fields of work are currently in the limelight. For example, in 2021, the Lasker Foundation honored Katalin Karikó and Drew Weissman for their foundational work on mRNA vaccines that paved the way to Covid-19 shots. And last year the Foundation awarded Google scientists Demis Hassabis and John Jumper for their creation of AlphaFold, the AI-based software for predicting protein structures that quickly swept through biotech labs. Although 2024 might be remembered as the year GLP-1 drugs exploded on the market, the science behind them dates back more than four decades to the early days of genetic engineering, when scientists were just learning how to clone and manipulate genes for the first time. Habener, while studying the biology of diabetes, discovered what would later be called GLP-1 by looking at glucagon genes from anglerfish. The animal was chosen for its unusual organ that makes copious quantities of the blood sugar-stimulating hormone, and because it skirted early rules restricting work on human genes. In 1982, Habener found that the fish genes contained code not only for glucagon, but a similar gene that looked like glucagon but with six extra amino acids on one end. A year later, glucagon biochemist Mojsov moved from New York to Boston and helped disentangle how that molecular endcap on GLP-1 gets cleaved to release an active molecule. Habener, Mojsov, and other collaborators in Boston soon went on to show that the cleaved hormone potently stimulates insulin secretion and lowers blood glucose levels. By the early 90s, it was clear that an artificial version of GLP-1 could become the basis of a powerful diabetes drug, and companies including Eli Lilly and Novo Nordisk soon began working on the idea. Of course, making a good drug often turns out to be a lot harder than expected. Simply injecting synthetic versions of GLP-1 into the blood didn’t work well because much of the molecule got chewed up by an enzyme called DPP-4, and the rest got sucked out of circulation by the kidneys. But Knudsen, a Danish scientist in charge of GLP-1 work at Novo Nordisk, figured out a way around that problem. By attaching fatty acids to the drug, she helped it hitch a ride on a common blood protein called albumin, keeping it moving throughout the body longer. The work led to Novo’s drug liraglutide, and subsequent chemical modifications helmed by other scientists at the company led to the successor semaglutide, now sold as Ozempic for diabetes and Wegovy for weight loss. The franchise is now a blockbuster, and Wall Street analysts have projected that the category could be one of the biggest in industry history.

TUESDAY, Sept. 17, 2024 -- For patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes , glucagon-like peptide 1 receptor agonist (GLP-1 RA) use is associated with a reduced risk for cirrhosis and for cirrhosis complications and mortality, according to a study published online Sept. 16 in JAMA Internal Medicine . Fasiha Kanwal, M.D., from the Baylor College of Medicine in Houston, and colleagues examined whether GLP-1 RA use is associated with a reduced risk for cirrhosis and its complications among patients with MASLD in a retrospective cohort study with an active comparator. Patients with MASLD and diabetes from 130 Veterans Health Administration hospitals and associated ambulatory clinics who initiated a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) were included; patients were propensity score-matched in a 1:1 ratio. Of the 16,058 patients who initiated GLP-1 RAs, 14,606 and 1,452 did not have and did have cirrhosis, respectively. These patients were matched to an equal number of DPP-4i initiators. The researchers found that GLP-1 RA use was associated with a lower risk for cirrhosis compared with DPP-4i use (9.98 versus 11.10 events per 1,000 person-years; hazard ratio, 0.86; 95 percent confidence interval, 0.75 to 0.98) among patients without cirrhosis. Compared with DPP-4i use, GLP-1 RA use was associated with a lower risk for the composite outcome of cirrhosis complications and mortality (hazard ratios [95 percent confidence intervals], 0.78 [0.59 to 1.04] and 0.89 [0.81 to 0.98], respectively). In patients with cirrhosis, there were no associations between GLP-1 RA use and outcomes. "These results support the need for long-term randomized clinical trials to test the benefits of GLP-1 RA use for primary prevention of cirrhosis in patients with MASLD," the authors write. Two authors disclosed ties to the biopharmaceutical industry.