People accept new popular drugs for weight loss such as Wegovy and Zepbound often report the number of pounds lost and associated health benefitsbut many doctors at weight loss clinics notice mysterious reactions in some people. Andres J. Acosta, a gastroenterologist at the Mayo Clinic, says some of his patients have expressed frustration and frustration at watching friends or coworkers lose significant weight while taking medications but lose little or no weight themselves—even if they stick to the diet. instructions for medications Great.
“They see themselves as failures,” Acosta says. But the drugs' effectiveness is likely beyond their direct control—scientists believe the lack of response may have something to do with what drives them. overweight first of all.
About 12 percent of Americans reported the use of one of the new drugs known as glucagon-like peptide 1 (GLP-1) receptor agonists for weight loss. Real data shows that as much as every fourth person these drugs include “nonresponders,” which many experts define as those who lose less than 5 percent of their body weight after three months of taking a GLP-1 drug. (Five percent is the threshold above which people begin to notice improvements in their health.) Novo Nordisk-funded clinical trials of semaglutide, the active ingredient in Wegovy's weight-loss drug and Ozempic diabetes drug, showed that up to 23 percent of people fell into the non-response category. IN Novo Nordisk's final testGiving people a higher dose of semaglutide did not reduce the proportion of non-responders. To better understand why people show such large differences in response to these drugs, scientists have begun to examine their underlying biology.
About supporting science journalism
If you enjoyed this article, please consider supporting our award-winning journalism. subscription. By purchasing a subscription, you help ensure a future of influential stories about the discoveries and ideas shaping our world today.
No two people answer exactly the same to any weight loss approach, be it medications, surgery or lifestyle changes such as diet and exercise, because obesity is a complex phenomenon. GLP-1 drugs cause weight loss primarily by make people feel full. Variations in biological pathways that influence this mechanism and lead to overweight or obesity may cause some people to benefit more from medications than others.
Researchers already know some factors that can influence how well a person responds to medications. In general, people with type 2 diabetes who take this medication tend to lose less weight than those who take it for weight loss, and men, on average, lose less weight than women. But researchers suspect genetics may also play a role.
A small proportion of obese people carry rare mutations in a single gene that cause what is called “monogenic obesity,” which leads to health problems early in life. But for most people, obesity is considered polygenic, meaning it can arise from thousands of genetic variants. Environmental, biological and behavioral factors also play a role, says Ruth Loos, a geneticist specializing in obesity and metabolism at the University of Copenhagen.
Acosta and his colleagues worked to identify four different biological phenotypes, or traits, of overweight people that may influence how they respond to new weight-loss drugs. For example, some people have a “hungry brain” phenotype and require an abnormally large number of calories to feel full compared to others. On the other hand, people with the hungry gut phenotype may become full quickly but soon experience hunger again. The team's latest research, published in Augustfound that some people feel full after eating 140 calories in one sitting, while others need more than 2,000 calories. While factors such as gender, body composition and hormone levels helped explain the difference, genetics also appeared to play an important role.
Acosta and his team developed a scoring system that combined genetic and physiological data to predict differences in the number of calories needed to feel full. Using this measure, the researchers found that people with the “hungry brain” phenotype tended to respond poorly to liraglutide, an early-generation GLP-1 drug, but they did better to phentermine-topiramate, a non-GLP-1 drug that acts as an appetite suppressant in the brain but is controversial because of its cardiovascular risks. On the other hand, people with a hungry gut phenotype responded better to liraglutide. Acosta, also the founder and shareholder of a precision obesity treatment company involved in the study, says this may be because GLP-1 drugs prolong feelings of fullness after eating. The team saw similar results with semaglutide in unpublished results presented at the American Gastroenterological Association conference last year.
Other research groups are studying specific genes that may influence GLP-1 drug response. Scientists at the Cleveland Clinic are studying neurobeachin, a gene that appears to influence how people lose weight when taking GLP-1 drugs. The number of variations—and specific types of variations—in the neurobiahin gene can be used to create a genetic score that predicts a person's response to a drug, says Daniel Rotroff, a precision medicine researcher at the Cleveland Clinic. In the analysis of Rotroff and colleaguespeople who had higher scores on these options were at least 50 percent more likely to not lose weight on liraglutide than people with lower scores. (The assessment did not predict how a person would respond to semaglutide.)
Some clues may explain why this gene may influence a person's response to GLP-1 drugs. Variations in neurobiachin may affect how effectively an enzyme called protein kinase A (PKA) helps the hypothalamus, the area of the brain that regulates appetite suppression. Because GLP-1 is known to activate PKA in other cells, genetic variations in neurobeahin could “ultimately influence how well the drug works for weight loss,” Rotroff explains.
In a previous study by other researchers, deactivation of one copy of neurobeachin forced mice to eat More foods rich in glucose and fructose, but not foods with artificial sweeteners, suggest that removing neurobeachin caused the mice to consume more calories, Rotroff says. Some preliminary studies suggested that genetic differences in the GLP-1 receptors themselves—the sites where the drug actively binds—may be associated with drug sensitivity.
Researchers also examined how eating patterns, especially those associated with sensory or psychological triggers, may shape people's responses to these new weight-loss drugs. A study published last month involving 92 people In Japan, people with type 2 diabetes who were prescribed GLP-1 drugs found that those who tended to overeat in response to external cues, such as the sight or smell of food, experienced the most weight loss over the course of a year. Those who ate in response to negative emotions experienced only a short-term decrease in appetite after taking the drugs.
Some research on genetic explanations for individual response to weight loss drugs has been conflicting. A great study published by Loos and her colleagues in Natural medicine in April, which used data from more than 10,000 people about discovered GLP-1 drugs. no significant association between genetic variants and weight loss outcomes. This discrepancy may reflect the need for larger data sets, says Andrea Ganna, a geneticist at Harvard Medical School and co-author of the study. Natural medicine paper. “Or, more likely, there are many other factors besides genetics that may explain response to treatment,” he says. Loos says research into patients who don't respond to treatment is still ongoing, but solving this mystery will help doctors and their patients choose treatment. “If we can determine in advance whether someone will respond or not, it can save people a lot of money,” Loos says. “But we can't do that yet. We need better science.”
Even if researchers someday create clinically useful genetic measures that help predict who responds best to weight-loss methods, Loos cautions that these tools should still not be viewed as accurate, but rather as possible indicators that someone might respond differently. Environment and lifestyle That will always be an important factor, she said. “People think your genetics are your destiny,” she says, “but they really aren’t.”
