When Mercedes was told by her doctor that she could be prescribed GLP-1 weight loss jabs in 2024, she broke down. \u201c[When] she said yes, I cried in her office. And I didn\u2019t really stop crying for a week,\u201d she said.<\/p>\n
\u201cFinally, after being overweight my entire life, this was going to save me. My struggle, my burden, my shame was finally going to come to an end.\u201d<\/p>\n
But as time went on it was hope, not weight, that fell away.<\/p>\n
\u201cI was on [Ozempic] for nine months. And then I went on Wegovy for four months, then Contrave [an oral, non-GLP-1 medication], and then Mounjaro, and that was for a few months, and then nine months ago I started on Zepbound,\u201d said Mercedes. \u201cNothing has worked.\u201d<\/p>\n
A recently retired teacher in her 50s, Mercedes is among a small proportion of people for whom the powerful new weight-loss drugs, championed by celebrities for their transformative effects, do not work.<\/p>\n
Ozempic, a type 2 diabetes medication, and Wegovy, which is licensed for weight loss, both contain a drug called semaglutide that mimics a hormone that occurs naturally in our bodies: GLP-1. These medications reduce the rate at which food is emptied from the stomach, suppresses appetite and increase the production of insulin \u2013 meaning many people lose weight.<\/p>\n
Mounjaro and Zepbound, also now household names, have an even greater weight-loss effect. They both contain the drug tirzepatide which mimics both GLP-1 and another hormone.<\/p>\n
The excitement around such \u201cGLP-1s\u201d has been hard to miss: the medications have grabbed headlines, with clinical trials suggesting they can help participants lose an average of 15% to 20% of their body weight. Studies suggest they could help<\/a> with conditions ranging from <\/a>heart problems<\/a> and addictions<\/a> to fatty liver disease<\/a>. In some cases experts say the effects may not be entirely related to weight loss<\/a>.<\/p>\n But not everyone experiences the benefits. Between 9% and a third of participants in clinical trials lose less than 5% of their body weight \u2013 depending on the type of drug and dose used.<\/p>\n Now researchers are trying to work out why \u2013 something they say could help doctors tailor the use of the drugs, maximise cost-effectiveness and reduce side-effects.<\/p>\n For Mercedes, the impact of non-response has been profound.<\/p>\n \u201cAside from the fact that it\u2019s not working and that it\u2019s so expensive, to say it\u2019s hard on the self-esteem is a humongous understatement,\u201d said Mercedes, who lives in Canada. \u201cIt\u2019s been a real struggle, with shame and regret and big bills and disappointment that my own body is not working the way it should.\u201d<\/p>\n Prof Alexander Miras, an obesity expert at Ulster University, said the efficacy of the drugs could not be blamed on patients. \u201cIf the drug does not reduce hunger and food intake for someone, it is just not going to work,\u201d he said.<\/p>\n Mercedes said she has tried hard to stick to lifestyle changes alongside the medications but, for her, the jabs did not suppress constant, intrusive thoughts about food.<\/p>\n \u201cI just thought: \u2018No, I\u2019ve got to get somewhere \u2026 I\u2019m going to die of obesity\u2019,\u201d she said. \u201cI was really strict with myself for a month \u2013 but the cravings, which I can only call like heroin withdrawal \u2026 it\u2019s just overwhelming. And the food talk never ended.\u201d<\/p>\n The extreme effort paid off, to an extent. \u201cI can honestly say I lost 20 pounds in that month, but not because of the medication,\u201d she said.<\/p>\n Mercedes is certainly not alone: the Guardian has heard from dozens of people for whom GLP-1 medications have had little effect.<\/p>\n Yury K, 57, also from Canada, said he tried a number of weight loss programmes before starting Wegovy for obesity. He exercises about five days a week, mainly with kettlebells, and does not eat junk food or fast food.<\/p>\n While Yury said he saw some improvements in his blood sugar levels and cholesterol while using the medication, as well as a reduction in food noise and appetite, he found his weight barely changed.<\/p>\n \u201cI started Wegovy at about 242lb and, after six months, I was still about 242lb. My weight can fluctuate a little because of water, but essentially there was no meaningful weight loss,\u201d he said. He also experienced unpleasant side effects, including constipation and sensitive skin.<\/p>\n \u201cThere is so much discussion about GLP-1 medications as if they work for everyone, and that was not my experience. When you put in the effort with diet and exercise, take the medication exactly as prescribed, and still see little benefit, it is difficult not to feel disappointed,\u201d he said.<\/p>\n Lucille*, 53, who is based in Luxembourg, told the Guardian she has been taking GLP-1 medications for four years \u2013 initially to help with insulin resistance \u2013 starting on a daily injection of a GLP-1 medication called Saxenda, before switching to Ozempic.<\/p>\n Yet despite being effective at first, Lucille says the medications no longer help her lose weight \u2013 even after switching to Mounjaro and taking the highest dose. \u201cIt\u2019s as if nothing is having an effect any more,\u201d she says. \u201cThe Mounjaro 5mg [dose] is outrageously expensive and so far none of these medications have been approved by my health insurance,\u201d she adds.<\/p>\n At present, the reason for such variations in response remains unclear. \u201cThe short answer to why some people don\u2019t respond is we don\u2019t really know,\u201d said Miras.<\/p>\n He said research had suggested factors such as motivation, intelligence, education and socioeconomics did not predict how patients would respond to GLP-1 medications.<\/p>\n But other characteristics might do. \u201cWe know, for example, that age plays a role \u2013 so older people lose less weight. Sex plays a role \u2013 men lose less than women,\u201d said Miras. \u201c[And] people with type 2 diabetes lose less weight compared to people without.\u201d<\/p>\n Studies have also suggested ancestry might have an impact, with the medications most effective in people of European ancestry, and least effective in people of African American ancestry.<\/p>\n Dr Mahesh Umapathysivam, an endocrinologist and clinical researcher at Adelaide University in Australia, said it was plausible that hormones could have an effect too.<\/p>\n \u201cThere is growing evidence that oestrogen alters GLP-1 response. We see that with the difference between male response and female response. Also, we know from some of the physiological studies that time of menstrual cycle also alters GLP-1 response,\u201d he said.<\/p>\n \u201cFinally, the use of menopausal hormone replacement therapy \u2013 which contains oestrogen \u2013 is associated with greater weight loss in semaglutide users.\u201d<\/p>\n