When Mercedes, a recently retired teacher in her 50s, was informed by her doctor in early 2024 that she could begin treatment with GLP-1 weight loss injections, she initially responded with overwhelming relief. After years of struggling with obesity, the prospect of these new medications heralded a potential end to her longtime challenges with weight. Yet, after nearly two years and multiple drugs, including Ozempic, Wegovy, Contrave, Mounjaro, and Zepbound, she has seen little to no sustained weight loss.
GLP-1 medications, which include semaglutide-based drugs such as Ozempic and Wegovy, work by mimicking a naturally occurring hormone that slows gastric emptying, suppresses appetite, and increases insulin production. Newer drugs like Mounjaro and Zepbound combine this mechanism with an additional hormone effect, reportedly offering enhanced weight loss results. Clinical trials have shown that many patients can lose between 15% and 20% of their body weight with these therapies, and some research suggests these drugs could also benefit heart conditions, addiction, and fatty liver disease.
However, a notable minority of users experience little to no weight loss. Estimates from clinical trials suggest that between 9% and one-third of patients may lose less than 5% of their body weight, depending on the medication and dosage. For individuals like Mercedes, the psychological and financial toll has been significant. She describes persistent cravings akin to “heroin withdrawal” and notes that the medications failed to quell constant food-related thoughts, despite strict lifestyle changes. She acknowledges that part of her limited weight loss was due to intense self-discipline rather than the drugs themselves.
Mercedes’ experience is echoed by others. Yury K, 57, also from Canada, said he experienced improved blood sugar and decreased appetite on Wegovy but saw no meaningful weight change after six months. He also suffered side effects such as constipation and skin sensitivity. Meanwhile, Lucille, 53, from Luxembourg, reported that after initial success on GLP-1 medications, the drugs lost effectiveness even at higher doses, incurring high personal costs unmitigated by insurance coverage.
Experts remain uncertain about why some individuals do not respond adequately to these treatments. Prof Alexander Miras of Ulster University emphasized that if a medication does not reduce hunger and food intake, it will not produce weight loss. Research has not found clear correlations with motivation, intelligence, education, or socioeconomic status as predictors of response. However, factors such as age, sex, presence of type 2 diabetes, and ancestral background appear to play roles. For instance, people of European ancestry tend to respond better than those of African American descent.
Additional investigations have highlighted potential hormonal and genetic influences. Variations in estrogen levels, tied to sex, menstrual cycle timing, and menopausal hormone therapy, may alter how patients respond to GLP-1 drugs. Genetic studies have identified variants that affect receptors in the brain or enzymes that modify hormones involved in appetite regulation, which might contribute to drug resistance.
Despite these insights, accurately predicting who will benefit remains elusive. Researchers and clinicians are exploring alternative treatments, including non-GLP-1 drugs like Mysimba (Contrave), which acts on similar brain pathways but differently, and bariatric surgery, which remains an option for some patients unresponsive to medication.
Prof Miras stressed that lack of weight loss with GLP-1 therapies is not a matter of patient fault or drug failure but rather variability in individual physiology. For patients like Mercedes, such clarity may offer some consolation amid ongoing frustration. The emergence of new drugs and personalized approaches could provide hope for those who have yet to find effective solutions through current GLP-1 medications.