Cravings ‘like heroin withdrawal’: what happens when weight-loss drugs don’t work?

When Mercedes was told by her doctor that she could be prescribed GLP-1 weight loss jabs in 2024, she broke down. “[When] she said yes, 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. My struggle, my burden, my shame was finally going to come to an end.”

But as time went on it was hope, not weight, that fell away.

“I 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,” said Mercedes. “Nothing has worked.”

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.

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, suppress appetite and increase the production of insulin – meaning many people lose weight.

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.

The excitement around such “GLP-1s” 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 with conditions ranging from heart problems and addictions to fatty liver disease. In some cases experts say the effects may not be entirely related to weight loss.

But not everyone experiences the benefits. Between 9% and a third of participants in clinical trials lose less than 5% of their body weight – depending on the type of drug and dose used.

Now researchers are trying to work out why – something they say could help doctors tailor the use of the drugs, maximise cost-effectiveness and reduce side-effects.

For Mercedes, the impact of non-response has been profound.

“Aside from the fact that it’s not working and that it’s so expensive, to say it’s hard on the self-esteem is a humongous understatement,” said Mercedes, who lives in Canada. “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.”

Prof Alexander Miras, an obesity expert at Ulster University, said the efficacy of the drugs could not 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.

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.

“I just thought: ‘No, I’ve got to get somewhere … I’m going to die of obesity’,” she said. “I was really strict with myself for a month – but the cravings, which I can only call like heroin withdrawal … it’s just overwhelming. And the food talk never ended.”

The extreme effort paid off, to an extent. “I can honestly say I lost 20 pounds in that month, but not because of the medication,” she said.

Mercedes is certainly not alone: the Guardian has heard from dozens of people for whom GLP-1 medications have had little effect.

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.

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.

“I 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,” he said. He also experienced unpleasant side effects, including constipation and sensitive skin.

“There 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,” he said.

Lucille*, 53, who is based in Luxembourg, told the Guardian she has been taking GLP-1 medications for four years – initially to help with insulin resistance – starting on a daily injection of a GLP-1 medication called Saxenda, before switching to Ozempic.

Yet despite being effective at first, Lucille says the medications no longer help 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 says. “The Mounjaro 5mg [dose] is outrageously expensive and so far none of these medications have been approved by my health insurance,” she adds.

At present, the reason for such variations in response remains unclear. “The short answer to why some people don’t respond is we don’t really know,” said Miras.

He said research had suggested factors such as motivation, intelligence, education and socioeconomics did not predict how patients would respond to GLP-1 medications.

But other characteristics might do. “We know, for example, that age plays a role – so older people lose less weight. Sex plays a role – men lose less than women,” said Miras. “[And] people with type 2 diabetes lose less weight compared to people without.”

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.

Dr Mahesh Umapathysivam, an endocrinologist and clinical researcher at Adelaide University in Australia, said it was plausible that hormones could have an effect too.

“There 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,” he said.

“Finally, the use of menopausal hormone replacement therapy – which contains oestrogen – is associated with greater weight loss in semaglutide users.”

Then there is the matter of genetics. A recent study highlighted the potential role of a genetic variant that affects receptors in the brain upon which the drugs work.

“People carrying the genetic variant, we found lose about an extra 0.76kg (1.6 lbs) on average, and people who carry two copies of the variant double that,” said Adam Auton, vice-president of human genetics at the 23andMe Research Institute, and the senior author of the study.

“For people with two copies, this accounts for about 10% of the weight people might expect to lose on these medications.”

Umapathysivam and colleagues have recently published a study into two genetic variants that affect the production of an enzyme, known as PAM, that modifies many hormones including GLP-1. The team found people with such variants appear to show resistance to GLP-1.

“GLP-1 resistance simply means a given amount of GLP-1 has less effect on the body,” Umapathysivam said. “The implication for treatment is that a certain dose of GLP-1 in someone with resistance might mean less weight loss, less glucose lowering, less insulin secretion or less slowing to the gastric emptying.”

Despite emerging research, it is not yet possible to accurately predict who will respond to weight loss jabs and who won’t.

But there are reasons for people like Mercedes to be hopeful. A series of promising new drugs are in development. “Another option is to change patients to a non-GLP-1 based drug called Mysimba [the UK brand name for Contrave]. It works in the same parts of the brain, but just slightly differently and therefore may be worth trying,” said Miras. “It is not available in the NHS, just privately.”

For some who struggle to lose weight with GLP-1 medications, weight-loss surgery may be the only option left. And, Miras says, “[A] lack of response to GLP-1 based drugs does not predict lack of response to [bariatric] surgery.”

And for those who lose little to no weight on GLP-1 medications, the message is clear. “It’s not your fault and it’s not the drug’s fault either, this is purely luck,” said Miras. “I’ve seen it before, it’s not very common, but it does happen.”

Mercedes began GLP-1 medications with huge amounts of hope and expectation. “There was just so much publicity around it. So many people [using the drugs said]: ‘Oh, I forgot to eat lunch,’ that I suppose subconsciously I just sort of ignored the prospect that … the drugs didn’t work,” she said.

“I wish I knew if there were other people out there, like me, for whom [GLP-1s] are just not effective at all.”

*Some names have been changed