On the rebound: What are the long-term risks of Ozempic?
Consultant endocrinologist at Galway University Hospital Francis Finucane has long been frustrated by the limited and sometimes intermittent access to semaglutide — the blockbuster drug better known by the brand names Ozempic and Wegovy.
As a consultant endocrinologist at Galway University Hospital who runs a publicly funded obesity clinic, Francis Finucane has long been frustrated by the limited and sometimes intermittent access to semaglutide — the blockbuster drug better known by the brand names Ozempic and Wegovy.
“At the moment, they’re only funded for patients with type 2 diabetes or patients with pre- diabetes and accompanying cardiovascular risk factors such as blood pressure or high cholesterol, which aren’t well controlled,” says Finucane.
“So three-quarters of the patients I see in clinical practice have to pay for these drugs themselves, even though, on average, they tend to have a lower level of social privilege than the general population.”
Over the past three years, Finucane has witnessed instances where patients have either been unable to afford to keep paying for semaglutide (Wegovy costs private payers €300 per month) or their access has been temporarily restricted due to supply chain problems.
Such cases have provided him with an insight into one of the enduring questions regarding this medication and other so-called GLP-1 weight-loss drugs: What happens when people stop taking them?
“I’ve had patients who had been taking semaglutide for anywhere between two months and two years, and they ended up having it withdrawn because the company [Danish pharmaceutical Novo Nordisk] ran out of stock.
"That interruption lasted for between one and six months, and if people stop the drug, they regain the weight they’ve lost,” says Finucane.
Dubbed ‘Ozempic rebound’, this pattern has been seen in numerous obesity clinics worldwide and clinical trials.
In a study of those taking weekly semaglutide injections, a third of participants were switched to a placebo injection midway through without their knowledge and gradually regained weight.
Researchers say this ‘rebound’ is one of the biggest ongoing challenges with semaglutide and the new wave of obesity drugs, such as tirzepatide and retatrutide, which work by mimicking various gut hormones — including GLP-1 — that act on the brain to control appetite.
However, it increasingly seems that to achieve lasting results, many people will need to take them for years and potentially decades.
In cases where people periodically cease and then restart treatment, clinicians are concerned that this could lead to problematic ‘weight cycling’, where individuals repeatedly lose and regain weight over time.
As this tends to result in a change in body composition, which shifts them towards a greater proportion of body fat and a lower proportion of lean muscle mass, weight cycling is known to result in a poorer metabolic profile.
Alex Miras, a Ulster University clinical professor of medicine, explains that this is because muscle plays a key role in insulin sensitivity and blood glucose control: “The problem with weight cycling is not only that people go back to where they were before they started medication, but generally speaking, the weight regain is accompanied by an accumulation of more fat and less muscle.”
The durability of the benefits is not only a concern for obesity but also the range of other conditions for which semaglutide is being studied.
The drug is touted as an answer to obesity-related chronic illnesses such as cardiovascular disease, chronic kidney disease, sleep disturbances, and even substance addictions.
However, while studies have indicated that semaglutide can disrupt cravings for alcohol and even opioids, preliminary research in animals seems to suggest that the desire for these substances is likely to return as soon as regular injections are stopped.
Cathy Breen, chairperson of the Association for the Study of Obesity Ireland, says it is not especially surprising that treatment may be required on a long-term and potentially lifelong basis, particularly in the context of complex conditions such as obesity: “With other diseases like diabetes, hypertension and asthma, the majority of people tend to stay on medications long-term and this is seen as normal. GLP-1 therapies are no different to any other medication that affects biological pathways in the body.
If the treatment is stopped, then the benefits are lost. If you stop taking a blood pressure drug, we wouldn’t be surprised that blood pressure would then increase.
However, for Ireland and many other countries, this all means that difficult calls may need to be made in coming years when it comes to balancing the economic benefits of controlling obesity for the healthcare system versus the drugs’ high cost.
But before such decisions can be taken, researchers argue that we need to understand much more about the spectrum of responses to weight-loss drugs, especially over time.
