Mercedes, a 50-something retired teacher from Canada, said she felt an overwhelming sense of hope when her doctor told her in 2024 that she could be prescribed GLP-1 weight loss injections. “I cried in her office. And I didn’t really stop crying for a week,” she said. “Finally, after being overweight my entire life, this was going to save me.” However, after trying several medications, including Ozempic, Wegovy, Contrave, Mounjaro, and Zepbound, she said, “Nothing has worked.” GLP-1 medications like Ozempic and Wegovy contain a drug called semaglutide, which mimics a naturally occurring hormone in the body. Clinical trials have shown these drugs can help people lose an average of 15% to 20% of their body weight. Other drugs like Mounjaro and Zepbound contain tirzepatide, which mimics both GLP-1 and another hormone. However, between 9% and a third of participants in these trials lose less than 5% of their body weight, depending on the drug and dosage used. For Mercedes, the lack of response has been deeply distressing. “It’s been a real struggle, with shame and regret and big bills and disappointment that my own body is not working the way it should,” she said. She tried to make lifestyle changes alongside the medications but found that the injections did not help suppress her constant thoughts about food. “The cravings, which I can only call like heroin withdrawal … it’s just overwhelming. And the food talk never ended.” Mercedes is not alone in her experience. Yury K, a 57-year-old from Canada, said he tried Wegovy for obesity but saw little change in his weight. He said he exercised regularly and avoided junk food, but after six months, he remained around the same weight. Similarly, Lucille*, 53, from Luxembourg, said she has been taking GLP-1 medications for four years but found they no longer helped her lose weight, even after switching to Mounjaro and taking the highest dose. “It’s as if nothing is having an effect any more,” she said. Research suggests that the effectiveness of these drugs varies among individuals. Prof Alexander Miras, an obesity expert at Ulster University, said the lack of response cannot be blamed on patients. “If the drug does not reduce hunger and food intake for someone, it is just not going to work,” he said. He noted that factors like motivation or socioeconomic status do not predict how patients respond to GLP-1 medications, but age, sex, and type 2 diabetes status might influence effectiveness. Studies have found that GLP-1 medications may be most effective in people of European ancestry and less so in people of African American ancestry. Dr Mahesh Umapathysivam, an endocrinologist and researcher in Australia, said there is growing evidence that estrogen, a hormone involved in menopause, can affect how these drugs work. He noted that women using menopausal hormone replacement therapy, which contains estrogen, tend to lose more weight on semaglutide. Recent research has also identified genetic factors that may influence how well GLP-1 drugs work. Some people have a genetic variant that makes them lose more weight, while others may have genetic variants that make them resistant to the drugs. However, it is still unclear how to accurately predict who will benefit from these medications. Despite these challenges, Miras said there are reasons for people like Mercedes to remain hopeful. New drugs are in development, and switching to a non-GLP-1 based drug called Mysimba could be an option. For some, weight-loss surgery may be the only remaining solution. “A lack of response to GLP-1 based drugs does not predict lack of response to [bariatric] surgery,” he said. “It’s not your fault and it’s not the drug’s fault either, this is purely luck.”