The new weight-loss drugs that shed pounds fast without side effects

view original post

Over the last four years, weight-loss drugs that dampen down appetite and promote satiety have revolutionised obesity medicine. They are currently being taken by 1.5 million people in the UK and have already generated billions of dollars in revenue around the world.

But obesity expert Prof Carel Le Roux is particularly excited about the next big drug to hit the skinny-jab market: CagriSema.

Not only did a major new clinical study of the drug show that weight loss would be faster, with overweight and obese participants in the study shedding 23 per cent of their body weight over 68 weeks, but the side effects were mostly temporary and mild. It may seem minor but “this will really help people who need to take these drugs longer-term”, he says.

While drugs like Wegovy consist of a single molecule, semaglutide, which mimics the gut hormone GLP-1, CagriSema goes a step further by combining semaglutide with cagrilintide, a secondary molecule which mimics another hunger-suppressing hormone called amylin which is made by the pancreas, and according to various studies over the last few years, seems to reduce nausea as a result.

“This will be a big, big paradigm shift,” declares Prof Le Roux. He explains that the unpleasant and sometimes crippling nausea, diarrhoea, constipation and stomach pain that can accompany medications like Wegovy and Mounjaro should cease to exist with this next iteration of therapies. “You should never have side effects. People who do will simply be on too high a dose and should tell their doctor to reduce it.”

b’

‘

CagriSema is just one of the drugs joining the original treatments that have pioneered the weight-loss revolution. There is also a raft of other newer alternatives. Here we take a peek into the pipeline to see what else is coming and when they might be available to buy.

Retatrutide: the drug that may be better than Mounjaro

CagriSema’s eye-catching weight-loss statistics reflect an emerging finding. Drugs that act on multiple hormonal pathways in the body make it possible for some people to lose almost a quarter of their body weight. A new drug called retatrutide, being developed by Eli Lilly, manufacturer of Mounjaro, is a so-called “triple agonist” which means that it mimics the actions of three hormones: GLP-1 and GIP in the gut, as well as the pancreatic hormone glucagon. Trial data on retatrutide has found that some individuals experienced 24 per cent weight loss, significantly more than Mounjaro, which mimics GLP-1 and GIP.

“It’s getting close to what you get with most forms of bariatric surgery,” says Prof John Wilding, an expert in obesity, diabetes and endocrinology at the University of Liverpool.

b’

‘

Researchers predict that there will be two consequences of this. Firstly, drugs like retatrutide and CagriSema will be used at lower doses in all but the most severely obese patients, lessening side effects. But such substantial weight loss will also make these therapies much more effective at tackling a vast range of obesity-related conditions.

“There are 13 cancers that are directly related to obesity, as well as things like hip and knee osteoarthritis, urinary incontinence, sleep apnoea and type 2 diabetes,” says Melanie Davies, professor of diabetes medicine at the University of Leicester. “So approaches where you can maximise weight loss in the most tolerable and easy way are going to impact on a whole series of conditions.”

MariTide: the weight-loss drug you can take once a month

While Wegovy and Mounjaro are weekly injections, imagine only needing to take a monthly injection and still being able to lose significant amounts of weight. That’s the selling point behind a drug called MariTide which is being developed by the pharma company Amgen. Confusingly, this works by mimicking the GLP-1 hormone but blocking the production of GIP, and while scientists aren’t 100 per cent sure why this works, it has been effective in trials, leading to weight loss of around 20 per cent in a year.

Orforglipron: the weight-loss drug that’s a pill rather than an injection

For those who don’t fancy injections, there could also soon be pills to pop. Eli Lilly has developed an oral pill that mimics GLP-1 called orforglipron, which completed a phase three trial earlier this year, while there are also combination hormone pills such as amycretin (GLP-1 and amylin), and VK2735 (GLP-1 and GIP) in development from various manufacturers.

Prof Davies predicts that the advent of pills will really transform clinical practice, as they will not only be more affordable but will be less cumbersome for the NHS.

“The issue with biologics [injectable drugs] is that they need to be stored,” she says. “It takes up fridge space, and distributing them is more expensive and complicated. Oral medications are clearly cheaper but also much, much easier. They’ll open up these medicines to a wider group of people.”

The benefits of the new drugs

Better for bones and muscles

One of the concerns that has been cited with current weight-loss drugs is that people don’t just shed body fat. Some studies have reported that 40 per cent of the weight that people lose is muscle, which could potentially make them more at risk of frailty later in life. Scientists have also long known that losing large amounts of weight can be accompanied by a loss of bone density.

But different combinations of hormones might be able to help with this. Prof Davies says that she thinks of the next generation of weight-loss drugs as akin to Lego, with different molecules being added on to GLP-1 drugs.