The landmark clinical trials that announced semaglutide and tirzepatide to the world showed that they could help people lose weight between 15 and 20% of their starting weight over time.
However, these figures represented the average weight-loss across all participants, and in reality, there is far more variation when it comes to how different people fare.
Even in the trials, a proportion of patients lost negligible amounts of weight — less than 5% of their starting weight — on semaglutide.
Finucane notes that for any intervention, whether GLP-1 drugs or bariatric surgery, there are always a certain number of ‘non-responders’: “We see this staggering variation where you get some people lose 40% of their body weight on the drug, but then one in 10 people don’t lose any weight at all, and we still need to try and understand why that is, because they don’t work for every patient.”
So far, research suggests that age and genetic differences in metabolism could be playing a role — while broadly speaking, it seems that women are more likely to respond well, possibly because they have a different fat distribution to men or because their smaller body size means that they have greater exposure to the drug.
Finucane points out that in the original trials, all participants were not only given a GLP-1 drug but encouraged to follow a healthy, low-calorie diet combined with an exercise programme — while in real life, people are unlikely to be as diligent.
However, even for responders, data suggests that most people hit a plateau at around the 18-month mark after commencing treatment — at which point their metabolism compensates by slowing down and the weight-loss stops.
Miras points out that in some cases, it appears that the potency of GLP-1s wears off and they start to regain some weight, while still taking the drug.
As a result, Novo Nordisk is thought to be conducting further studies looking to identify the optimal maintenance regimen for people continuing to take GLP-1 drugs and retain their weight loss over the longer term.
With the field of weight-loss drugs still relatively nascent, Finucane says we still don’t know much about whether certain people might be more vulnerable to adverse events after taking these drugs over a long period — such as a heightened risk of the muscle-loss disease, sarcopenia.
In one research study last year, concerns were raised about the amount of muscle mass reduction incurred by some participants in clinical trials of these drugs, which Finucane says we need to continue monitoring.
“There may be specific individuals who are at more risk of protein insufficiency or muscle dysfunction, but I don’t think it’s a common problem,” he says.
However, like many obesity specialists, Finucane is concerned about the potential longer-term health risks experienced by people taking these drugs who don’t meet the clinical criteria for obesity.
In the US, reports suggest that a growing number of people are turning to micro-dosing of GLP-1 drugs, regularly injecting themselves with very small doses in the hope of becoming slimmer without incurring the common side effects of nausea and gastrointestinal issues.
Aside from the fact that such use diverts valuable medicine stocks away from those who need them, Finucane points out that micro-dosing could come with risks.
Like all drugs, he says that GLP-1s may elicit unforeseen side effects in some people because they stimulate numerous receptors located around the body: “We know that the GLP-1 receptor is expressed not just in the brain or the gut, but also in the heart, the blood vessels, skin, lungs,
kidneys, everywhere.
"The impact of long-term exposure to this drug has not been addressed and won’t be for many years.
In obese patients, we think the benefits outweigh the risks because it prevents progression to diabetes, reduces cardiovascular risk and many other things.
"But when you’re talking about people taking these drugs out of a cultural desire for thinness, then the possible risks definitely outweigh the benefits."
Over time, obesity treatment is likely to become more personalised. A new European research project known as ‘Sophia’, led by scientists at University College Dublin, is attempting to ultimately develop tests which will help clinicians predict how a particular person will respond to GLP-1 drugs compared with other approaches — such as various diets, surgery and perhaps eventually, whether they will have any long-term risks.
This could make it easier for obesity specialists to decide whether it will be beneficial for a particular patient to take a drug like semaglutide on a more permanent basis.
However, Finucane says these drugs need to become more affordable for more patients: “Ultimately, the most important thing that has to happen is that the prices of these very expensive drugs need to come down substantially.
"The companies are charging as much as the market will tolerate for these drugs, which they have the right to do.
"But understandably, the Government is concerned that if they provided them to every patient in Ireland who could benefit, the system would go broke.”
- World Obesity Day is on Tuesday, March 4
