GLP-1 weight-loss medications do not produce meaningful weight loss for everyone. Between 9% and one-third of participants in clinical trials lost less than 5% of their body weight, depending on the drug and dose.
Researchers have not identified a reliable way to predict who will respond poorly. Possible influences include age, sex, type 2 diabetes, ancestry, hormones and genetics, but the evidence is still developing.
How the medicines are supposed to work
Ozempic and Wegovy contain semaglutide, which mimics the naturally occurring hormone GLP-1. The medicines slow the rate at which food leaves the stomach, suppress appetite and increase insulin production. Mounjaro and Zepbound contain tirzepatide, which mimics GLP-1 and another hormone and has a greater weight-loss effect in clinical studies.
Why some people may respond less
The reason for poor response remains unclear. Prof Alexander Miras of Ulster University said motivation, intelligence, education and socioeconomic circumstances did not appear to predict response. Research has instead pointed to characteristics including age, sex and diabetes: older people and men tend to lose less weight, as do people with type 2 diabetes compared with those without it.
Studies have also suggested that ancestry may influence response. Dr Mahesh Umapathysivam of Adelaide University said hormones could matter, including oestrogen, the menstrual cycle and menopausal hormone replacement therapy. Other research has identified genetic variants affecting drug receptors or the production of PAM, an enzyme involved in modifying hormones including GLP-1. These findings do not yet allow doctors to predict an individual’s result accurately.
What poor response can feel like
Mercedes, a recently retired teacher in her 50s who lives in Canada, said she used Ozempic for nine months, Wegovy for four months, Contrave, Mounjaro and then Zepbound. She said the medicines did not stop intrusive thoughts about food and that the financial cost, disappointment and effect on her self-esteem had been substantial.
Yury K, 57, said his weight remained about 242lb after six months on Wegovy, although he noticed improvements in blood sugar and cholesterol and less food noise and appetite. He also reported constipation and sensitive skin. Lucille, 53, said GLP-1 medicines initially helped with insulin resistance but later stopped producing weight loss, including after switching to Mounjaro.
What may happen next
Researchers say understanding different responses could help doctors tailor treatment, improve cost-effectiveness and reduce side-effects. Miras said a non-GLP-1 medicine called Mysimba, known as Contrave in the US, may be an option for some people, although he said it is not available through the NHS and is offered privately.
Weight-loss surgery may also be considered for some people who lose little or no weight on GLP-1 medicines. Miras said a lack of response to GLP-1-based drugs does not predict a lack of response to bariatric surgery.
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