Dimitris Papamargaritis, an associate professor at the University of Leicester, says that combining amylin and GLP-1, as in CagriSema, may help avoid muscle loss as amylin seems to play a role in maintaining body composition. “Early lab studies suggest that adding amylin could help people lose more fat while sparing muscle, though this still needs confirmation in humans,” he says.

There’s also another possibility: using GLP-1-based drugs in combination with a new class of experimental medications called anti-activin myostatin agents which have previously been used to try to prevent age-related muscle loss in postmenopausal women, and to reduce frailty in the elderly.

One of the leading candidates is an injectable antibody called bimagrumab which acts on a pathway in the body to stimulate muscle growth. When used in combination with Wegovy in a phase two trial published in June, participants not only lost 22 per cent of their body weight over 72 weeks, but 93 per cent of the weight lost was fat – a remarkable finding.

“It’s also not just about muscle volume, but muscle quality,” says Prof Davies. “The key is getting fat out of the muscle and improving its function, and some of these anti-activin myostatin agents are thought to help with this.”

Weight maintenance and better blood sugar control

Once you’ve been restored to a healthier weight, what next? That’s still been one of the major unresolved questions with weight-loss drugs, with studies often finding that people begin regaining the lost weight as soon as they cease treatment.

Prof Davies says that drugs which solely mimic amylin, such as cagrilintide or another medication called pramlintide, have the potential to also be used as long-term weight maintenance solutions as they have fewer side effects than GLP-1-based drugs.

Amylin also has another hidden power – it works to normalise blood sugar, and pramlintide is already licensed as a treatment for diabetes in the US.

As well as helping with body weight, combining amylin with other gut hormones could also lead to a much better solution for managing type 2 diabetes, Dr Papamargaritis says, potentially preventing some of the long-term consequences of uncontrolled blood sugar.

Targeting fatty liver

Fatty liver disease – a condition which progressively impairs liver function, ultimately leading to organ scarring – is one of the most common metabolic diseases driven by the accumulation of excess body fat, affecting at least one in five people in the UK.

However, there is growing optimism that this condition can be reversed through combinations of gut hormones. In this instance, Davies says that companies are bolting molecules that mimic glucagon onto GLP-1, because this hormone is known to be particularly active in reducing fat storage in the liver.

Last year, a clinical trial with retatrutide – which contains a glucagon mimic – found that participants who received the highest dose lost 82 per cent of their liver fat over 24 weeks. In May, results released from a trial of a GLP-1 and glucagon combination called mazdutide, developed by a company called Innovent Biologics, saw participants lose 73 per cent of their liver fat over a similar timeframe.

“I think we’re moving towards these more personalised approaches, where it’s almost like a recipe book,” says Prof Davies. “You put in the different ingredients to get the right effect. If you want to protect the liver, then you add glucagon. If you want to preserve muscle or improve blood sugar control, you add amylin.”

When will the drugs be accessible?

Although there are many weight-loss drugs available privately, they are increasingly expensive. And while the NHS has begun a phased rollout of Mounjaro for weight management, the criteria are currently extremely strict. To be eligible for the drug, patients must have a BMI of at least 40, along with at least four of the following five obesity-related conditions: type 2 diabetes, high blood pressure, heart and vascular disease, high cholesterol and obstructive sleep apnoea.

“It’s a slower rollout than many of us would like, because of the cost implications, and so the NHS has put in this funding variation that rolls it out very slowly initially,” says Prof Wilding.

But the newer versions are coming. The pill version, orforglipron, could become available as early as next year, while Eli Lilly has also hinted at a possible US launch of retatrutide sometime in 2026, with the drug then potentially reaching the UK in either 2026 or 2027 pending regulatory approval. Prof Wilding says that it’s possible that CagriSema could become available at the end of 2026 or early 2027.

As the portfolio of available weight-loss drugs starts to broaden, Prof Wilding is hoping that the NHS will take a more long-term vision, especially with recent research presented at the world’s largest heart health conference in Madrid demonstrating that GLP-1 drugs alone are capable of cutting the risk of hospitalisation and premature death from heart failure by around 50 per cent in people with obesity and type 2 diabetes. Similarly dramatic findings have been seen in a range of other conditions from chronic kidney disease to stroke. Prof Wilding points to a report published earlier this year from analysts at the Tony Blair Institute which suggested that if these medicines were rolled out across the NHS at scale and made available to all overweight individuals, they could save the UK economy £52bn by 2050.

“I think what the NHS probably needs to do here is look at the long-term benefits of using these medicines on health, rather than focusing on the short term budgetary impact which is significant,” says Prof Wilding.

For Prof Le Roux, the main message is that we need to stop viewing these medications simply in terms of weight loss, given their potential to prevent long-term illness and premature death from so many chronic conditions. “It’s going to be less and less about weight loss and it’s going to be more and more about health gain,” he says.

Broaden your horizons with award-winning British journalism. Try The Telegraph free for 1 month with unlimited access to our award-winning website, exclusive app, money-saving offers and more.