In recent years, weight-loss drugs such as Wegovy and Zepbound, which belong to a class called glucagon-like peptide 1 (GLP-1) receptor agonists, have garnered significant attention for their effectiveness in helping many individuals shed excess pounds and improve related health conditions. However, despite the enthusiasm surrounding these medications, healthcare professionals have observed a perplexing pattern: while some patients experience substantial weight loss, others see little to no benefit, even when they follow the prescribed regimen meticulously. This disparity has led scientists to explore the possible genetic and biological underpinnings that might explain why GLP-1 drugs work well for some people but not for others.
### The Puzzle of Nonresponse to GLP-1 Drugs
According to gastroenterologist Andres J. Acosta of the Mayo Clinic, some patients who take these medications feel frustrated and disappointed when they fail to lose weight, especially after witnessing friends or colleagues achieve significant results. This sense of personal failure, Acosta notes, is often misplaced because the effectiveness of these drugs is influenced by factors beyond an individual’s control. Emerging research suggests that the biological causes of a person’s excess weight may determine their responsiveness to GLP-1 drugs.
About 12 percent of Americans have reported using GLP-1 receptor agonists for weight loss, and real-world data indicate that up to 25 percent of these users are “nonresponders.” Experts typically define nonresponse as losing less than 5 percent of body weight after three months of treatment—a threshold below which health benefits are usually minimal. Clinical trials, including those funded by Novo Nordisk—the maker of semaglutide, the active ingredient in Wegovy and Ozempic—have also found that roughly one in four participants fall into this nonresponder category. Increasing the semaglutide dose has not significantly reduced the proportion of nonresponders, prompting researchers to look more deeply into the biological reasons behind these varied outcomes.
### Understanding Obesity’s Complexity
Obesity is a multifaceted condition influenced by a combination of genetic, environmental, biological, and behavioral factors. No single approach to weight loss—whether medication, surgery, or lifestyle changes—works identically for everyone. GLP-1 drugs primarily induce weight loss by promoting feelings of fullness or satiety, reducing appetite and food intake. However, variations in the biological pathways that regulate these sensations might affect how well an individual responds to the medication.
Research has identified some demographic and medical factors that influence drug response. For example, people with type 2 diabetes generally lose less weight on GLP-1 drugs compared to those using them solely for weight loss. Additionally, men tend to lose less weight than women on these medications. Beyond these factors, genetics is increasingly recognized as a potential key player in determining drug effectiveness.
### Genetic Factors and Biological Phenotypes
While a small number of people with obesity have rare, single-gene mutations causing “monogenic obesity,” most cases are polygenic, meaning they result from the combined effects of thousands of genetic variants. Ruth Loos, a geneticist at the University of Copenhagen specializing in obesity and metabolism, emphasizes that genetic factors interact with environmental and behavioral influences to shape obesity risk.
Acosta and his colleagues have contributed to this understanding by identifying four distinct biological phenotypes linked to excess weight, which may influence drug response. One such phenotype is the “hungry brain,” where individuals require an unusually high number of calories to feel full. Conversely, the “hungry gut” phenotype describes people who become satiated quickly but soon feel hungry again. Their recent study revealed dramatic differences: some participants felt full after consuming as little as 140 calories in one sitting, while others needed more than 2,000 calories to reach satiety. Although sex, body composition, and hormone levels explained part of this variation, genetics appeared to play a significant role.
To quantify these differences, Acosta’s team developed a composite score combining genetic and physiological data. They found that individuals with the “hungry brain” phenotype responded poorly to liraglutide, an earlier GLP-1 drug, but fared better on phentermine-topiramate, a non-GLP-1 medication that suppresses appetite via the brain—though it carries some cardiovascular risk concerns. In contrast, people with the “hungry gut” phenotype showed better results with liraglutide. Acosta hypothesizes that because GLP-1 drugs prolong feelings of fullness after meals, they